tbuckley/cabot-search huggingface dataset:
Multi-institutional analysis of high-risk prostate cancer patients treated with stereotactic body radiotherapy.
Authors: Naomi Y Jiang, Christopher R. King, Alan J. Katz, Sean P. Collins, Nima Aghdam, Simeng Suy, Kevin L. Stephans, Chandana A. Reddy, Irving D. Kaplan, Limor Appelbaum, Audrey Dang, Ye Yuan, Nicholas George Nickols, Michael L. Steinberg, Patrick Kupelian, Amar Upadhyaya Kishan
Journal: Journal of Clinical Oncology (2019)

51 Background: Stereotactic Body Radiotherapy (SBRT) delivers ablative doses of radiation (RT) over a course of five treatments and has been increasingly used as a definitive RT option for low- and intermediate-risk prostate cancer (PCa). Ongoing prospective trials are evaluating the efficacy of SBRT for high-risk PCa, but clinical outcomes reports are limited. Methods: Patients treated for high-risk PCa between 2006-2017 at any of five institutions were included. SBRT doses ranged from 35-40 Gy in 5 fractions per institutional standards, with one institution using an integrated boost approach. The Phoenix definition was used to define biochemical failure (BCR). Physician-reported genitourinary (GU) and gastrointestinal (GI) toxicity outcomes were scored using the Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events systems. Results: In total, 182 patients were included in this study with a median follow-up time of 38.4 months (mos). The median age was 72. Most patients (72%) had Gleason 8-10 disease. Sixty-eight percent of patients received androgen deprivation therapy (ADT) for a median of 9 mos (interquartile range 6-9 mos). The rate of distant metastases was 3.8%. There were no acute Grade 3 (G3) or higher GU or GI toxicities. Three patients (1.6%) experienced a late G3 GU toxicity and one patient (0.5%) experienced a late G3 GI toxicity. The incidence of BCR was significantly higher in patients who did not receive ADT (30% vs. 15%, p = 0.02 by Chi-square). Conclusions: In this multi-institutional study, SBRT demonstrated an acceptable safety profile for the treatment of high-risk PCa. Longer term follow-up is necessary to evaluate the oncologic efficacy of this approach, but given the potentially higher incidence of BCR without ADT, ADT likely has an important oncologic role even with SBRT regimens.
High Dose Mitoxantrone Based "5+1" Induction Chemotherapy Regimen in Newly Diagnosed Acute Myeloid Leukemia
Authors: Neeraj Y Saini, Jan Cerny, Vanessa Furtado, Angela Desmond, Zheng Zhou, Glen D. Raffel, Imran Puthawala, Jayde Bednarik, Lindsey Shanahan, Patricia Minehart Miron, Bruce Woda, Muthalagu Ramanathan, Rajneesh Nath
Journal: Blood (2018)
Matrine attenuates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway
Authors: Can Hu, Xin Zhang, Wenying Wei, Ning Zhang, Haiming Wu, Zhenguo Ma, Lingli Li, Wei Deng, Qizhu Tang
Journal: Acta Pharmaceutica Sinica B (2019)

