tbuckley/cabot-search huggingface dataset:
EMBR-28. CNS DISTRIBUTIONAL KINETICS OF PANOBINOSTAT IN THE MOUSE
Authors: Wenqiu Zhang, Afroz Mohammad, Rachael Sirianni, William Elmquist
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor and has the potential for leptomeningeal spread, often responsible for the preponderance of morbidity and mortality in MB patients. Adverse sequelae following high dose craniospinal radiation and aggressive chemotherapies, including neurocognitive deficits and endocrine disorders, impairs patient quality of life and thus call for new therapeutic strategies. Panobinostat is a pan-histone deacetylase (HDAC) inhibitor that has been shown to be effective against MBs in vitro. The objective of the current study is to evaluate the key pharmacokinetic (PK) parameters and the mechanisms influencing the brain penetration of panobinostat in the mouse model, often used in MB preclinical efficacy trials. Pharmacokinetic studies were conducted using FVB wild-type (WT) mice and triple-knockout (TKO, Mdr1a/b–/–Bcrp1–/–) transporter-deficient mice. Panobinostat was administered intravenously (10 mg/kg) and concentrations at selected time points in plasma, brain and spinal cord were determined using LC-MS/MS. PK parameters, including systemic clearances, volumes of distribution, half-lives, and areas-under-the-concentration time curve (AUC) were calculated by using non-compartmental analysis. In WT mice, the CNS penetration was initially limited; however, it increased with time and the brain-to-plasma (B/P) and spinal cord-to-plasma (SC/P) distributional partition coefficients (AUC ratios) were 3.7 and 1.4, respectively. The B/P and SC/P ratios of panobinostat in BBB transporter-deficient TKO mice were 1.7- and 2.3-fold higher than those in WT mice, respectively. Our data suggest that P-glycoprotein (P-gp) and/or breast cancer resistance protein (Bcrp) efflux transporters, localized in BBB, may influence the delivery of panobinostat to tumors in the brain following systemic intravenous administration. These systemic and CNS distributional parameters will inform future preclinical efficacy studies of panobinostat for MB. As such, studies investigating other administration routes that can bypass the BBB, such as the intrathecal injection of novel formulations, are ongoing.
Prognostic value of galectin-1 and galectin-3 expression in local urothelial bladder cancer.
Authors: Jason Zhu, Chad Livasy, Erin E Donahue, James Thomas Symanowski, Claud Grigg, Justin T. Matulay, James T Kearns, Derek Raghavan, Earle F Burgess, Peter E Clark
Journal: Journal of Clinical Oncology (2021)

