tbuckley/cabot-search huggingface dataset:
Magnetic resonance elastography for prediction of long‐term progression and outcome in chronic liver disease: A retrospective study
Authors: Tolga Gidener, Meng Yin, Ross A. Dierkhising, Alina M. Allen, Richard L. Ehman, Sudhakar K. Venkatesh
Journal: Hepatology (2021)

Although magnetic resonance elastography (MRE) has been well-established for detecting and staging liver fibrosis, its prognostic role in determining outcomes of chronic liver disease (CLD) is mostly unknown.This retrospective study consisted of 1269 subjects who underwent MRE between 2007 and 2009 and followed up until death or last known clinical encounter or end of study period. Charts were reviewed for cirrhosis development, decompensation, and transplant or death. The cohort was split into baseline noncirrhosis (group 1), compensated cirrhosis (group 2), and decompensated cirrhosis (group 3). Cox-regression analysis with age, sex, splenomegaly, CLD etiology, Child-Pugh Score (CPS), Fibrosis-4 Index (FIB-4) score, and Model for End-Stage Liver Disease (MELD)-adjusted HR for every 1-kPa increase in liver stiffness measurement (LSM) were used to assess the predictive performance of MRE on outcomes. Group 1 (n = 821) had baseline median LSM of 2.8 kPa, and cirrhosis developed in 72 (8.8%) subjects with an overall rate of about 1% cirrhosis/year. Baseline LSM predicted the future cirrhosis with multivariable adjusted HR of 2.38 (p < 0.0001) (concordance, 0.84). In group 2 (n = 277) with baseline median LSM of 5.7 kPa, 83 (30%) subjects developed decompensation. Baseline LSM predicted the future decompensation in cirrhosis with FIB-4 and MELD-adjusted HR of 1.22 (p < 0.0001) (concordance, 0.75). In group 3 (n = 171) with median baseline LSM of 6.8 kPa (5.2, 8.4), 113 (66%) subjects had either death or transplant. Baseline LSM predicted the future transplant or death with HR of 1.11 (p = 0.013) (concordance 0.53) but not in CPS and MELD-adjusted models (p = 0.08).MRE-based LSM is independently predictive of development of future cirrhosis and decompensation, and has predictive value in future transplant/death in patients with CLD.
Hospitalizations and Outcomes of T1MI Observed Before and After the Introduction of MI Subtype Codes
Authors: Cian P. McCarthy, Dhaval Kolte, Kevin F. Kennedy, Ambarish Pandey, Inbar Raber, Andrew Oseran, Rishi K. Wadhera, Muthiah Vaduganathan, James L. Januzzi, Jason H. Wasfy
Journal: Journal of the American College of Cardiology (2021)
Impaired Awareness of Hypoglycemia and Severe Hypoglycemia in Drivers With Diabetes: Insights From the Association of British Clinical Diabetologists Nationwide Audit
Authors: Harshal Deshmukh, Emma G. Wilmot, Pratik Choudhary, Parth Narendran, Najeeb Shah, Dennis Barnes, Shafie Kamruddin, Rumaisa Banatwalla, Peter Christian, Simon Saunders, Alistair Lumb, Roselle Herring, Jane Patmore, Chris Walton, Robert E.J. Ryder, Thozhukat Sathyapalan
Journal: Diabetes Care (2021)

Hypoglycemia is an acute complication in people living with diabetes, with 83% of those with type 1 diabetes experiencing hypoglycemia at least once a month and even higher rates of 5 events per week recorded on continuous glucose monitoring (1). There are limited population-based data on the prevalence of impaired awareness of hypoglycemia (IAH) and severe hypoglycemia (SH) in drivers with diabetes in the U.K. and worldwide. The availability of these data can inform policy decisions and help optimize treatment options for people living with diabetes (2).

