tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of 2 Fingolimod Doses vs Glatiramer Acetate for the Treatment of Patients With Relapsing-Remitting Multiple Sclerosis
Authors: Bruce A. C. Cree, Myla D. Goldman, John R. Corboy, Barry A. Singer, Edward J. Fox, Douglas L. Arnold, Corey Ford, Bianca Weinstock-Guttman, Amit Bar-Or, Susanne Mientus, Daniel Sienkiewicz, Ying Zhang, Rajesh Karan, Nadia Tenenbaum
Journal: JAMA Neurology (2020)

Doses of fingolimod lower than 0.5 mg per day were not investigated during the fingolimod clinical development program. Whether lower doses of fingolimod might retain efficacy with fewer safety risks remains unknown.
Association of Habitual Physical Activity With Cardiovascular Disease Risk
Authors: Honghuang Lin, Mayank Sardana, Yuankai Zhang, Chunyu Liu, Ludovic Trinquart, Emelia J. Benjamin, Emily S. Manders, Kelsey Fusco, Jelena Kornej, Michael M. Hammond, Nicole L. Spartano, Chathurangi H. Pathiravasan, Vik Kheterpal, Chris Nowak, Belinda Borrelli, Joanne M. Murabito, David D. McManus
Journal: Circulation Research (2020)

Rationale: A sedentary lifestyle is associated with increased risk for cardiovascular disease (CVD). Smartwatches enable accurate daily activity monitoring for physical activity measurement and intervention. Few studies, however, have examined physical activity measures from smartwatches in relation to traditional risk factors associated with future risk for CVD. Objective: To investigate the association of habitual physical activity measured by smartwatch with predicted CVD risk in adults. Methods and Results: We enrolled consenting FHS (Framingham Heart Study) participants in an ongoing eFHS (electronic Framingham Heart Study) at the time of their FHS research center examination. We provided participants with a smartwatch (Apple Watch Series 0) and instructed them to wear it daily, which measured their habitual physical activity as the average daily step count. We estimated the 10-year predicted risk of CVD using the American College of Cardiology/American Heart Association 2013 pooled cohort risk equation. We estimated the association between physical activity and predicted risk of CVD using linear mixed effects models adjusting for age, sex, wear time, and familial structure. Our study included 903 eFHS participants (mean age 53±9 years, 61% women, 9% non-White) who wore the smartwatch ≥5 hours per day for ≥30 days. Median daily step count was similar among men (7202 with interquartile range 3619) and women (7260 with interquartile range 3068; P =0.52). Average 10-year predicted CVD risk was 4.5% (interquartile range, 6.1%) for men and 1.2% (interquartile range, 2.2%) for women ( P =1.3×10 −26 ). Every 1000 steps higher habitual physical activity was associated with 0.18% lower predicted CVD risk ( P =3.2×10 −4 ). The association was attenuated but remained significant after further adjustment for body mass index ( P =0.01). Conclusions: In this community-based sample of adults, higher daily physical activity measured by a study smartwatch was associated with lower predicted risk of CVD. Future research should examine the longitudinal association of prospectively measured daily activity and incident CVD.
Anticancer effects of polyadenylic-polyuridylic acid (poly[A:U]) and uncoupling of chemokine receptor signaling: Role of CCR5 and CXCR3
Authors: R. Conforti, Y. Ma, Y. Morel, C. Paturel, M. Terme, S. Viaud, N. Chaput, F. Andre, G. Kroemer, L. Zitvogel
Journal: Journal of Clinical Oncology (2009)