e16520 Background: Galectin-1 (Gal-1) and Galectin-3 (Gal-3) are carbohydrate binding proteins which regulate cellular adhesion, proliferation, and apoptosis in solid tumors . Prior studies have reported that Gal-3 expression is associated with non-muscle invasive UC progression to muscle invasive disease. Therefore, we assessed whether UC Gal-1 and Gal-3 protein expression in cystectomy specimens was prognostic for overall survival (OS) or recurrence free survival (RFS). Methods: Tissue microarrays (TMA) were generated from chemotherapy naïve cystectomy specimens. Biopsies included benign urothelium, noninvasive papillary UC (Ta), UC in situ (Tis), and invasive UC (p1-pT4: INV). Gal-1 and Gal-3 IHC expression was scored by intensity (0-3) and % of cells staining positive (0-100). An H-score (product of % and intensity) was utilized for analysis. Clinical data including pathologic T stage, N stage, surgical margins, tumor size, and Charlson Comorbidity Index (CCI) were included in multivariable analysis. Results: 656 biopsies were evaluated from 301 patients. 198 (30%) were from benign urothelium, 28 (4%) Ta, 178 (27%) Tis, and 252 (38%) were INV. With a median follow up of 64 months, median OS was 47.5 mo and median RFS was 38.4 mo. Gal-1 H-score was significantly higher in INV specimens than non-INV specimens, and the inverse relationship was found with Gal-3 (median Gal-1 H-score was 0 across non-invasive tissue types and 200 in invasive, p &lt; 0.01 and median Gal-3 score was 270 across non-invasive tissue types and 70 in invasive, p &lt; 0.01). In multivariable analysis, T stage, N stage, margins, tumor size, PCV pre-op and CCI score were prognostic of OS and RFS. Gal-1 and Gal-3 H-scores were not predictive of RFS (Gal-1: HR 1.0, p = 0.67, Gal-3: HR 1.0, p = 0.25) or OS (Gal-1: HR 1.0, p = 0.71, Gal-3: HR 1.0, p = 0.37). Intra-tumoral Gal-1 and Gal-3 expression heterogeneity was observed. 203 (67%) patients had 2 or more tissue specimens and of these, 99 (49%) had discordant H-scores at the same level of invasion. Conclusions: In this cohort, both Gal-1 and Gal-3 expression correlated with biopsy T stage; however, the highest intra-tumor H-score per specimen did not independently predict for RFS or OS. This result differs from prior observations from smaller cohorts that showed an association between Gal-3 expression and RFS, suggesting that intra-tumoral Gal-1/Gal-3 heterogeneity may confound the study of Gal-1 and Gal-3 as a potential biomarker in UC. The biological significance of intra-tumoral Gal heterogeneity in UC merits further investigation.
Real-world risk of anosmia with cancer directed systemic therapy: A pharmacovigilance assessment using FDA Adverse Events Reporting System (FAERS) database.
Authors: Anahat Kaur, Shuai Wang, Arlene Yu, Tarek N. Elrafei, Lewis Steinberg, Abhishek Kumar
Journal: Journal of Clinical Oncology (2021)

e18790 Background: Anosmia is a rare and under-reported adverse event associated with the use of several oncologic drugs. Instances of olfactory disturbances following administration of chemotherapeutic agents have been sporadically documented in case reports and case series. We aimed to conduct a more comprehensive study to generate signal for anosmia as adverse effect of drugs used for oncologic indications. Methods: The United States Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) database, a pharmacovigilance database, was used to extract data. All reported cases of anosmia in the database were filtered for an indication of cancer. Descriptive analysis was conducted using SPSS 26. Results: Total 10250 cases of anosmia were extracted from FAERS database. Out of these, cancer as an indication for medication use was noted in 139 cases. Some of the most common suspect medications exclusively associated with more than one case of anosmia were palbociclib (n=16), enzalutamide (13), pazopanib (8), cabozantinib (8), letrozole (6), leuprolide (5), niraparib (5), rucaparib (4), tamoxifen (4), capecitabine (3), everolimus (3), anastrazole (2), exemestane (2), zoledronic acid (2), vandetanib (2) and vismodegib (2). Detailed description of medications with highest number of reported cases is listed in Table. Median age at diagnosis was 66 years (interquartile range 58-71). Anosmia was reported more commonly in females (64% ) as compared to males (33.8%). Reactions were reported to the FDA more commonly by consumers (56.8%) as compared to healthcare professionals (40.3% cases). Out of 139 patients with anosmia, 93 (66.9%) had concomitant ageusia, 8 (5.7 %) had dysgeusia and 6 (4.3%) patients had neuropathy. Conclusions: This study demonstrates a signal for anosmia as side effect in patients receiving select oncologic medications based on the FAERS database. It is worth noting that none of the suspect medications identified in this study have anosmia listed as known adverse reaction on accompanying package insert. Further studies need to be conducted to confirm if causal relationship exists between use of these drugs and olfactory function compromise. [Table: see text]
소세포 폐암의 간전이에 의하여 발생한 전격간기능상실 1예
Authors: 황영태, shin jung woo, 이준호, 황대성, 음준범, 최혜정, Neunghwa Park
Journal: Clinical and Molecular Hepatology (2007)

