tbuckley/cabot-search huggingface dataset:
Changes in Outpatient Buprenorphine Dispensing During the COVID-19 Pandemic
Authors: Jessica Duncan Cance, Erin Doyle
Journal: JAMA (2020)

This study examined outpatient buprenorphine dispensing patterns in Texas before vs after the Drug Enforcement Administration temporarily relaxed outpatient buprenorphine prescribing regulations in March 2020 in response to the COVID-19 pandemic.
RARE-49. CHOROID PLEXUS ADENOMA WITHOUT ASSOCIATED HYDROCEPHALUS PRESENTING AS PRECOCIOUS PUBERTY
Authors: Kaylyn Utley, Michael Dedekian, James Wilson, Stanley Chaleff
Journal: Neuro-Oncology (2020)

Abstract Precocious puberty (PP) is a rare presentation of intracranial pathology unrelated to the pituitary. PP in this setting is considered a paraneoplastic phenomenon, achieved through synthesis of sex-hormones by the tumor itself or via alterations in the release of gonadotrophins from the pituitary. The latter has been described with masses adjacent to the pituitary or with those which cause hydrocephalus. We describe a case of a choroid plexus papilloma (CPP) without hydrocephalus presenting as precocious puberty. An 18 month-old female presented with 4-months of weight loss, bilateral galactorrhea and constipation. Her weight decreased from the 15th to below the 1st percentile. CBC, celiac and thyroid studies were normal. Prolactin was at the upper limit of normal (25.8;ref 3.3–26.3). Breast ultrasound demonstrated symmetric breast tissue development. She was referred to pediatric gastroenterology for constipation and failure to thrive. Caloric supplementation, bowel regimen and barium enema were recommended. One week later, she was admitted with dehydration, painful constipation and further weight loss in the setting of an acute febrile illness. MRI revealed a normal pituitary and an intraventricular mass without hydrocephalus. She underwent gross total resection of the mass, later determined to be a choroid plexus papilloma. The patient’s galactorrhea resolved abruptly following resection. Because of her galactorrhea, our patient underwent neuroimaging revealing an incidental mass without associated hydrocephalus. To our knowledge, precocious puberty and hyperprolactinemia have not been described in neoplasms distant from the pituitary. Thus, these lesions should be recognized as a potential etiology of precocious puberty and hyperprolactinemia.
DDRE-17. INITIAL CLINICAL EXPERIENCE USING OSIMERTINIB IN PATIENTS WITH RECURRENT MALIGNANT GLIOMAS WITH EGFR ALTERATIONS
Authors: Marin Abousaud, Naqeeb Faroqui, Fang-Chi Hsu, Glenn Lesser, Roy Strowd, Shakti Ramkissoon, Madan Kwatra, Kristin Strickland Houston, Annette Carter, Alisha DeTroye
Journal: Neuro-Oncology (2020)

Abstract EGFR alterations are commonly observed in malignant gliomas (MG), especially glioblastomas, making this pathway an appealing therapeutic target. Unlike other EGFR tyrosine kinase inhibitors (TKIs), osimertinib (osi), a third-generation, irreversible EGFR-TKI commonly used to treat EGFR-mutant lung cancer, is able to effectively penetrate the blood brain barrier (BBB) and achieve therapeutic concentrations in brain tissue. METHODS: A retrospective chart review identified six patients (pts) aged 46–74 years with recurrent MG and known EGFR alterations identified by next generation sequencing who received at least one dose of osi between 1/1/2018 and 5/26/2020. Patients received osi 80 mg by mouth once daily and continued treatment until disease progression, the development of unacceptable side effects, medical complications, or death. RESULTS: All patients had EGFR amplification. Other EGFR alterations identified included EGFRvIII (1 pt), deletion of introns 1–7 (3 pts) and deletion of introns 13–15 (2 pts). Four of the six patients were evaluable for response. Three patients (75.0%) had stable disease (SD) as best response and one patient (25.0%) was refractory to treatment. One patient with an EGFRvIII mutation achieved stable disease on osi and remained on treatment for 236 days. Thrombocytopenia developed in 2 patients (grade 2 (1), grade 3 (1) in patient also on concurrent bevacizumab) and 1 patient developed grade 1 diarrhea and pneumonia. Overall, this heavily pretreated patient population tolerated osi therapy and half of the patients had a best response of SD which lasted from 77 to 236 days. CONCLUSIONS: Osi has a tolerable safety profile in this heavily pretreated brain tumor population, and it may benefit selected patients with recurrent MG containing EGFR alterations. Further clinical investigations are needed, particularly in patients whose tumors express an EGFRvIII mutation, to identify which EGFR alterations may sensitize tumors to this BBB penetrant EGFR-TKI.
OTHR-07. CHRONIC ENCEPHALOPATHY DUE TO METHOTREXATE NEUROTOXICITY AS A RARE COMPLICATION IN A CHILD WITH LEUKEMIA: A CASE REPORT
Authors: Achmad Rafli, Srisadono Fauzi Adiprabowo, Ludi Dhyani Rahmartani, Setyo Handryastuti
Journal: Neuro-Oncology (2020)