3063 Background: Several tumor cells express toll-like receptors (TLRs) which constitute putative therapeutic targets. Methods: To dissect the clinical outcome of the host versus cell autonomous effects of the TLR3 agonist poly(A:U), we took advantage of two murine TLR3 expressing tumor models (melanoma and glioblastoma) that produced large amounts of CCL5 (a CCR5 ligand) and CXCL10 (a CXCR3 ligand) in response to the poly(A:U) and type I IFN in vitro and in vivo. We tested in vivo a triple combination based on vaccine against tumor antigens (V), chemotherapy (C), and TLR3 agonist (poly[A:U]) (T). Results: Single agents (V, C, or T) and combinations of two agents (VC, VT, or CT) failed to improve tumor progression. However, the sequential tritherapy (VCT) significantly retarded tumor growth and prolonged the survival of tumor-bearing C57BL/6 mice. The antitumor effects of VCT (immunochemotherapy) failed to be observed in nu/nu and TRIF -/- mice, indicating the contribution of T cells and TRIF-dependent signals to the therapeutic effect. Knockout of CCR5 improved the efficacy of immunochemotherapy. The VCT combination induced the recruitment of IFNγ + /CD8 +/ CXCR3 + T lymphocytes supporting the notion that this subset of T cells contributes to the antitumor efficacy of immunochemotherapy. Knockout of the CXCR3 gene annihilated the beneficial effects of VCT. The source of the deleterious CCL5 was the TLR3-activated tumor cells in that stable inhibition of the chemokine production by targeted shRNA CCL5 ameliorated the efficacy of VCT tritherapy. Altogether, 11% of wild-type mice were completely protected from melanoma by VCT sequential regimen. Conclusions: This study supports the notion that poly(A:U) can act on tumor epithelia to promote the release of beneficial CXCL10 for the recruitment of intratumoral CTLs but also the release of deleterious CCL5 acting on host immunosuppressors. Uncoupling chemokine release and/or prior vaccination may enable the CXCR3L-dependent CTL to overrule the CCR5-dependent suppression and may be integrated in future trials using TLR3 agonists. [Table: see text]
Photopenic Defects in Gliomas With Amino-Acid PET and Relative Prognostic Value
Authors: Timothée Zaragori, Angelo Castello, Eric Guedj, Antoine Girard, Norbert Galldiks, Nathalie L. Albert, Egesta Lopci, Antoine Verger
Journal: Clinical Nuclear Medicine (2020)

Abstract The aim is to explore the concept of photopenic defects in newly diagnosed glioma patients with the 2 widely used 11 C-MET and 18 F-FDOPA PET amino acid tracers. Thirty-two 11 C-MET and 26 18 F-FDOPA PET scans with amino acid PET-negative gliomas were selected in this European multicentric study. Of these gliomas, 16 11 C-MET and 10 18 F-FDOPA PET scans with photopenic defects were identified, exhibiting lower mean tumor-to-background ratio as compared with isometabolic gliomas ( P &lt; 0.001). Gliomas with photopenic defects had no different progression-free survival than isometabolic gliomas in the whole population ( P = 0.40), but shorter progression-free survival in the subgroup of World Health Organization grade II IDH-mutant astrocytomas (35 vs 68 months; P = 0.047).
Abstract 6414: Using 3D models to test the efficacy of targeting cancer-associated fibroblast exosomes to overcome chemoresistance in pancreatic cancer
Authors: Chae Young Eun, Charlene DeKalb, Weikun Xiao, Xinyu Zhang, Reginald Hill
Journal: Cancer Research (2020)