전이 간암에 의한 간기능상실은 매우 드물 뿐만 아니라, 복부전산화단층촬영에서 미만성 침윤 병변을 보여 조기 진단이 어렵고 예후도 극히 불량하다. 따라서 발생 빈도는 매우 희귀하나 갑자기 진행하는 간의 침윤 병변의 감별진단을 위하여 전이 간암과 이로 인한 간기능상실 발생 가능성을 고려하여 조기에 간생검을 시행하는 적극적인 진단 방법이 고려되어야 할 것으로 생각한다. 저자들은 황달과 간비대로 전원된 69세 여자 환자에서 복부전산화단층촬영에서 미만성 침윤 병변을 확인한 후 간생검으로 전이된 소세포 폐암을 진단하였고, 이후 급속한 간기능 악화로 전격간기능 상실이 발생하여 사망한 임상에서 드문 사례를 경험하였다.
Intraperitoneal endoscopic salvage using an enteral stent for a misdeployed lumen-apposing metal stent during endoscopic ultrasound-guided gastroenterostomy
Authors: Sergio Bazaga, Albert Garcia-Sumalla, Berta Laquente, Joan B. Gornals
Journal: Endoscopy (2021)

A 57-year-old man with duodenal carcinoma and a biliary self-expandable metal stent (SEMS) presented with gastric outlet obstruction and an endoscopic ultrasound (EUS)-guided gastroenterostomy was proposed.
Prevalence of COVID-19 in Iran: results of the first survey of the Iranian COVID-19 Serological Surveillance programme
Authors: Kazem Khalagi, Safoora Gharibzadeh, Davood Khalili, Mohammad Ali Mansournia, Siamak Mirab Samiee, Saeide Aghamohamadi, Maryam Mir-Mohammad-Ali Roodaki, Seyed Mahmoud Hashemi, Katayoun Tayeri, Hengameh Namdari Tabar, Kayhan Azadmanesh, Jafar Sadegh Tabrizi, Kazem Mohammad, Firoozeh Hajipour, Saeid Namaki, Alireza Raeisi, Afshin Ostovar
Journal: Clinical Microbiology and Infection (2021)
A multiparameter model for prediction of pathological nodal status in clinically early stage oral cancer using machine learning.
Authors: Indranil Mallick, Saheli Saha, Sanjoy Chatterjee, Paromita Roy
Journal: Journal of Clinical Oncology (2021)

e18025 Background: The current approach to neck treatment in clinical T1-2 oral cancers is to offer elective nodal dissection to all patients, despite the fact that the majority of patients are pathologically node negative. This is due to the poor predictive ability of clinico-radiological assessment and subsequently poorer survival in those in whom neck dissection is omitted based on this. A robust prediction model for pathological nodal status may allow individualized decisions for neck dissection. Our aim was to develop a multiparameter prediction model to identify pathological node-negative status using machine learning. Methods: We identified 497 patients with cT1-2 oral cancer from a single institutional database from 2011-2018 who underwent primary resection and neck dissection. We compared the sensitivity, positive predictive value and accuracy of prediction of pathologically negative neck from clinico-radiological staging alone vs. a model created from multiple parameters including clinical features (clinico-radiological nodal status, ages, sex, subsite of primary lesion) and pathological features of the resected primary tumor (maximum dimension, depth of invasion, lymphovascular invasion, perineural invasion, grade and margins of resection). The multiparameter model was built from a training dataset of the first 400 patients using an ensemble of logistic regression, random forests and support vector machines. A cohort of 97 patients was used for independent validation. Results: In this cohort 232 (47%) were clinico-radiologically node negative, while 307(62%) were pathologically node negative. The sensitivity, positive predictive value and accuracy of the clinico-radiologically assigned nodal status was 56%, 74% and 61%, while that of the multiparameter machine learning model was 87%, 89% and 89% respectively. The area under curve (AUC) of the clinico-radiological prediction was 0.62 whereas that of the multiparameter predictive model was 0.91. In the validation dataset, 58/62 pathologically node negative patients were predicted correctly by the model. The accuracy of the model on the external validation dataset was 82%. Conclusions: The performance of the multiparameter predictive model was considerably superior to clinico-radiological neck staging for prediction of pathological node negative neck. This could be validated on an independent dataset. This could be considered for prospective clinical evaluation of individualized neck dissection.
Treatment-emergent central sleep apnea associated with non-positive airway pressure therapies in obstructive sleep apnea patients: A systematic review
Authors: Mathieu Berger, Geoffroy Solelhac, Christian Horvath, Raphael Heinzer, Anne-Kathrin Brill
Journal: Sleep Medicine Reviews (2021)