To understand the prevalence of IAH and SH in drivers with diabetes, we obtained data from the nationwide audit of FreeStyle Libre (FSL), conducted by the Association of British Clinical Diabetologists (ABCD). Baseline pre-FSL data included demographics, HbA1c values from the previous 12 months, Gold score (3) (to assess hypoglycemia awareness), and SH. Rates of recurrent SH, defined as two or more episodes of hypoglycemia requiring third-party assistance in the 12 months prior to FSL initiation (4), were documented by clinicians.

The study consisted of 13,127 adults (aged ≥17 years) with diabetes, and information about driving was available for 4,262 (96% type 1 diabetes) of those (3,210 drivers and 1,052 nondrivers). Of those with a driving license, 3,182 had a group 1 driving license (a license to drive a motor car and a motorcycle), 25 had a group 2 driving …
A randomized phase 2 trial of idiotype vaccination and adoptive autologous T-cell transfer in patients with multiple myeloma
Authors: Muzaffar H. Qazilbash, Neeraj Y. Saini, Soung-chul Cha, Zhe Wang, Edward A. Stadtmauer, Veerabhadran Baladandayuthapani, Heather Lin, Beryl Tross, Medhavi Honhar, Sheetal S. Rao, Kunhwa Kim, Michael Popescu, Szymon Szymura, Tiantian Zhang, Aaron Anderson, Qaiser Bashir, Elizabeth J. Shpall, Robert Z. Orlowski, Bruce L. Levine, Naseem Kerr, Alfred Garfall, Adam Cohen, Dan T. Vogl, Karen Dengel, Carl H. June, Richard Champlin, Larry W. Kwak
Journal: Blood (2021)
Health-related quality of life outcomes in adults with nonmuscle-invasive bladder cancer receiving a mitomycin-containing reverse thermal gel as a primary treatment (Optima II: Phase 2b, single-arm, open-label trial).
Authors: Angela M. Stover, Ramsankar Basak, Dana Mueller, Angela B. Smith
Journal: Journal of Clinical Oncology (2021)

270 Background: The standard of care for low-grade non‐muscle‐invasive bladder cancer (LG NMIBC) is transurethral resection of the bladder tumor, which can worsen health‐related quality of life (HRQOL). The “OPTimized Instillation of Mitomycin for Bladder Cancer Treatment” (Optima II, clinicaltrials.gov: NCT03558503) is a Phase 2b, open label, single arm, multicenter trial evaluating a nonsurgical alternative as a primary treatment. Patients receive six weekly instillations of UGN-102, a mitomycin-containing reverse thermal gel with a sustained release time of up to 8 hours. We report on HRQOL changes between baseline and the primary endpoint of 3 months. Methods: A total of 63 patients enrolled in the Optima II trial at 20 sites in the U.S. and 2 sites in Israel between October 2018 and October 2020. Of the 63 patients enrolled, 44 were in the HRQOL cohort and completed a quarterly questionnaire. The QLQ-NMIBC24 has six subscales (urinary symptoms, malaise, future health worries, bloating and flatulence, sexual functioning, and male sexual problems) and five single items (intravesical treatment issues, sexual intimacy, worry about contaminating partner, sexual enjoyment, and female sexual problems) assessed with 24 items. Items were rescaled to 0-100 and reverse-coded so that higher scores indicate worse symptom burden. Longitudinal score changes were evaluated using the Sign test. We examined demographic and clinical characteristics associated with HRQOL change scores with regression modeling. A p-value of ≤0.01 was used. Results: The HRQOL cohort was 61% men, 57% age 65+, and 89% non-Hispanic White. Clinically, most LG NMIBC patients had multiple tumors (88%) with prior NMIBC episodes (77%), and two or more prior transurethral resection of bladder procedures (TURBT) (85%). Approximately half (55%) had their most recent TURBT surgery within 12 months of trial enrollment. No patients had missing HRQOL data at baseline or the primary end point of 3 months. The chemoablative reverse thermal gel used as a primary treatment did not cause decrements in patient-reported urinary symptoms, bloating/ flatulence, malaise, fever, general health, or future health worries. Sexual function mildly worsened between baseline and 3 months, and abated by 6 months. Demographic and clinical characteristics were not correlated with HRQOL change scores. By 3 months, 31/44 (70%) LG NMIBC patients achieved a complete response (negative endoscopic examination, cytology, and for-cause biopsy) and 0 experienced a recurrence. By 12 months, 8/44 (18%) patients had a recurrence. Conclusions: Adults with LG NMIBC in a Phase 2b trial who received a mitomycin-containing reverse thermal gel with sustained release maintained their HRQOL through 3 months. A Phase 3 trial is warranted. Clinical trial information: NCT03558503.
Paracetamol use during pregnancy — a call for precautionary action
Authors: Ann Z. Bauer, Shanna H. Swan, David Kriebel, Zeyan Liew, Hugh S. Taylor, Carl-Gustaf Bornehag, Anderson M. Andrade, Jørn Olsen, Rigmor H. Jensen, Rod T. Mitchell, Niels E. Skakkebaek, Bernard Jégou, David M. Kristensen
Journal: Nature Reviews Endocrinology (2021)