Abstract Methotrexate (MTX) is an essential component of chemotherapy for childhood acute lymphoblastic leukemia (ALL). Both intravenous (IV) and most commonly intrathecal (IT) routes of MTX have been complicated in acute, subacute, and chronic neurotoxicity syndromes. A 9-year-old girl had been diagnosed with standard risk ALL since 2011 with first chemotherapy protocol was Indonesian protocol standard risk ALL 2006 and remission in 2012. On July 2015, patient was diagnosed as relapse ALL and underwent Indonesian protocol high risk ALL 2013. The last chemotherapy protocol of patient was Indonesian protocol high risk ALL 2013 maintenance phase 89th weeks with total dosage of MTX was 336 mg (IT), 6000 mg/m2 (IV), and 2500 mg/m2 orally. Her presenting symptom was progressive decrease of consciousness since 3 months before hospital admission. First brain computed tomography (CT-Scan) and magnetic resonance imaging (MRI) revealed brain atrophy. One month later she had abnormality in behavior and functional ability with second brain CT-Scan revealed brain atrophy and lacunar infarct in left pons. This case can be in accordance with chronic encephalopathy due to MTX. It is important to recognize early complications taking the form of subclinical or symptomatic CNS damage (e.g. headache, dizziness, tremor, ataxia, aphasia, dysarthria, emotional instabilities, seizures, hemiparesis, encephalopathy) that can occur in the course of chemotherapy especially MTX. Determination of the cause of encephalopathy is associated with considerable difficulty despite the use of various diagnostic methods and also treatment of MTX neurotoxicity is mainly supportive and recovery is usually complete. Keywords: imaging, methotrexate, neurotoxicity, leukemia
Intrapulmonary shunt measured by bedside pulse oximetry predicts worse outcomes in severe COVID-19
Authors: Aleksandra Kotwica, Harry Knights, Nikhil Mayor, Emma Russell-Jones, Theodore Dassios, David Russell-Jones
Journal: European Respiratory Journal (2020)

<b>Using simple bedside pulse oximetry to create oxygen–haemoglobin desaturation curves may be useful in triaging patients with COVID-19. Intrapulmonary shunting is associated with worse outcomes in COVID-19, and the degree of shunt may predict outcomes.</b>https://bit.ly/2KVv0m2
Multi-stage learning for segmentation of aortic dissections using a prior aortic anatomy simplification
Authors: Duanduan Chen, Xuyang Zhang, Yuqian Mei, Fangzhou Liao, Huanming Xu, Zhenfeng Li, Qianjiang Xiao, Wei Guo, Hongkun Zhang, Tianyi Yan, Jiang Xiong, Yiannis Ventikos
Journal: Medical Image Analysis (2020)
100P Patient-derived tissue cultures of esophagogastric-junction cancer (EGJC) and gastric cancer (GC): An ex vivo model to study individual response of immunotherapy
Authors: J. Körfer, M. Hußtegge, I. Gockel, A. Monecke, G. Schumacher, A. Weimann, K. Winter, I. Bechmann, F. Lordick, S. Kallendrusch
Journal: Annals of Oncology (2020)
Clinical characteristics and 3-month outcomes in cancer patients with incidental <i>versus</i> clinically suspected and confirmed pulmonary embolism
Authors: Marisa Peris, Juan J. López-Nuñez, Ana Maestre, David Jimenez, Alfonso Muriel, Behnood Bikdeli, Ido Weinberg, Cihan Ay, Lucia Mazzolai, Alicia Lorenzo, Manuel Monreal
Journal: European Respiratory Journal (2020)