Abstract Exosomes play a critical role in promoting proliferation and survival of cancer cells. These extracellular vesicles that range in size from 30-100nm in diameter are released by many different cell types and contain proteins, nucleic acids, and micro RNAs that can modify the content and state of recipient cells. Our previous studies have shown that cancer-associated fibroblasts (CAFs), which make up the bulk of pancreatic ductal adenocarcinoma (PDAC) tumors, hypersecrete exosomes upon chemotherapy treatment. When these exosomes were taken up by surrounding cancer cells, we observed more cell proliferation and drug resistance. Considering these findings, there is clearly a need of therapeutic strategies that target exosome biogenesis and secretion. Here, we investigate the effectiveness of several compounds, including farnesyl transferase inhibitors, imidazoles, and nonsteroidal anti-inflammatory drugs (NSAIDs), in blocking exosome secretion and suppressing chemoresistance in PDAC CAF and cancer cell lines. We observed decrease in exosome secretion upon ketoconazole, tipifarnib, and neticonazole treatment, using GW4869 (a neutral sphingomyelinase inhibitor) as our control. Furthermore, we established a 3D organoid model from our PDAC mouse models to better understand the impact of these drugs on exosome secretion in tumors with different genetic alterations. Together, our 2D and 3D models illuminate the potential for pharmacological targeting of exosome secretion as a treatment option that can improve the current standard-of-care treatment in PDAC. Citation Format: Chae Young Eun, Charlene DeKalb, Weikun Xiao, Xinyu Zhang, Reginald Hill. Using 3D models to test the efficacy of targeting cancer-associated fibroblast exosomes to overcome chemoresistance in pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6414.
Structural Optimization and Enhanced Prodrug-Mediated Delivery Overcomes Camptothecin Resistance in High-Risk Solid Tumors
Authors: Ferro Nguyen, Peng Guan, David T. Guerrero, Venkatadri Kolla, Koumudi Naraparaju, Lauren M. Perry, Danielle Soberman, Benjamin B. Pressly, Ivan S. Alferiev, Michael Chorny, Garrett M. Brodeur
Journal: Cancer Research (2020)

Camptothecins are potent topoisomerase I inhibitors used to treat high-risk pediatric solid tumors, but they often show poor efficacy due to intrinsic or acquired chemoresistance. Here, we developed a multivalent, polymer-based prodrug of a structurally optimized camptothecin (SN22) designed to overcome key chemoresistance mechanisms. The ability of SN22 vs. SN38 (the active form of irinotecan/CPT-11) to overcome efflux pump-driven drug resistance was tested. Tumor uptake and biodistribution of SN22 as a polymer-based prodrug (PEG-[SN22]4) compared with SN38 was determined. The therapeutic efficacy of PEG-[SN22]4 to CPT-11 was compared in: (i) spontaneous neuroblastomas (NB) in transgenic TH-MYCN mice; (ii) orthotopic xenografts of a drug-resistant NB line SK-N-BE(2)C (mutated TP53); (iii) flank xenografts of a drug-resistant NB-PDX; and (iv) xenografts of Ewing sarcoma and rhabdomyosarcoma. Unlike SN38, SN22 inhibited NB cell growth regardless of ABCG2 expression levels. SN22 prodrug delivery resulted in sustained intratumoral drug concentrations, dramatically higher than those of SN38 at all time points. CPT-11/SN38 treatment had only marginal effects on tumors in transgenic mice, but PEG-[SN22]4 treatment caused complete tumor regression lasting over 6 months (tumor free at necropsy). PEG-[SN22]4 also markedly extended survival of mice with drug-resistant, orthotopic NB and it caused long-term (6+ months) remissions in 80% to 100% of NB and sarcoma xenografts. SN22 administered as a multivalent polymeric prodrug resulted in increased and protracted tumor drug exposure compared with CPT-11, leading to long-term "cures" in NB models of intrinsic or acquired drug resistance, and models of high-risk sarcomas, warranting its further development for clinical trials. SIGNIFICANCE: SN22 is an effective and curative multivalent macromolecular agent in multiple solid tumor mouse models, overcoming common mechanisms of drug resistance with the potential to elicit fewer toxicities than most cancer therapeutics.
Correlation of FcγR IIa-H131R and IIIa-V158F polymorphisms and clinical outcome of trastuzumab in both neoadjuvant and metastatic setting in patients with HER-2 positive breast cancer
Authors: K. Tamura, C. Shimizu, F. Koizumi, T. Kouno, N. Katsumata, T. Kinoshita, K. Aogi, K. Nishio, M. Ando, Y. Fujiwara
Journal: Journal of Clinical Oncology (2009)