This systematic review summarizes the prevalence of treatment-emergent central sleep apnea (TECSA) occurring with therapies other than positive airway pressure (PAP) for the management of obstructive sleep apnea (OSA). We describe its natural course as well as the proposed underlying pathophysiological mechanisms and the clinical management of affected patients. A systematic search of PubMed, Embase, Web of science, and the Cochrane Library was performed until June 2020. Eighteen studies (n = 284 patients) were included. TECSA was observed in 31 patients with the use of four different medical devices (mandibular advancement device, hypoglossal nerve stimulation, tongue stabilizing device and nasal expiratory PAP) and after three different types of surgical treatments (tracheostomy, maxillofacial surgery and oro-nasal surgery). Due to the paucity of data available, it was not possible to establish a clear prevalence rate of TECSA for each alternative treatment. After the initiation of non-PAP treatments, a systematic reassessment of the treatment efficacy with follow-up sleep studies will be helpful to identify TECSA. A spontaneous resolution over time was described as well as a persistence of TECSA. In this case, treatment should focus on patients' specific underlying pathophysiology. Overall, the limited current literature suggests that this phenomenon is rare (<4%).
Abstract 11594: Initial Energy Dose and Survival to Hospital Discharge for Pediatric In-hospital Cardiac Arrest Due to Pulseless Ventricular Arrhythmia
Authors: Derek B Hoyme, Yunshu Zhou, Saket Girotra, Marc Berg, Robert A Berg, Sarah E Haskell, Mary Fran Hazinski, Javier J Lasa, Peter A Meaney, Vinay M Nadkarni, Ricardo A Samson, Dianne L Atkins
Journal: Circulation (2019)

The American Heart Association (AHA) recommends an initial defibrillation energy dose of 2 J/kg to treat pediatric in-hospital cardiac arrest (IHCA) with initial ventricular fibrillation (VF) or pu...
Deeply Infiltrating iRGD‐Graphene Oxide for the Intensive Treatment of Metastatic Tumors through PTT‐Mediated Chemosensitization and Strengthened Integrin Targeting‐Based Antimigration
Authors: Honglan Wang, Jiyuan Zhou, Ying Fu, Yuzhao Zheng, Weiyang Shen, Jianping Zhou, Tingjie Yin
Journal: Advanced Healthcare Materials (2021)

Abstract A limited infiltration and the subsequent low effective drug concentration result in poor chemotherapeutic outcomes against tumors, and even further promote tumor resistance and metastatic. Herein, iRGD‐modified graphene oxide (GO) nanosheets (IPHG) are developed for the intensive treatment of metastatic tumors using focus‐specific penetrated delivery together with photothermal therapy‐mediated chemosensitization and photothermal therapy‐strengthened integrin targeting‐based antimigration. In vitro and in vivo data verified the mechanism of the tumor‐selective infiltration of IPHG is based on a rigid 2D structure‐associated advantage regarding hemodynamics and endothelial contact, followed by iRGD‐endowed transendothelial and intratumoral transport. Once IPHG‐DOX‐penetrated 4T1 tumors are exposed to near‐infrared irradiation, hyperthermia stress and photothermal therapy‐elevated effective drug concentrations result in chemosensitization and prominent tumor suppression. Meanwhile, the specific binding of iRGD to integrins and photothermal therapy leads to the synergistic perturbation of cytoskeleton remodeling and subsequent impairment of cell motility and metastasis. The tailored design of IPHG validates a promising paradigm for drug delivery to combat tumor resistance and metastasis resulting from poor target access for single chemotherapy.
Phase 1 study of SHR-1701, a bifunctional fusion protein targeting PD-L1 and TGF-β, in patients with advanced solid tumors.
Authors: Dan Liu, Jifang Gong, Tianshu Liu, KunYan Li, Xianli Yin, Yunpeng Liu, Yongsheng Wang, Linna Wang, Wenliang Wang, Yanyan Zhang, Lin Shen
Journal: Journal of Clinical Oncology (2021)