Background Current guidelines suggest treating cancer patients with incidental pulmonary embolism (PE) similarly to those with clinically suspected and confirmed PE. However, the natural history of these presentations has not been thoroughly compared. Methods We used the data from the RIETE (Registro Informatizado de Enfermedad TromboEmbólica) registry to compare the 3-month outcomes in patients with active cancer and incidental PE versus those with clinically suspected and confirmed PE. The primary outcome was 90-day all-cause mortality. Secondary outcomes were PE-related mortality, symptomatic PE recurrences and major bleeding. Results From July 2012 to January 2019, 946 cancer patients with incidental asymptomatic PE and 2274 with clinically suspected and confirmed PE were enrolled. Most patients (95% versus 90%) received low-molecular-weight heparin therapy. During the first 90 days, 598 patients died, including 42 from PE. Patients with incidental PE had a lower all-cause mortality rate than those with suspected and confirmed PE (11% versus 22%; OR 0.43, 95% CI 0.34–0.54). Results were consistent for PE-related mortality (0.3% versus 1.7%; OR 0.18, 95% CI 0.06–0.59). Multivariable analysis confirmed that patients with incidental PE were at lower risk of death (adjusted OR 0.43, 95% CI 0.34–0.56). Overall, 29 (0.9%) patients developed symptomatic PE recurrences, and 122 (3.8%) had major bleeding. There were no significant differences in PE recurrences (OR 0.62, 95% CI 0.25–1.54) or major bleeding (OR 0.78, 95% CI 0.51–1.18). Conclusions Cancer patients with incidental PE had a lower mortality rate than those with clinically suspected and confirmed PE. Further studies are required to validate these findings, and to explore optimal management strategies in these patients.
EXTH-50. ACTIVATION OF THE MITOCHONDRIAL CLPP PROTEASE IS SYNTHETICALLY LETHAL WITH HDAC1/2 INHIBITION IN GLIOBLASTOMA MODEL SYSTEMS
Authors: Salveena Schiffgens, Trang Nguyen, Chang Shu, Bianchetti Elena, Consuelo Torrini, Georg Karpel-Massler, Markus Siegelin
Journal: Neuro-Oncology (2020)

Abstract Novel therapeutic targets are critical to unravel for recalcitrant malignancies, such as the most common primary brain tumor in adults, glioblastoma (GBM). Heterogeneity remains a hallmark of primary glial brain tumors and therefore targeting several pathways simultaneously is an appropriate approach. Here, we showed that pharmacological activation of the mitochondrial ClpP protease through utilization of the novel imipridone compounds (ONC206 and ONC212) in combination with global (Panobinostat) and selective (romidepsin) HDAC – inhibitors caused synergistic reduction of viability in established and patient-derived xenograft (PDX) cultures of human GBM. This effect occurred independent of TP53 status and was partially mediated by activation of a cell death with apoptotic features accompanied by activation of initiator and effector caspases as well as cleavage of PARP. Consistently, the combination treatment altered the expression of anti-apoptotic and pro-apoptotic Bcl-2 family members, resulting in down-regulation of Bcl-xL and Mcl-1. Knockdown experiments targeting Noxa, BIM, Bcl-xL and Mcl-1 confirmed a functional implication of these proteins in the reduction of cellular viability mediated by the combination treatment. Importantly, knockdown of the ClpP protease significantly rescued the reduction of cellular viability by ClpP activators and the combination treatment, respectively, suggesting critical involvement of this protein. Finally, using a PDX model, we demonstrated that the combination treatment of romidepsin and ONC206 reduced tumor growth more potently than single treatments or vehicle by enhanced reduction of cellular proliferation and pronounced induction of cell death in vivo. Collectively, these observations suggest that the efficacy of HDAC-inhibitors might be significantly enhanced through ClpP activators in model systems of human GBM.
USH2A is a Meissner’s corpuscle protein necessary for normal vibration sensing in mice and humans
Authors: Fred Schwaller, Valérie Bégay, Gema García-García, Francisco J. Taberner, Rabih Moshourab, Brennan McDonald, Trevor Docter, Johannes Kühnemund, Julia Ojeda-Alonso, Ricardo Paricio-Montesinos, Stefan G. Lechner, James F. A. Poulet, Jose M. Millan, Gary R. Lewin
Journal: Nature Neuroscience (2020)
Joy, Suffering, and the Goals of Medicine
Authors: Benzi M. Kluger, Cynthia W. Garvan, Robert G. Holloway
Journal: JAMA Neurology (2020)