Abstract Paracetamol ( N -acetyl- p -aminophenol (APAP), otherwise known as acetaminophen) is the active ingredient in more than 600 medications used to relieve mild to moderate pain and reduce fever. APAP is widely used by pregnant women as governmental agencies, including the FDA and EMA, have long considered APAP appropriate for use during pregnancy when used as directed. However, increasing experimental and epidemiological research suggests that prenatal exposure to APAP might alter fetal development, which could increase the risks of some neurodevelopmental, reproductive and urogenital disorders. Here we summarize this evidence and call for precautionary action through a focused research effort and by increasing awareness among health professionals and pregnant women. APAP is an important medication and alternatives for treatment of high fever and severe pain are limited. We recommend that pregnant women should be cautioned at the beginning of pregnancy to: forego APAP unless its use is medically indicated; consult with a physician or pharmacist if they are uncertain whether use is indicated and before using on a long-term basis; and minimize exposure by using the lowest effective dose for the shortest possible time. We suggest specific actions to implement these recommendations. This Consensus Statement reflects our concerns and is currently supported by 91 scientists, clinicians and public health professionals from across the globe.
P14.03 Shifting trends and entity-specific aspects in patients with brain metastasis: real-life analysis from 6031 individuals over an observation period of 30 years
Authors: A Steindl, T J Brunner, K Heimbach, K Schweighart, G M Moser, H M Niziolek, E Moor, J Kreminger, A M Starzer, K Dieckmann, B Gatterbauer, G Widhalm, M Preusser, A S Berghoff
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND We aimed to investigate the changing clinical characteristics of patients with brain metastases (BM) over the last three decades as the foundation for modern BM specific clinical trial planning. MATERIAL AND METHODS 6031 patients with newly diagnosed BM from different solid tumors treated between 1986–2020 were identified from the Vienna Brain Metastasis Registry. RESULTS The fraction of BM originating from the most common BM causing primary tumors (lung cancer, breast cancer and melanoma) was stable over the observation period from 1986–2020. BM from renal cell carcinoma, colorectal cancer and cancer of unknown primary (CUP) decreased over time (p&amp;lt;0.001). Synchronous diagnosis of BM and primary tumor was more frequently observed in lung cancer and CUP patients compared to breast cancer patients (p&amp;lt;0.001). An increasing fraction of patients presented with asymptomatic BM (1986–1999: 20.2% vs. 2010–2020: 30.4%; p&amp;lt;0.001), specifically in lung cancer (p&amp;lt;0.001), melanoma (p&amp;lt;0.001) and renal cell cancer (p=0.004). A decrease of neurosurgical procedures (1986–1999: 39.3% vs. 2010–2020: 20.4%) and an increase of radiation treatments (1986–1999: 56.5% vs. 2010–2020: 73.0%) and systemic therapies (1986–1999: 0.6% vs. 2010–2020: 2.4%; p&amp;lt;0.001) was observed. Furthermore, median overall survival significantly increased across entities (1986–1999: 5 months vs. 2010–2020: 7 months; p=0.001). Intracranial progression as the cause of death increased across entities (p&amp;lt; 0.001). The prognostic DS-GPA (Hazard ratio [HR] 1.42; p&amp;lt; 0.001) and the Lung-molGPA (HR 1.67; p&amp;lt;0.001) could be validated. CONCLUSION We observed changes of BM presentation and clinical parameters during the observation period depending on primary tumor origins. Future BM studies should follow an entity-specific approach and address the characteristics of modern BM cohorts.
Outcomes of a pilot study exploring the role of digital health coaching for men with prostate cancer.
Authors: Nathan Handley, Kuang-Yi Wen, Sameh Gomaa, Ayako Shimada, Benjamin Leiby, Kelly Jean Brassil, Lindsey Jackson, Anne Calvaresi, Adam P. Dicker
Journal: Journal of Clinical Oncology (2021)