Oxidative stress and cardiomyocyte apoptosis are involved in the pathogenesis of doxorubicin (DOX)-induced cardiotoxicity. Matrine is well-known for its powerful anti-oxidant and anti-apoptotic capacities. Our present study aimed to investigate the effect of matrine on DOX-induced cardiotoxicity and try to unearth the underlying mechanisms. Mice were exposed with DOX to generate DOX-induced cardiotoxicity or normal saline as control. H9C2 cells were used to verify the effect of matrine in vitro. DOX injection triggered increased generation of reactive oxygen species (ROS) and excessive cardiomyocyte apoptosis, which were significantly mitigated by matrine. Mechanistically, we found that matrine ameliorated DOX-induced uncoupling protein 2 (UCP2) downregulation, and UCP2 inhibition by genipin could blunt the protective effect of matrine on DOX-induced oxidative stress and cardiomyocyte apoptosis. Besides, 5′-AMP-activated protein kinase α2 (Ampkα2) deficiency inhibited matrine-mediated UCP2 preservation and abolished the beneficial effect of matrine in mice. Besides, we observed that matrine incubation alleviated DOX-induced H9C2 cells apoptosis and oxidative stress level via activating AMPKα/UCP2, which were blunted by either AMPKα or UCP2 inhibition with genetic or pharmacological methods. Matrine attenuated oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity via maintaining AMPKα/UCP2 pathway, and it might be a promising therapeutic agent for the treatment of DOX-induced cardiotoxicity.
Omitted Disclosures of Potential Conflicts of Interest in Articles Published in <i>JAMA Oncology</i>
Authors: Charles S. Fuchs
Journal: JAMA Oncology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Central and Peripheral Determinants of Exercise Capacity in Heart Failure Patients With Preserved Ejection Fraction
Authors: Emil Wolsk, David Kaye, Jan Komtebedde, Sanjiv J. Shah, Barry A. Borlaug, Daniel Burkhoff, Dalane W. Kitzman, Carolyn S.P. Lam, Dirk J. van Veldhuisen, Piotr Ponikowski, Mark C. Petrie, Christian Hassager, Jacob E. Møller, Finn Gustafsson
Journal: JACC Heart Failure (2019)
A 17-Gene Leukemia Stem Cell (LSC) Score in Adult Patients (Pts) with Acute Myeloid Leukemia (AML) Reveals a Distinct Mutational Landscape and Refines Current European Leukemianet (ELN) Genetic Risk Stratification
Authors: Marius Bill, Deedra Nicolet, Ann-Kathrin Eisfeld, Krzysztof Mrózek, Christopher J. Walker, Jessica Kohlschmidt, Dimitrios Papaioannou, Jonathan E. Kolitz, Bayard L. Powell, John C. Byrd, Ramiro Garzon, Clara D. Bloomfield
Journal: Blood (2018)
Abstract 374: FGF2 Isoform-selective as well as Non-selective Signals Protect Cardiomyocytes from Doxorubicin-induced Cell Death
Authors: Navid Koleini, Barbara E Nickel, Robert R Fandrich, Lorrie A Kirshenbaum, Peter A Cattini, Elissavet Kardami
Journal: Circulation Research (2016)

Introduction: Doxorubicin (DOX) induced cardiotoxicity, including cardiomyocyte cell death, remains a major challenge for anticancer therapies. DOX can disrupt the balance between synthesis and degradation systems by affecting major cellular signaling pathways including the mammalian target of Rapamycin (mTOR), and AMP-activated kinase (AMPK). Fibroblast Growth Factor 2 (FGF2), a multifunctional protein expressed by heart cells and downregulated by DOX, consists of two types of isoforms, low molecular weight, Lo-FGF2, (~18 kDa) and high molecular weight, Hi-FGF2, (&gt;20 kDa), displaying isoform-selective and non-selective properties. We have studied the effects of added FGF2 isoforms on DOX induced dysregulation of signaling pathways impacting on cardiomyocyte survival and autophagy. Methods and Results: Primary cultures of neonatal rat cardiomyocytes were subjected to 0.5 μM DOX in the absence or presence of pretreatment with FGF2 isoforms, at 10 ng/ml. Both Hi- and Lo- FGF2 decreased DOX-induced injury and cell death, measured by LDH release, a Live-Dead assay, and activation of caspase 3. Neither isoform prevented the DOX-induced cell death in MCF7 cells, a breast cancer cell line. In myocytes, both isoforms prevented the DOX-induced downregulation of mTORC1 activity (phospho-Ser2448). The mTOR inhibitor Rapamycin prevented the beneficial effects of FGF2. Hi-FGF2, but not Lo-FGF2, significantly increased AMPK activity (phospho-Thr172) pre- and post-DOX. Compound C, an inhibitor of AMPK, prevented the protective effect of Hi- , but not Lo-, FGF2. To assess autophagy, cardiomyocytes were transduced with an adenoviral vector for GFP-LC3. Numbers of GFP-LC3 aggregates (dots) per cell were measured, and suggested that both Hi- and Lo-FGF2 prevented the DOX-induced increases in autophagy and autophagy flux, as also indicated by increased levels of p62 post-DOX in the presence of FGF2. Pharmacological inhibition of autophagy by 3-Methyladenine was protective against DOX. Conclusions: FGF2 isoforms protect cardiomyocytes against acute DOX damage, by activating mTORC1 (both Hi or Lo FGF2), as well as, in the case of Hi-FGF2, the AMPK pathway. Protection by FGF2 isoforms was associated with prevention of accelerated flux.
A study into the pharmacodynamic biomarker effects of olaparib (PARP Inhibitor) ± degarelix (GnRH antagonist) given prior to radical prostatectomy (RP) CANCAP03.
Authors: Simon Pacey, Mark David Linch, Howard Kynaston, Anne Warren, Alex Freeman, Ruth Tysoe, Greg Shaw, Krishna Narahari, Satish Kumar, Henno Martin, Bihani Kularatne, Vincent Gnanapragasam, Barry Davies, Josephine Khan, Ola Bratt, Harveer Dev, Charles Massie, Nimish Shah
Journal: Journal of Clinical Oncology (2019)