1100 Background: The antibody dependent cell mediated cytotoxicity (ADCC) affects an efficacy of Immunoglobulin G1 antibody, including trastuzumab which is a humanized anti-HER-2 monoclonal antibody, through fragment C receptor (FcγR) polymorphisms. One report suggested that allotype of two kinds of FcγR single nucleotide polymorphisms (SNPs) are associated with clinical outcome of patients (pts) with metastatic breast cancer (BC) who received combination trastuzumab with taxane. Ethnic difference was reported in frequency of these SNPs between Western and Asian pts. The objective of this prospective study was to evaluate whether these SNPs are associated with pathological complete response (pCR) in neoadjuvant (N) setting with pts who received trastuzumab based chemotherapy, and objective response (OR) in metastatic (M) setting in pts who received single trastuzumab. Methods: Eligible criteria include HER-2 positive BC, chemotherapy-naïve, measurable disease, PS 0–2 and adequate organ functions. Pts in N setting received standard FEC (5-fluorouracil/epirubicin/cyclophosphamide q3w for 4cycles followed by weekly paclitaxel/trastuzumab for 12 weeks. Pts in M setting received single trastuzumab q1w until progression. 384 SNPs of different FcγR loci were assessed from genomic DNA extracted from peripheral blood by GOLDEGATE beads array (illumina Co.). Results: Nineteen operable and 36 metastatic HER-2 positive BC pts have been enrolled in each N and M setting, respectively. pCR in N setting was 26.3%, and OR in M setting was 22.2%. The frequencies of FcγRIIa131 genotypes were H/H 43%, H/R 49%, R/R 8%, and that of FcγRIIIa158 were V/V 43%, V/F 47%, F/F 10%, respectively. 131H/H genotype was significantly correlated with pCR (p = 0.0034) and OR (p = 0.037). 158V/V genotype had a tendency to be correlated with pCR (p = 0.067) and was significantly correlated with OR (p = 0.037). The median PFS was 8.9 months for pts with 131H/H and 3.8 months for R carriers (H/R or R/R). Conclusions: Our data for the first time suggest that these two SNPs predict pCR to trastuzumab based chemotherapy in N setting, and OR to single trastuzumab in M setting. No significant financial relationships to disclose.
The Inherent Unfairness of COVID-19 Drug Access Pathways
Authors: Kayte Spector-Bagdady, Misty Gravelin, Kevin J. Weatherwax, Andrew G. Shuman
Journal: The American Journal of Bioethics (2020)

Click to increase image sizeClick to decrease image sizeThis article refers to:Ethically Allocating COVID-19 Drugs Via Pre-approval Access and Emergency Use Authorization Additional informationFundingThis work was funded in part by the National Center for Advancing Translational Sciences [1U01TR002488-01] (AGS, KJW, MG) and [UL1TR002240] (KSB, KJW, MG) as well as the Center for Bioethics and Social Sciences in Medicine of the University of Michigan (KSB, AGS).
Incidence Trends and Burden of Human Papillomavirus-Associated Cancers Among Women in the United States, 2001-2017
Authors: Ashish A Deshmukh, Ryan Suk, Meredith S Shiels, Haluk Damgacioglu, Yueh-Yun Lin, Elizabeth A Stier, Alan G Nyitray, Elizabeth Y Chiao, Gizem S Nemutlu, Jagpreet Chhatwal, Kathleen Schmeler, Keith Sigel, Kalyani Sonawane
Journal: JNCI Journal of the National Cancer Institute (2020)