102 Background: As the most common cancer among men in the US, prostate cancer (PCa) affects nearly 250,000 men annually, accounting for over 13% of all new cancer cases. Health-related quality of life (HRQoL) during and post-treatment is impacted by sexual, urinary and bowel function which can persist for months or years after treatment completion. As individuals primarily manage such symptoms in the community setting there is a need for interventions that can address overall health and wellness concerns needs of men with PCa beyond the clinical setting. Digital health coaching (DHC) is one such solution that has potential to address HRQoL for individuals with cancer. Methods: The aim of this pilot study was to evaluate the feasibility of a DHC program for individuals with PCa. One hundred English-speaking men with PCa requiring active treatment within the past 2 years were recruited from across the Delaware Valley. Consented individuals were enrolled in a 3-month DHC program, consisting of a weekly call from a health advisor along with delivery of evidence-based supplemental content via text or email focused on exercise nutrition, physical, emotional and sexual health, as well as financial toxicity. Secondary endpoints evaluated the relationship between the DHC intervention and health self-efficacy, as measured by the Cancer Behavior Inventory-Brief Form (CBI-B), quality of life (EPIC-CP), financial toxicity (COST) and global health (PROMIS- SF10). Results: 82 individuals enrolled in the study for which the mean age was 68 years old (1.2 % Black, 2.4% Rural). The feasibility threshold of 60% was met with 58 individuals completing the 3-month program (proportion = 70.7%, 90% CI: 61.4, 78.9). Health self-efficacy improved with a mean change in CBI-B of 4.1 (95% CI: 0.4, 7.8). The financial toxicity improved with a mean score change of 2.5 (95% CI: 1.0, 4.0). All symptom scores of EPIC-CP were improved by showing a decrease of mean scores. PROMIS-GH also improved in both mental and physical health domains with mean changes of 0.5 and 1.4 (95% CIs for mental: -1.6, 2.6, for physical: -0.1, 2.8). Conclusions: DHC demonstrated feasibility in a cross-sectional population of men with PCA recruited in the community setting. Data suggest that HRQoL, health-self efficacy and global health can be positively impacted by DHC. Results support the further evaluation of DHC in larger RCTs.
Bortezomib induces schedule-dependent modulation of gemcitabine pharmacokinetics and pharmacodynamics in non-small cell lung cancer and peripheral blood mononuclear cells
Authors: J. Voortman, C. Ceresa, E. Giovannetti, A. C. Laan, R. Honeywell, G. Giaccone, G. J. Peters
Journal: Annals of Oncology (2008)
LONG-TERM SAFETY AND EFFICACY OF LOMITAPIDE IN PATIENTS WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA: FIVE-YEAR DATA FROM THE LOMITAPIDE OBSERVATIONAL WORLDWIDE EVALUATION REGISTRY (LOWER)
Authors: James A. Underberg, Christopher P. Cannon, Dominique Larrey, Lukas Makris, Helen Phillips, Dirk Blom
Journal: Journal of the American College of Cardiology (2020)
Vitiligo-like depigmentation in a patient treated with PD-1 antibody
Authors: Jing Jing, Xiao-Yong Man
Journal: BMJ (2021)

This is melanoma associated vitiligo in a man in his 70s after treatment with a monoclonal antibody for malignant melanoma (fig 1).