2503 Background: Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a promising therapeutic strategy for multiple tumor types. SHR-1701 is a novel bifunctional anti-PD-L1/TGF-βRII agent. This dose escalation and expansion phase 1 study aimed to evaluated the safety and preliminary anti-tumor acitivity of SHR-1701 in refractory solid tumors. Methods: The dose escalation period was initiated by accelerated titration (1 mg/kg Q3W) and then switched to 3+3 scheme (3, 10, 20, and 30 mg/kg Q3W and 30 mg/kg Q2W). The dose expanded at doses of 10, 20, and 30 mg/kg Q3W and 30 mg/kg Q2W. The primary objectives were to determine the safety profile, MTD, and RP2D of SHR-1701. Results: 17 pts (1 mg/kg Q3W [n = 1]; 3, 10, 20 and 30 mg/kg Q3W [n = 3 each]; 30 mg/kg Q2W [n = 4]) were enrolled in dose escalation part. No DLT was observed and MTD was not reached. Another 32 pts (10 mg/kg Q3W [n = 8]; 20 and 30 mg/kg Q3W [n = 9 each]; 30 mg/kg Q2W [n = 6]) were enrolled in dose expansion part. Of 49 enrolled pts, 33 pts (67.3%) had received ≥2 lines of prior systemic therapy. As of data cutoff on Oct 30, 2020, the median duration of SHR-1701 exposure was 6.0 weeks (range, 2.0-78.6). The most common reported TRAEs were increased ALT/AST, anemia, hypothyroidism, and increased bilirubin/conjugated bilirubin, with incidence &gt; 15%. The incidence of irAEs reported by the investigator was 46.9% and 4 pts received systemic corticosteroids. Hypothyroidism and rash were the most common irAEs with incidence &gt; 10%. The incidence of Grade ≥3 TRAEs was 18.4%. The incidence of Grade ≥3 irAEs was 10.2%. 1 pt suffered early death for liver failure more likely caused by tumor progression. PK analysis showed a linear dose-exposure relationship with SHR-1701 dosing from 1 to 30 mg/kg. The peripheral PD-L1 target occupancy rate exceeded 90%, and nearly complete TGF-β1 trapping was detected in all dose groups. Of 49 enrolled pts, 45 pts completed at least once efficacy evaluation. The ORR was 17.8% (95% CI, 8.0%-32.1%), with 8 pts achieving PR (2 lung adenocarcinoma, 1 HCC, 1 ESCC, 1 dMMR-CRC, 1 renal cancer, 1 epiglottis cancer, and 1 pancreatic acinar cell carcinoma). The DCR was 40.0% (18/45; 95% CI, 25.7%-55.7%). Majority of responses (7/8) were still ongoing, and the median DoR had not been reached yet. Based on data of saftety, PK, PD, and efficacy, we recommended 30 mg/kg Q3W as the RP2D. Conclusions: SHR-1701 showed acceptable safety profile and encouraging antitumor activity in refractory solid tumors, establishing the foundation for further exploration. Clinical trial information: NCT03710265.
Clinical outcomes for plasma-based comprehensive genomic profiling versus tissue testing in advanced lung adenocarcinoma.
Authors: Ray D. Page, Leylah Drusbosky, Hiba I. Dada, Victoria M. Raymond, Davey B. Daniel, Stephen G. Divers, Karen L. Reckamp, Miguel Angel Villalona-Calero, Justin Iver Odegaard, Richard B. Lanman, Vassiliki Papadimitrakopoulou, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2021)