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MBRS-63. THE ROLE OF THE SWI/SNF COMPLEX SUBUNIT SMARCD3 IN MEDULLOBLASTOMA
Authors: Brad Poore, Han Zou, Vaibhav Sharma, Ian Pollack, Baoli Hu
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma is the most common malignant brain tumor in children, with the Group 3 (G3) having the worst prognosis of the subgroups (WNT, SHH, and Group 4). We aimed to determine the underlying differences between G3 and the other subgroups, with an emphasis on genes that control the epigenome for developing effective treatments for patients with this disease. To this end, we found that G3 has elevated expression of the SWI/SNF subcomponent, SMARCD3 (P&amp;lt;0.001), which serves to guide the SWI/SNF complex to different genomic regions through interactions with various transcription factors. However, little is known about function of SMARCD3 in cancer, particularly in medulloblastoma. Clinically, elevated SMARCD3 mRNA resulted in a poorer prognosis in medulloblastoma patients (P&amp;lt;0.0001), which was further validated in 63 patient tumors by immunohistochemical staining for SMARCD3. Interestingly, tumors that had metastasized often had elevated expression of SMARCD3, in all subgroups of medulloblastomas (P&amp;lt;0.0001) and G3 only (P&amp;lt;0.01) based on analyzing multiple published databases. An orthotopic mouse model further supported that SMARCD3 is highly expressed in metastatic tumors compared to primary tumors. Importantly, CRISPR-CAS9-mediated SMARCD3 deletion decreased cell migration in medulloblastoma cell lines. Mechanistically, SMARCD3 deletion led to decreased H3K27me3, suggesting that SMARCD3 may cooperate with PRC2 in regulation of gene expression. Together, our results indicate that SMARCD3 plays a significant role in the development of metastatic dissemination in medulloblastoma, especially in the G3 subgroup. Thus, targeting the SMARCD3-containing SWI/SNF Complex may effectively prevent tumor dissemination and improve clinical outcomes in children with medulloblastoma.
Endometrial function in women with polycystic ovary syndrome: a comprehensive review
Authors: Stefano Palomba, Terhi T Piltonen, Linda C Giudice
Journal: Human Reproduction Update (2020)

Abstract BACKGROUND Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. An endometrial component has been suggested to contribute to subfertility and poor reproductive outcomes in affected women. OBJECTIVE AND RATIONALE The aim of this review was to determine whether there is sufficient evidence to support that endometrial function is altered in women with PCOS, whether clinical features of PCOS affect the endometrium, and whether there are evidence-based interventions to improve endometrial dysfunction in PCOS women. SEARCH METHODS An extensive literature search was performed from 1970 up to July 2020 using PubMed and Web of Science without language restriction. The search included all titles and abstracts assessing a relationship between PCOS and endometrial function, the role played by clinical and biochemical/hormonal factors related to PCOS and endometrial function, and the potential interventions aimed to improve endometrial function in women with PCOS. All published papers were included if considered relevant. Studies having a specific topic/hypothesis regarding endometrial cancer/hyperplasia in women with PCOS were excluded from the analysis. OUTCOMES Experimental and clinical data suggest that the endometrium differs in women with PCOS when compared to healthy controls. Clinical characteristics related to the syndrome, alone and/or in combination, may contribute to dysregulation of endometrial expression of sex hormone receptors and co-receptors, increase endometrial insulin-resistance with impaired glucose transport and utilization, and result in chronic low-grade inflammation, immune dysfunction, altered uterine vascularity, abnormal endometrial gene expression and cellular abnormalities in women with PCOS. Among several interventions to improve endometrial function in women with PCOS, to date, only lifestyle modification, metformin and bariatric surgery have the highest scientific evidence for clinical benefit. WIDER IMPLICATIONS Endometrial dysfunction and abnormal trophoblast invasion and placentation in PCOS women can predispose to miscarriage and pregnancy complications. Thus, patients and their health care providers should advise about these risks. Although currently no intervention can be universally recommended to reverse endometrial dysfunction in PCOS women, lifestyle modifications and metformin may improve underlying endometrial dysfunction and pregnancy outcomes in obese and/or insulin resistant patients. Bariatric surgery has shown its efficacy in severely obese PCOS patients, but a careful evaluation of the benefit/risk ratio is warranted. Large scale randomized controlled clinical trials should address these possibilities.
DIPG-64. INTERNATIONAL PRECLINICAL DRUG DISCOVERY AND BIOMARKER PROGRAM INFORMING AN ADOPTIVE COMBINATORIAL TRIAL FOR DIFFUSE MIDLINE GLIOMAS
Authors: Justyna M Przystal*, Sridevi Yadavilli*, Christina Colman Abadi*, Viveka Nand Yadav, Sandra Laternser, Chiara Cianciolo Cosentino, Sebastian M Waszak, Rodrigo Cartaxo, Matt Biery, Carrie Myers, Samantha Jayasekara, James M Olson, Mariella G Filbin, Nicholas A Vitanza, Jason Cain, Carl Koschmann#, Sabine Müller#, Javad Nazarian#
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION DMG-ACT (DMG- multi-arm Adaptive and Combinatorial Trial) aims to implement a highly innovative clinical trial design of combinatorial arms for patients with diffuse midline gliomas (DMGs) at all disease stages that is adaptive to pre-clinical data generated in eight collaborating institutions. The goals of the team are to: i) rapidly identify and validate promising drugs for clinical use, and ii) predict biomarkers for promising drugs. METHODS In vitro (n=15) and in vivo (n=8) models of DMGs across seven institutions were used to assess single and combination treatments with ONC201, ONC206, marizomib, panobinostat, Val-083, and TAK228. In vivo pharmacokinetic assays using clinically relevant dosing of ONC201, ONC206, and panobinostat were performed. Predictive biomarkers for ONC201 and ONC206 were identified using extensive molecular assays including CRISPR, RNAseq, ELISA, FACS, and IHC. RESULTS Inhibitory concentrations (IC50) were established and validated across participating sites. In vivo validation of single and combination drug assays confirmed drug efficacy as increased survival for: ONC201 (p=0.01), ONC206 (p=0.01), ONC201+ONC206 (p=0.02), and ONC201+panobinostat (p=0.01). Marizomib showed toxicity in murine/zebrafish PDXs models. Murine pharmacokinetic analysis showed peak brain levels of ONC201 and ONC206 above pre-clinical IC50. Molecular testing and analyses of existing drug screen across 537 cancer cell lines validated mitochondrial stress and ATF4 as the main targets induced by ONC201/6. CONCLUSION Thorough preclinical testing in a multi-site laboratory setting is feasible and identified ONC201 in combination with ONC206 as promising therapeutics for DMGs. Preclinical and correlative-clinical studies are ongoing.
Sweet gum extract inhibits proliferation of prostate cancer through dual inhibition of PI3K/Akt and mTOR pathways.
Authors: Peiying Yang, Zhijun Liu, Carrie Cartwright, Diana Chan, Dong Liu, Jibin Ding, Robert Newman
Journal: Cancer Research (2008)