Fig 1 

He presented with rapidly growing depigmented macules and patches (about 1 …
P11.05 Evaluation of a dialogue support tool tailored to support patients with brain tumors in identifying areas for improvement in a new proton clinic
Authors: M H Lund, H Simonsen, A W Kristensen
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Proton therapy has been available in Denmark in the recent 2 years. The aim of this project was to evaluate the course of treatment with proton therapy from a patient perspective and thereby identify areas for improvement. A secondary aim was to test the use of a dialogue support tool when interviewing patients with brain tumors. The tool supports the oral questions with visual pictograms. MATERIAL AND METHODS During 2020, structured interviews based on a dialogue support tool were conducted with 17 adult patients (&amp;gt;18 years) with brain tumours at the end of their treatment with proton therapy. Three radiation therapists (RTTs) conducted individual interviews in quiet surroundings in the clinic. The dialogue support tool consisted of the following elements; a poster showing the course of treatment, pictograms of activities during the treatment course. Furthermore, green, yellow and red smileys representing a satisfied, neutral or unsatisfied evaluation of the treatment pathways reported by the patients. During the interview the RTT placed the pictograms on the poster one by one. The patient evaluated each pictogram as satisfied, neutral or unsatisfied. If the patient evaluated a pictogram as neutral or unsatisfied, the RTT asked the patient for suggestions on improvements related to the specific activity. The last pictogram represented an evaluation of the dialogue support tool. The patient evaluations were documented systematically, collected and analysed. The emerging areas for improvement were discussed by the authors until consensus was reached. RESULTS The following topics were identified as areas for improvements of the course of treatment: A need for more detailed information on proton therapy in the referring clinics before initiation of treatment. Lack of shared decision between patient and doctor regarding choice of radiotherapy modality. Barriers to understand patient information on website due to reading difficulties, reduced cognitive function or visual impairment. A need for detailed information on the possibilities regarding transportation, accommodation and accompanying relatives. Patients reported confusion with being assigned a doctor responsible for their treatment because the patients met many doctors during the course of treatment. Evaluation of the dialogue support tool: The patients experienced that the dialogue support tool made it easier to understand the oral questions. CONCLUSION The structured interviews supported by the dialogue support tool was a suitable approach to detect areas of improvement in the course of treatment with proton therapy. The poster helped to visualise the course of treatment and the pictograms clarified the questions. The findings represent patient-identified topics relevant for further development in clinical practice.
OS06.3A LSD1-directed therapy curtails glioblastoma tumorigenicity by limiting the adaptation of tumor initiating cells to stressful environments
Authors: S Faletti, D Osti, E Ceccacci, C Richichi, B Costanza, G Marotta, D Corà, G Pelicci
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Glioblastoma (GBM) is a fatal tumor whose aggressiveness, heterogeneity, therapy resistance and poor blood-brain-barrier penetration hinder the amelioration of the standard-of-care. Included in the GBM mass are the tumor initiating cells (TICs), representing the driver of GBM growth and relapse in virtue of their stem-like traits and therapy-resistance. Being constantly exposed to environmental stress, including nutrients deficiency, hypoxia and therapeutic insults, all GBM cells -and TICs in particular- have to be highly adaptive in order to survive. Thus, their ability to cope with stress could be targeted to curtail TICs maintenance and the whole GBM aggressiveness. The key of TICs adaptation relies, among the others, on their epigenetic plasticity, hence encouraging epigenetic drugs testing. MATERIAL AND METHODS By exploiting patient-derived GBM TICs and orthotopic xenograft models, we tested the antitumorigenic features of a novel, selective, orally bioavailable and brain-penetrant Lysine-specific histone demethylase 1 inhibitor (LSD1i). We confirmed the specificity of its effects by LSD1 genetic targeting. A combination of RNA-seq, Chromatin Immunoprecipitation(ChIP)-seq, Mass Spectrometry and reverse genetic experiments unraveled LSD1 molecular players in GBM TICs. RESULTS We identified LSD1 as a druggable target in human GBM: LSD1i treatment, mirrored by LSD1 genetic targeting, impairs growth, viability, stem-like traits and in vivo tumorigenicity of GBM TICs. Mechanistically, LSD1 is crucial for the expression of the activating transcription factor 4 (ATF4), which coordinates the integrated stress response (ISR) to manage stressful stimuli as nutrient deprivation and endoplasmic reticulum stress. By mimicking these stress cues in vitro, we found that LSD1i triggers a delayed but unabated ATF4 translation which provokes an over-lasting ISR, eventually culminating in GBM TICs apoptosis. Lastly, LSD1 demethylase activity is dispensable for ATF4 induction. Rather, LSD1i exerts its anti-tumorigenic potential by interfering with LSD1 scaffolding function in GBM TICs. CONCLUSION LSD1-directed therapy is likely a promising strategy to hinder GBM. By sensitizing GBM TICs to stress, LSD1i endangers the GBM TICs pool. The effectiveness of LSD1i administration in different patient-derived GBM TICs and xenografts, regardless of their molecular profile, places a strong rationale toward the clinical translation of this approach for GBM management. FUNDING Italian association for Cancer Research (AIRC) and Italian Ministry of Health
Drug repurposing: Misconceptions, challenges, and opportunities for academic researchers
Authors: C. Glenn Begley, Mark Ashton, Jonathan Baell, Michael Bettess, Michael P. Brown, Brett Carter, William N. Charman, Christopher Davis, Simon Fisher, Ian Frazer, Anand Gautam, Michael P. Jennings, Philip Kearney, Eloise Keeffe, Darren Kelly, Angel F. Lopez, Michael McGuckin, Michael W. Parker, Craig Rayner, Brett Roberts, James S. Rush, Mark Sullivan
Journal: Science Translational Medicine (2021)

