tbuckley/cabot-search huggingface dataset:
The association of malnutrition and sarcopenia with geriatric assessment impairment and outcomes in patients with bladder cancer undergoing cystectomy.
Authors: Megan Seema Gurjar, Chelsea K. Osterman, Kirsten A. Nyrop, Marc Bjurlin, Hung-Jui Tan, Matthew E. Nielsen, Eric M. Wallen, Matthew I. Milowsky, Hyman B. Muss, Angela B. Smith
Journal: Journal of Clinical Oncology (2021)

423 Background: Malnutrition and sarcopenia are linked to decreased functional status in older adults with malignancy, but their effect on geriatric assessment (GA) impairment in patients with bladder cancer (BC) undergoing radical cystectomy (RC) is unknown. We investigated the association between malnutrition and sarcopenia with GA impairment and postoperative outcomes. Methods: Patients with BC undergoing RC between 2012 – 2019 were enrolled in a prospective cohort study of GA before RC. Malnutrition was evaluated by a dietitian pre-RC per the Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition diagnostic criteria. Sarcopenia, defined by a skeletal muscle index of &lt; 52.4 cm 2 /m 2 in males and &lt; 38.5 cm 2 /m 2 in females, was determined using SliceOmatic software to analyze pre-RC CT images at the L3 vertebra. Patients with vs without malnutrition and those with vs without sarcopenia were compared using Fisher’s exact and Wilcoxon rank sum tests. Results: Of 73 patients, 59 had GA + nutrition evaluation and 51 had GA + sarcopenia assessment (overall median age 68 [IQR 62-74], 76% male). The prevalence of malnutrition was 7% and sarcopenia was 63%. A numerically greater proportion of patients with malnutrition or sarcopenia were impaired on ≥ 1 GA measure compared to those without malnutrition (100% vs 78%, p=0.57) or sarcopenia (78% vs 68%, p=0.52), although this was not statistically significant (Table). Median hospital length of stay (LOS) was increased for patients with vs without sarcopenia (4 vs 5 days, p=0.005). Post-RC complication rate was similar for patients with vs without malnutrition (100% vs 75%, p=0.56) and patients with vs without sarcopenia (81% vs 74%, p=0.73), but malnourished patients were more likely to have Clavien-Dindo grade 3+ complications than those without malnutrition (100% vs 27%, p = 0.009). Conclusions: In our cohort of patients with BC undergoing RC, those with malnutrition or sarcopenia may have an increased rate of impairment on GA compared to those without malnutrition or sarcopenia. Sarcopenia was associated with increased LOS while malnutrition was associated with increased major complications. Our results are limited by small sample size, and future work is needed to elucidate whether addressing these modifiable factors improves functional status and postoperative outcomes. Research Sponsor: U.S. National Institutes of Health[Table: see text]
Systemic Immunotherapy with Micellar Resiquimod–Polymer Conjugates Triggers a Robust Antitumor Response in a Breast Cancer Model
Authors: Hamilton Kakwere, Hua Zhang, Elizabeth S. Ingham, Marina Nura‐Raie, Spencer K. Tumbale, Riley Allen, Sarah M. Tam, Bo Wu, Cheng Liu, Azadeh Kheirolomoom, Brett Z. Fite, Asaf Ilovitsh, Jamal S. Lewis, Katherine W. Ferrara
Journal: Advanced Healthcare Materials (2021)