9027 Background: Somatic genomic testing is recommended by numerous expert guidelines to inform targeted therapy treatment for patients with advanced lung adenocarcinoma (aLUAD). The NILE study was a prospective observational study that demonstrated non-inferiority of cell-free circulating tumor DNA (cfDNA)-based tumor genotyping compared to tissue-based genotyping to find targetable genomic alterations in patients with newly diagnosed aLUAD. As the cohort has matured, clinical outcomes data can now be reported. Methods: This prospective, multicenter North American study (NCT03615443) enrolled patients with previously untreated aLUAD who had standard of care (SOC) tissue genotyping performed and concurrent comprehensive cfDNA analysis using the commercially available Guardant360 assay (Guardant Health, Redwood City, CA). After 12 months of study enrollment, objective response rates, disease control rate, and time to treatment data were collected for patients with targetable genomic alterations, as defined by NCCN guidelines, who were treated with physician’s choice of therapy. Results: Among 282 patients on the study, 89 (31.6%) had an actionable biomarker detected by tissue (21.3%) and/or cfDNA (27.3%) analysis. Sixty-one (68.5%) of these patients were treated with an FDA-approved targeted therapy guided by somatic genotyping results ( EGFR, ALK, ROS1). Thirty-three patients were eligible for clinical response evaluation and demonstrated an objective response rate of 58% and disease control rate of 94%. Twenty-five (76%) achieved a durable response &gt; 6 months; 17 (52%) achieved a durable response &gt; 12 months. Patients responded to targeted therapy regardless of the variant allele frequency of the target alteration. The time to treatment (TtT) was significantly faster for cfDNA-informed biomarker detection as compared to tissue genotyping (median 18 vs 31 days, respectively; p = 0.0008). Conclusions: This is the first prospective community-based study to find that cfDNA detects guideline-recommended biomarkers at a rate similar to tissue genotyping, and therapeutic outcomes based on plasma-based comprehensive genomic profiling are comparable to published tissue-based targeted therapy clinical outcomes. The NILE study complements and confirms findings in the prospective FLAURA and SLLIP studies, which exclusively enrolled at academic sites. Clinical trial information: NCT03615443.
Mitochondria: Their relevance during oocyte ageing
Authors: Jiska van der Reest, Gustavo Nardini Cecchino, Marcia C. Haigis, Paweł Kordowitzki
Journal: Ageing Research Reviews (2021)

The oocyte is recognised as the largest cell in mammalian species and other multicellular organisms. Mitochondria represent a high proportion of the cytoplasm in oocytes and mitochondrial architecture is different in oocytes than in somatic cells, characterised by a rounder appearance and fragmented network. Although the number of mitochondria per oocyte is higher than in any other mammalian cell, their number and activity decrease with advancing age. Mitochondria integrate numerous processes essential for cellular function, such as metabolic processes related to energy production, biosynthesis, and waste removal, as well as Ca2+ signalling and reactive oxygen species (ROS) homeostasis. Further, mitochondria are responsible for the cellular adaptation to different types of stressors such as oxidative stress or DNA damage. When these stressors outstrip the adaptive capacity of mitochondria to restore homeostasis, it leads to mitochondrial dysfunction. Decades of studies indicate that mitochondrial function is multifaceted, which is reflected in the oocyte, where mitochondria support numerous processes during oocyte maturation, fertilization, and early embryonic development. Dysregulation of mitochondrial processes has been consistently reported in ageing and age-related diseases. In this review, we describe the functions of mitochondria as bioenergetic powerhouses and signal transducers in oocytes, how dysfunction of mitochondrial processes contributes to reproductive ageing, and whether mitochondria could be targeted to promote oocyte rejuvenation.
Ywhae Located on Chromosome 17p13 Promotes Myeloma Cells Proliferation Via Induction of Anti-Apoptosis and Survival Signaling Pathways
Authors: Yan Xu, Mariateresa Fulciniti, Mehmet Kemal Samur, Raphael Szalat, Matthew Ho, Michael A Lopez, Na Li, Jianhong Lin, Tommaso Perini, Srikanth Talluri, Jiye Liu, Kenneth Wen, Giada Bianchi, Li Zhang, Lijie Xing, An Gang, Liang Lin, Yu-Tzu Tai, Lugui Qiu, Kenneth C Anderson, Nikhil Munshi
Journal: Blood (2017)