The assumption that drug repurposing efficiently delivers new drugs ignores the realities of drug development required to achieve regulatory approval.
METTL3-m6A-Rubicon axis inhibits autophagy in nonalcoholic fatty liver disease
Authors: Zishan Peng, Yingying Gong, Xuejie Wang, Weiman He, Liting Wu, Luyao Zhang, Li Xiong, Yanrui Huang, Lei Su, Peijie Shi, Xiaopei Cao, Rengyun Liu, Yanbing Li, Haipeng Xiao
Journal: Molecular Therapy (2021)

N6-methyladenosine (m6A) mRNA modification plays critical roles in various biological events and is involved in multiple complex diseases. However, the role of m6A modification in autophagy in nonalcoholic fatty liver disease (NAFLD) remains largely unknown. Here, we report that m6A modification was increased in livers of NAFLD mouse models and in free fatty acid (FFA)-treated hepatocytes, and the abnormal m6A modification was attributed to the upregulation of methyltransferase like 3 (METTL3) induced by lipotoxicity. Knockdown of METTL3 promoted hepatic autophagic flux and clearance of lipid droplets (LDs), while overexpression of METTL3 inhibited these processes. Mechanistically, METTL3 directly bound to Rubicon mRNA and mediated the m6A modification, while YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), as a partner of METTL3, interacted with the m6A-marked Rubicon mRNA and promoted its stability. Subsequently, RUBICON inhibited autophagosome-lysosome fusion and further blocked clearance of LDs. Taken together, our results showed a critical role of METTL3 and YTHDF1 in regulating lipid metabolism via the autophagy pathway and provided a novel insight into m6A mRNA methylation in NAFLD.