Abstract Resiquimod is an immunopotent toll‐like receptor 7/8 agonist with antitumor activity. Despite being potent against skin cancers, it is poorly tolerated systemically due to toxicity. Integrating resiquimod into nanoparticles presents an avenue to circumvent the toxicity problem. Herein, the preparation of degradable nanoparticles with covalently bound resiquimod and their systemic application in cancer immunotherapy is reported. Dispersion in water of amphiphilic constructs integrating resiquimod covalently bound via degradable amide or ester linkages yields immune‐activating nanoparticles. The degradable agonist–nanoparticle bonds allow the release of resiquimod from the carrier nanoparticles. In vitro assays with antigen presenting cells demonstrate that the nanoparticles retain the immunostimulatory activity of resiquimod. Systemic administration of the nanoparticles and checkpoint blockade (aPD‐1) to a breast cancer mouse model with multiple established tumors triggers antitumor activity evidenced by suppressed tumor growth and enhanced CD8 + T‐cell infiltration. Nanoparticles with ester links, which hydrolyze more readily, yield a stronger immune response with 75% of tumors eliminated when combined with aPD‐1. The reduced tumor growth and the presence of activated CD8 + T‐cells across multiple tumors suggest the potential for treating metastatic cancer.
Impact of active surveillance for prostate cancer on the risk of depression and anxiety: Patient-reported outcomes (PROs) from the Vican Prospective Cohort.
Authors: Geraldine Pignot, Rajae Touzani, Patricia Marino, Jochen Walz, Stanislas Rybikowski, Thomas Maubon, Naji Salem, Julien Mancini, Gwenaelle Gravis, Marc Karim Bendiane, Anne Deborah Bouhnik
Journal: Journal of Clinical Oncology (2021)

220 Background: Active surveillance (AS) is an option for low-risk localized prostate cancer and its use is on the rise due to the good long-term oncologic results. However, its impact on the quality of live of patients, particularly in terms of anxiety and emotional responses related to cancer is poorly evaluated. Methods: The french VICAN cohort is a representative sample of 4174 patients treated for cancer and survivors after 5 years. Patient-reported Outcomes (PROs) were collected prospectively by self-questionnaires on quality of live (SF-12) and treatments side effects. Among the 447 patients with prostate cancer, patients managed by active surveillance (AS), radiotherapy (RT), or radical prostatectomy (RP), for localized T1-T2 N0 M0 cancer with a Gleason score &lt; 8 were selected. Data regarding depressive symptoms and percieved anxiety were analysed comparatively. Results: A total of 301 patients were included, among whom 68 (22.6%) managed by AS, 170 (56.5%) treated by RP and 63 (20.9%) treated with RT. Patients treated with AS had a lower clinical stage (p = 0.04) compared with patients in RP and RT groups. Regarding the impact on the quality of live, there was no significant difference in terms of depressive symptoms (no depressive symptoms reported for 82.4% of patients in the AS group vs 88.8% in RP and 74.6% in RT, p = 0.468) or percieved anxiety (no anxiety reported in 63.3% of cases in the AS group vs 71.2% in RP and 66.6% in RT, p = 0.214). Conclusions: Patients managed by AS for localized prostate cancer do not report more depressive symptoms or anxiety than patients treated with curative treatment (RP or RT). This confirms the importance of offering this therapeutic option if the histopathological criteria allow it and if the patient is compliant.
High flow oxygen and risk of mortality in patients with a suspected acute coronary syndrome: pragmatic, cluster randomised, crossover trial
Authors: Ralph A H Stewart, Peter Jones, Bridget Dicker, Yannan Jiang, Tony Smith, Andrew Swain, Andrew Kerr, Tony Scott, David Smyth, Anil Ranchord, John Edmond, Martin Than, Mark Webster, Harvey D White, Gerard Devlin
Journal: BMJ (2021)

Abstract Objective To determine the association between high flow supplementary oxygen and 30 day mortality in patients presenting with a suspected acute coronary syndrome (ACS). Design Pragmatic, cluster randomised, crossover trial. Setting Four geographical regions in New Zealand. Participants 40 872 patients with suspected or confirmed ACS included in the All New Zealand Acute Coronary Syndrome Quality Improvement registry or ambulance ACS pathway during the study periods. 20 304 patients were managed using the high oxygen protocol and 20 568 were managed using the low oxygen protocol. Final diagnosis of ST elevation myocardial infarction (STEMI) and non-STEMI were determined from the registry and ICD-10 discharge codes. Interventions The four geographical regions were randomly allocated to each of two oxygen protocols in six month blocks over two years. The high oxygen protocol recommended oxygen at 6-8 L/min by face mask for ischaemic symptoms or electrocardiographic changes, irrespective of the transcapillary oxygen saturation (SpO 2 ). The low oxygen protocol recommended oxygen only if SpO 2 was less than 90%, with a target SpO 2 of less than 95%. Main outcome measure 30 day all cause mortality determined from linkage to administrative data. Results Personal and clinical characteristics of patients managed under both oxygen protocols were well matched. For patients with suspected ACS, 30 day mortality for the high and low oxygen groups was 613 (3.0%) and 642 (3.1%), respectively (odds ratio 0.97, 95% confidence interval 0.86 to 1.08). For 4159 (10%) patients with STEMI, 30 day mortality for the high and low oxygen groups was 8.8% (n=178) and 10.6% (n=225), respectively (0.81, 0.66 to 1.00) and for 10 218 (25%) patients with non-STEMI was 3.6% (n=187) and 3.5% (n=176), respectively (1.05, 0.85 to 1.29). Conclusion In a large patient cohort presenting with suspected ACS, high flow oxygen was not associated with an increase or decrease in 30 day mortality. Trial registration ANZ Clinical Trials ACTRN12616000461493.
Abstract 15605: Comparison of Clinical Outcomes in Lamin A/C-Associated Cardiomyopathy and Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Wendy Ying, Cynthia A James, Brittney Murray, Emily E Brown, Nuria Amat, Jan M Griffin, Crystal Tichnell, Julia Cadrin-Tourigny, Hugh Calkins, Daniel P Judge
Journal: Circulation (2017)