Human papillomavirus (HPV)-associated anal and oropharyngeal cancer incidence has increased in recent years among US women. However, trends in incidence and burden (annual number of cases) of noncervical HPV-associated cancers relative to cervical cancer remain unclear. Using the 2001-2017 US cancer statistics dataset, we evaluated contemporary incidence trends and burden (annual number of cases) of HPV-associated cancers among women by anatomic site, race or ethnicity, and age. Overall, cervical cancer incidence plateaued among White women but continued to decline among Black and Hispanic women. Anal cancer incidence surpassed cervical cancer incidence among White women aged 65-74 years of age (8.6 and 8.2 per 100 000 in 2015) and 75 years or older (6.2 and 6.0 per 100 000 in 2014). The noncervical cancer burden (n = 11 871) surpassed the cervical cancer burden (n = 11 527) in 2013. Development of efficacious screening strategies for noncervical cancers and continued improvement in cervical cancer prevention are needed to combat HPV-associated cancers among women.
Guillain-Barré syndrome after adoptive cell therapy with tumor-infiltrating lymphocytes
Authors: Angela Orcurto, Andreas Hottinger, Benita Wolf, Blanca Navarro Rodrigo, Maria Ochoa de Olza, Aymeric Auger, Thierry Kuntzer, Denis Comte, Virginie Zimmer, Philippe Gannon, Lana Kandalaft, Olivier Michielin, Stefan Zimmermann, Alexandre Harari, Lionel Trueb, George Coukos
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is a promising experimental immunotherapy that has shown high objective responses in patients with melanoma. Current protocols use a lymphodepletive chemotherapy before infusion of ex vivo expanded TILs, followed by high-dose interleukin-2 (IL-2). Treatment-related toxicities are mainly attributable to the chemotherapy regimen and to the high-dose IL-2 and are generally reversible. Neurological side effects have rarely been described. Nevertheless, due to improvements in cell production techniques and due to combinations with other immunomodulating molecules, side effects not previously described may be encountered. Case presentation We report the case of a 53-year-old heavily pretreated patient with melanoma who developed Guillain-Barré syndrome (GBS) 19 days after ACT using autologous TILs, given in the context of a phase I trial. He presented with dorsal back pain, unsteady gait and numbness in hands and feet. Lumbar puncture showed albuminocytological dissociation, and nerve conduction studies revealed prolonged distal motor latencies in median, ulnar, tibial and peroneal nerves, compatible with a GBS. The patient was treated with intravenous immunoglobulins and intensive neurological rehabilitation, with progressive and full recovery at 21 months post-TIL-ACT. Concomitant to the onset of GBS, a cytomegalovirus reactivation on immunosuppression was detected and considered as the most plausible cause of this neurological side effect. Conclusion We describe for the first time a case of GBS occurring shortly after TIL-ACT for melanoma, even though we could not identify with certainty the triggering agent. The report of such rare cases is of extreme importance to build on the knowledge of immune cellular therapies and their specific spectrum of toxicities.
Efficacy of Rituximab and Plasma Exchange in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis with Severe Kidney Disease
Authors: Marta Casal Moura, Maria V. Irazabal, Alfonso Eirin, Ladan Zand, Sanjeev Sethi, Bijan J. Borah, Jeffrey L. Winters, James P. Moriarty, Rodrigo Cartin-Ceba, Alvise Berti, Misbah Baqir, Gwen E. Thompson, Ashima Makol, Kenneth J. Warrington, Viengneesee Thao, Ulrich Specks, Fernando C. Fervenza
Journal: Journal of the American Society of Nephrology (2020)