35 Background: Novel agents given prior to RP allows the study of drug effect(s) in primary human prostate cancer (PC), supporting future clinical study development. Pre-clinical and clinical data (mostly in setting of castration resistant PC) support PARP ± androgen inhibition as therapy for some patients (pt). We undertook a study of olaparib (O) ± degarelix (D) prior to RP. Methods: 20 evaluable (pre and post RP tissue available with 86% dose compliance) pt randomised 1:1 to O or O+D. Primary endpoint: measure PARP inhibition by IHC. Secondary endpoints were feasibility, safety, tolerability. Exploratory objectives: changes PSA, circulating tumour DNA &amp; intra-tumoral immune cells. Men, due for RP, with high volume or aggressive PC, consented and were treated with O (300mg bd) 15 days ± D (240mg once), prior to RP. Diagnostic biopsy and RP tissue were collected. Adverse events (AE) were graded according to CTCAE v4 and followed up to resolution or 6-weeks post RP. Results: 24 men recruited, 4 not evaluable (opted radiotherapy, surgery date altered, not by AE). Interim results are presented of available data. Conclusions: 2 weeks of O (± D) can be given prior to RP with acceptable safety profile. Exploratory analyses of tumour tissue are ongoing however, preliminary data confirm PSA drop noted for pt on both regimens. While expected for O+D this is the first report of PSA changes following a short course of single agent PARPi (O) in pt with local/ hormone sensitive PC. Clinical trial information: NCT02324998. [Table: see text]
Review: In adults with chest pain, a HEART score ≥ 4 has 96% sensitivity and 45% specificity for predicting MACE
Authors: Benton R. Hunter, Jonathan M. Kirschner
Journal: Annals of Internal Medicine (2019)

Source Citation Fernando SM, Tran A, Cheng W, et al. Prognostic accuracy of the HEART score for prediction of major adverse cardiac events in patients presenting with chest pain: a systematic review and meta-analysis. Acad Emerg Med. 2019;26:140-51. 30375097
Resolving inflammation in nonalcoholic steatohepatitis
Authors: Matthew Spite
Journal: Journal of Clinical Investigation (2019)

Chronic unresolved inflammation contributes to the development of nonalcoholic steatohepatitis (NASH), a disorder characterized by lipotoxicity, fibrosis, and progressive liver dysfunction. In this issue of the JCI, Han et al. report that maresin 1 (MaR1), a proresolving lipid mediator, mitigates NASH by reprograming macrophages to an antiinflammatory phenotype. Mechanistically, they identified retinoic acid-related orphan receptor α (RORα) as both a target and autocrine regulator of MaR1 production. Because NASH is associated with many widely occurring metabolic diseases, including obesity and type 2 diabetes, identification of this endogenous protective pathway could have broad therapeutic implications.
Interleukin-17A blockade reduces albuminuria and kidney injury in an accelerated model of diabetic nephropathy
Authors: Carolina Lavoz, Yenniffer Sánchez Matus, Macarena Orejudo, J. Daniel Carpio, Alejandra Droguett, Jesús Egido, Sergio Mezzano, Marta Ruiz-Ortega
Journal: Kidney International (2019)