Introduction: Lamin A/C gene (LMNA) mutations cause severe cardiac manifestations, including dilated cardiomyopathy, arrhythmia, and conduction block. Arrhythmogenic right ventricular cardiomyopath...
Genetic correlates of socio-economic status influence the pattern of shared heritability across mental health traits
Authors: Andries T. Marees, Dirk J. A. Smit, Abdel Abdellaoui, Michel G. Nivard, Wim van den Brink, Damiaan Denys, Titus J. Galama, Karin J. H. Verweij, Eske M. Derks
Journal: Nature Human Behaviour (2021)
Differential effect of body mass index (BMI) on outcomes of patients treated with docetaxel in prostate cancer: An exploratory analysis.
Authors: Saurav Verma, Ranjit Kumar Sahoo, Prabhjot Singh, Brusabhanu Nayak, KP Haresh, Atul Batra
Journal: Journal of Clinical Oncology (2021)

129 Background: Docetaxel is a lipophilic drugs with a high affinity for adipose tissue resulting in a higher volume of distribution.There are contradictory data with regards to the differential effect of docetaxel based on BMI in breast cancer patients. However, there are no such data in patients with prostate cancer. A We performed an exploratory analysis to determine if the benefit of docetaxel in patients with metastatic castration resistant prostate cancer (mCRPC) is modified by BMI. Methods: This is a post hoc analysis of data retrieved from the phase III ENTHUSE M1C study that assessed the efficacy and safety of additional zibotentan in combination with docetaxel in patients with mCRPC (ClinicalTrials.gov identifier: NCT00617669). BMI (kg/m2) was categorized as: 18.5 to &lt; 25, lean; 25 to &lt; 30, overweight; and ≥ 30, obese. Cox regression models were constructed to determine the impact of BMI on progression-free survival (PFS) and overall survival (OS) after adjusting for baseline characteristics. Results: A total of 466 patients were eligible for current analysis, of whom 34%, 46% and 20% were &lt; 65 years, 65-74 years and &gt; 75 years, respectively. The median total and free baseline PSA were 99.5 (interquartile range [IQR], 33.6 to 237.0) ng/mL and 13.9 (IQR, 5.4 to 37.4) ng/mL, respectively. There were 31% (n = 145), 46% (n = 213) and 23% (n = 108) lean, overweight and obese patients. Visceral metastasis was present in 52% patients, while the number of bone metastases were 1-3 in 15%, 4 in 5%, 5-20 in 58% and ≥ 21 in 23%. The median number of cycles of docetaxel administered were 10 (IQR, 6-10). The median PFS was 7.3, 7.7 and 8.4 months (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.81 to 1.06; P = .26) for lean, overweight and obese patients, respectively. The median OS was 10.3, 10.7 and 12.4 months (HR, 0.75; 95% CI, 0.63 to 0.89; P = .01) for lean, overweight and obese patients, respectively. After adjusting for baseline and tumor related characteristics, there was no association of BMI with PFS (overweight, HR, 0.92; 95% CI, 0.73 to 1.17; P = .50; obese, HR, 0.90; 95% CI, 0.67 to 1.18; P = .42) while overweight (HR, 0.68; 95% CI, 0.52 to 0.91; P = .01) and obese (HR, 0.61; 95% CI, 0.43 to 0.88; P = .01) patients had significantly better OS as compared with lean patients. Conclusions: The differential effect of docetaxel based on BMI was not observed in patients with mCRPC. Interestingly, obese patients had a significantly longer OS, which warrants further investigation.
Abstract PO022: Metabolic and transcriptional adaptations under hypoxic stress promote breast cancer progression
Authors: Tao Dai, Aaron Novickis, Eriko Katsuta, Kazuaki Takabe, Scott I. Abrams, Subhamoy Dasgupta
Journal: Cancer Research (2021)