1431  Prostate cancer is the most commonly diagnosed malignant disease in U.S. men and the second leading cause of death in this population. Studies on epidemiology, genetics, and molecular pathogenesis of prostate cancer strongly suggest that activation of PI3 kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) pathways play important roles in the development of this disease. Dual inhibition of both of these pathways may provide a novel and effective treatment for this disease. Certain herbal extracts have long been considered effective in the prevention or treatment of prostate cancer. Liquidambar styraciflua L., known as sweet gum, contains lupine and oleanane-type triterpenoids and has shown potential in inhibiting the proliferation of multiple human cancer cell lines. We examined the anticancer activity of a methanolic fraction of sweet gum (LIS-100) in human prostate cancer and its associated mechanism(s). The anti-proliferative effect of sweet gum extract was tested against human prostate cancer (PC3, LNCaP, DU145), human colon HCT116, human pancreatic cancer (PANC-1, BxPC3 and AsPC-1), and human non-small cell lung cancer A549 cells. Our preliminary study demonstrated that LIS-100 inhibited the proliferation of multiple cell lines with IC50 values ranging from 1.85 to 31.25 μg/ml although it was most potent against prostate cancer (IC50 1.85 and 2.75 μg/ml for PC3 and LNCaP cells, respectively). LIS-100 inhibits proliferation of PC3 cells through G2/M cell cycle arrest at low concentrations (10-50 μg/ml), but induced apoptosis at higher concentration (125 μg/ml). It inhibited cyclin D1 expression, Stat3 and restored the tumor suppressor Rb protein function in PC3 cells. Additionally, LIS-100 (2.5 μg/ml) altered the phosphorylation of multiple cell signaling proteins, especially those associated with PI3K/Akt/mTOR pathways. LIS-100 not only inhibited phosphorylation of the effector of mTOR, p70S6 kinase at ser389, and ribosomal S6 protein at Ser235/236, it also inhibited the phosphorylation of Akt and eIF4E in both PC3 and LNCaP cells, yet increased the tumor suppressor protein eIF4BP1. These modulations were concentration-dependent. In comparison to a known mTOR inhibitor (rapamycin derivative) which enhances cell survival pathways, such as PI3K-Akt and 4lF4E, this extract has the ability to inhibit both PI3k/Akt and mTOR pathways. When the extract was administered orally to CD-1 mice, no signs of toxicity were observed even at doses as high as 500 mg/kg. Additionally, the extract inhibited the growth of PC3 xenograft by 46% and 64% when it was administered at 250 mg/kg orally and 50 mg/kg intraperitonially, respectively. Taken together, our research suggests that sweet gum has important potential to inhibit the proliferation of human prostate cancer cells through, at least partially, dual inhibition of PI3K/AKt and mTOR pathways.