Treatment of patients with ANCA-associated vasculitis (AAV) and severe renal involvement is not established. We describe outcomes in response to rituximab (RTX) versus cyclophosphamide (CYC) and plasma exchange (PLEX).A retrospective cohort study of MPO- or PR3-ANCA-positive patients with AAV (MPA and GPA) and severe kidney disease (eGFR <30 ml/min per 1.73 m2). Remission, relapse, ESKD and death after remission-induction with CYC or RTX, with or without the use of PLEX, were compared.Of 467 patients with active renal involvement, 251 had severe kidney disease. Patients received CYC (n=161) or RTX (n=64) for remission-induction, and 51 were also treated with PLEX. Predictors for ESKD and/or death at 18 months were eGFR <15 ml/min per 1.73 m2 at diagnosis (IRR 3.09 [95% CI 1.49 to 6.40], P=0.002), renal recovery (IRR 0.27 [95% CI 0.12 to 0.64], P=0.003) and renal remission at 6 months (IRR 0.40 [95% CI 0.18 to 0.90], P=0.027). RTX was comparable to CYC in remission-induction (BVAS/WG=0) at 6 months (IRR 1.37 [95% CI 0.91 to 2.08], P=0.132). Addition of PLEX showed no benefit on remission-induction at 6 months (IRR 0.73 [95% CI 0.44 to 1.22], P=0.230), the rate of ESKD and/or death at 18 months (IRR 1.05 [95% CI 0.51 to 2.18], P=0.891), progression to ESKD (IRR 1.06 [95% CI 0.50 to 2.25], P=0.887), and survival at 24 months (IRR 0.54 [95% CI 0.16 to 1.85], P=0.330).The apparent benefits and risks of using CYC or RTX for the treatment of patients with AAV and severe kidney disease are balanced. The addition of PLEX to standard remission-induction therapy showed no benefit in our cohort. A randomized controlled trial is the only satisfactory means to evaluate efficacy of remission-induction treatments in AAV with severe renal involvement.
Radical prostatectomy in clinically localized prostate cancer—The risk of extraprostatic spread by NCCN risk group and its implications for adjuvant therapy: An analysis of 23,988 patients
Authors: D. Schreiber, J. Rineer, M. Olsheski, D. Vongtama, A. Wortham, S. Sura, E. Nwokedi, P. Han, K. Choi, M. Rotman
Journal: Journal of Clinical Oncology (2009)

5125 Background: Swanson et al recently reported an update of SWOG 8794 (ASTRO 2008, oral presentation) revealing a 10% absolute overall survival benefit at 15 years with adjuvant radiation therapy for patients with extraprostatic extension (EPE) or positive margins after radical prostatectomy (RP). In this population based analysis, we analyze and report on the pathologic rates of EPE or positive margins in clinically localized prostate cancer as well as how often these patients have received adjuvant radiation therapy. Methods: The Surveillance, Epidemiology and End Results (SEER) registry was used to identify patients between 2004–2005 with clinically staged T1-T2c prostate cancer who underwent RP. Patients were stratified using NCCN risk groups into low (T1c- T2a, PSA less than 10ng/ml, Gleason 2–6), intermediate (T2b, PSA 10–20ng/ml, Gleason 7), and high (T2c, PSA greater than 20ng/ml, Gleason 8–10). Results: 23,988 patients were identified: 6,314 in the NCCN low risk group (LR), 12,052 in the NCCN intermediate risk group (IR), and 5,622 in the NCCN high risk group (HR). Overall, 68.2% of patients had organ-confined disease with negative margins. However, the risk of EPE or positive margins increased with the NCCN risk group, PSA value, and Gleason score (see table ). Of those who met criteria for adjuvant radiation, 11.9% received the treatment: 4.7% of the LR group, 9.2% of the IR group and 18.9% of the HR group. Conclusions: This is, to our knowledge, the largest reported multi-institutional surgical series of clinically localized prostate cancer. Patients can use this data to be counseled on their risk of requiring adjuvant radiation based on their pre-treatment parameters. This data also reveals that nearly one third of all patients met the indications for adjuvant radiation, but only a small percentage of them received this treatment. [Table: see text] No significant financial relationships to disclose.
The Effect Of Alpha1-Proteinase Inhibitor (a1-Pi) Therapy On Changes In Regional Lung Density: Post-Hoc Analysis Of The Rapid/rapid Extension Trial
Authors: D. Reed, N.G. McElvaney, K.R. Chapman, J. Burdon, N. Seersholm, B. Stoel, M. Wencker, O. Vit, M. Fries, J.M. Edelman, D. Parr
Journal: American Journal of Respiratory and Critical Care Medicine (2017)