Abstract To sustain energy production for survival in hypoxia, tumor cells undergo metabolic rewiring predominantly by accentuating glucose uptake through hypoxia-driven enhanced expression of glycolytic enzymes. 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is one of the hypoxia response glycolytic enzyme which primarily balances the glucose flux between glycolysis and pentose phosphate pathway. However, the necessity to increase PFKFB4 expression under hypoxia is poorly understood. Here, we show that PFKFB4 dependent adaptation in hypoxia promotes a tumor-intrinsic genetic alteration acquiring invasive phenotype in breast cancer. Specifically, we found that CRISPR-Cas9 PFKFB4-knock-out (KO) breast cancer cells were defective in migration under normoxic condition (21% O2) compared to wild-type (WT) cells; while this migratory defect was found more severe under hypoxic stress (1% O2). To elucidate the mechanisms of PFKFB4-driven migration, we performed RNA-sequencing which revealed that PFKFB4 induces expression of focal adhesion pathway genes including ITGB3 (integrin β3), which are essential regulators of migration and invasion. While validating the target genes by qPCR and immunoblotting, we found that a great number of focal adhesion target genes were hypoxia-response genes including ITGB3, as their expression was significantly enhanced in hypoxia, which was completely abrogated in the absence of PFKFB4. Rescuing ITGB3-expression in PFKFB4-KO cells was sufficient to restore the migratory defects in both normoxic and hypoxic conditions, suggesting that PFKFB4 promotes migration by inducing focal adhesion genes such as ITGB3 expression. Previously we have shown that PFKFB4 directly activates steroid receptor coactivator 3 (SRC-3, also known as NCOA3) so we analyzed promoter occupancy of SRC-3 on the proximal promoter of ITGB3. Our data revealed strong occupancy of SRC-3 on the ITGB3 promoter, which also contains a canonical hypoxia response element (HRE), suggesting that PFKFB4/SRC-3 signaling axis may stimulate HIF-1A transcriptional response. By further elucidating the roles of PFKFB4/SRC-3/HIF-1A axis in hypoxia in breast tumor mouse models, we will demonstrate how metabolic and transcriptional adaptations in the TME stimulates breast cancer progression and metastasis. Citation Format: Tao Dai, Aaron Novickis, Eriko Katsuta, Kazuaki Takabe, Scott I. Abrams, Subhamoy Dasgupta. Metabolic and transcriptional adaptations under hypoxic stress promote breast cancer progression [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO022.
Abstract IA012: Engineering precision cancer immunotherapy
Authors: Michel DuPage
Journal: Cancer Research (2021)

Abstract The treatment of cancer has been revolutionized by the development of immune-based therapies designed to boost the number and function of cytotoxic T cells that kill tumor cells. However, it is already apparent that this strategy alone will not benefit all patients, as the majority of cancers generate a highly immunosuppressive tumor microenvironment (TME) that shuts down even the most potent T cells. Furthermore, as a consequence of ramping up the immune system, these immune stimulating drugs instigate significant autoimmune toxicity. We aim to develop a radical new strategy to circumvent both challenges by identifying immunosuppressive regulatory mechanisms unique to cancerous tissues, thereby uncovering pathways active only in tumors that can be targeted to generate precision cancer immunotherapies that preserve immune tolerance in healthy tissues. The focus will be on Regulatory T cells (Tregs), a subset of immunosuppressive CD4+T cells that lie at the fulcrum of immunity, directing cells of the immune system to go or stop. In cancer, Tregsinfiltrate tumors and dampen anti-tumor immune responses, but Tregs also play an essential role in preventing autoimmunity. This proposal will test the hypothesis that human cancers generate an immunosuppressive TME by enforcing a unique epigenetic program in intratumoral Tregsthat, if identified, could provide new targets to selectively modulate tumor-infiltrating Tregsand limit autoimmunity. To do this, the research will employ genetically engineered mouse (GEM) cancers, an accurate and flexible platform to test the full complement of factors that make up the TME of human cancers, combined with sophisticated genetic tools to track Treg entry and activity in the TME. Our investigations thus far have led us to the investigation of Ezh2 activity, a H3K27 methyltransferase, in defining Treg behavior selectively in the TME. Citation Format: Michel DuPage. Engineering precision cancer immunotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA012.
Pediatric Clinical Classification System for Use in Inpatient Settings
Authors: Peter J. Gill, Mohammed Rashidul Anwar, Thaksha Thavam, Matt Hall, Jonathan Rodean, Sanjay Mahant
Journal: JAMA Pediatrics (2021)

This cross-sectional study assesses the specificity of the Pediatric Clinical Classification System and Healthcare Cost and Utilization Project diagnosis categories for clinical classification in pediatric inpatient settings.
A dysfunctional TRPV4–GSK3β pathway prevents osteoarthritic chondrocytes from sensing changes in extracellular matrix viscoelasticity
Authors: Pranay Agarwal, Hong-pyo Lee, Piera Smeriglio, Fiorella Grandi, Stuart Goodman, Ovijit Chaudhuri, Nidhi Bhutani
Journal: Nature Biomedical Engineering (2021)
Peri‐implantitis is not periodontitis: Scientific discoveries shed light on microbiome‐biomaterial interactions that may determine disease phenotype
Authors: Georgios A. Kotsakis, Daniel G. Olmedo
Journal: Periodontology 2000 (2021)

Abstract Peri‐implantitis is an immune‐mediated biological complication that is attributed to bacterial biofilms on the implant surface. As both periodontitis and peri‐implantitis have similar inflammatory phenotypes when assessed cross‐sectionally, treatment protocols for peri‐implantitis were modeled according to those used for periodontitis. However, lack of efficacy of antimicrobial treatments targeting periodontal pathogens coupled with recent discoveries from open‐ended microbial investigation studies create a heightened need to revisit the pathogenesis of peri‐implantitis compared with that of periodontitis. The tale of biofilm formation on intraoral solid surfaces begins with pellicle formation, which supports initial bacterial adhesion. The differences between implant‐ and tooth‐bound biofilms appear as early as bacterial adhesion commences. The electrostatic forces and ionic bonding that drive initial bacterial adhesion are fundamentally different in the presence of titanium dioxide or other implant alloys vs mineralized organic hydroxyapatite, respectively. Moreover, the interaction between metal surfaces and the oral environment leads to the release of implant degradation products into the peri‐implant sulcus, which exposes the microbiota to increased environmental stress and may alter immune responses to bacteria. Clinically, biofilms found in peri‐implantitis are resistant to beta‐lactam antibiotics, which are effective against periodontal communities even as monotherapies and demonstrate a composition different from that of biofilms found in periodontitis; these facts strongly suggest that a new model of peri‐implant infection is required.
Spermatogonium-Derived Complete Hydatidiform Mole
Authors: Hirokazu Usui, Makio Shozu
Journal: New England Journal of Medicine (2021)

A complete hydatidiform mole (CHM) is a conceptus with only sperm-derived chromosomes. Here, we report on a CHM with genomic DNA identical to that of the paternal somatic cells. The CHM developed in a woman who had undergone intrauterine implantation of a blastocyst obtained through in vitro injection of a presumed round spermatid into one of her oocytes. The CHM was genetically identical to peripheral white cells of her husband and contained no maternally derived nuclear DNA. We hypothesize that a spermatogonium, rather than a round spermatid, was inadvertently selected for the procedure. The CHM developed into a gestational trophoblastic neoplasia, which resolved after chemotherapy. (Funded by the Japan Society for the Promotion of Science.).