Diabetic nephropathy (DN) is one of the most common complications of diabetes, and currently the first end-stage renal disease worldwide. New strategies to treat DN using agents that target inflammatory pathways have attracted special interest. Recent pieces of evidences suggest a promising effect of IL-17A, the Th17 effector cytokine. Among experimental DN models, mouse strain BTBR ob/ob (leptin deficiency mutation) develops histological features similar to human DN, which means an opportunity to study mechanisms and novel therapies aimed at DN regression. We found that BTBR ob/ob mice presented renal activation of the factors controlling Th17 differentiation. The presence of IL-17A-expressing cells, mainly CD4+ and γδ lymphocytes, was associated with upregulation of proinflammatory factors, macrophage infiltration and the beginning of renal damage. To study IL-17A involvement in experimental DN pathogenesis, treatment with an IL-17A neutralizing antibody was carried out starting when the renal damage had already appeared. IL-17A blockade ameliorated renal dysfunction and disease progression in BTBR ob/ob mice. These beneficial effects correlated to podocyte number restoration and inhibition of NF-κB/proinflammatory factors linked to a decrease in renal inflammatory-cell infiltration. These data demonstrate that IL-17A takes part in diabetes-mediated renal damage and could be a promising therapeutic target to improve DN.Graphical abstract
A phase II and biomarker study of cabozantinib (XL-184) in patients (pts) with advanced cholangiocarcinoma (CCA).
Authors: Lipika Goyal, Hui Zheng, Matthew Yurgelun, Thomas Adam Abrams, Eunice Lee Kwak, James M. Cleary, Michelle Knowles, Eileen Regan, Amy Gisondi, Susan Sheehan, Anna Khachatryan, Valentina Nardi, Darrell R. Borger, Gabriel Dan Duda, Andrew X. Zhu
Journal: Journal of Clinical Oncology (2015)

e15124 Background: Advanced CCA carries a poor prognosis, and no standard treatment exists beyond the first line gemcitabine/platinum-based regimen. We performed a single arm phase II and biomarker study of cabozantinib, a dual VEGFR and MET inhibitor, in pts with advanced CCA (NCT01954745). Methods: Eligible pts had histologically confirmed unresectable or metastatic CCA and had progressed after 1-2 lines of chemotherapy. Cabozantinib was given at 60 mg orally daily for 28-day cycles. The primary endpoint was PFS. A Simon two stage design was used, and 9 of 20 pts had to be progression free at 16 weeks to proceed to stage 2. MET expression was evaluated by IHC. Plasma biomarkers of angiogenesis were measured at baseline and after 1 and 2 weeks of treatment. Results: The study enrolled 19 pts (male 32%; median age 67yo; intra- vs extrahepatic CCA, 84% vs 16%; 1 vs 2 previous lines of chemotherapy, 53% vs 47%%). After 12 pts failed to be progression free at 16 weeks, the study was terminated as it was determined that the criterion for proceeding to stage 2 could not be met. The median follow-up was 5.2 months (mos). No objective responses were seen. Five patients (24%) had stable disease at 16 weeks. Median PFS was 1.7 mos (95% CI, 1.1-3.8), and median OS was 5.2 mos (95% CI, 2.7-10.5). Grade 3/4 AEs occurred in 89% of pts and included but were not limited to neutropenia, epistaxis, bowel perforation, enterocutaneous fistula in 1 pt (5%) each and hypertension in 2 pts (11%). Plasma VEGF, PlGF and SDF1α increased after 1 and 2 weeks of treatment (all p < 0.01), and plasma sVEGFR2 decreased after 2 weeks (p = 0.0026). MET overexpression (2+ or 3+ by IHC) was seen in 4 of 10 pts evaluated. The pt with the longest disease control (9.2 mos) had 3+ tumor MET expression, but MET overexpression did not correlate with outcome in the 10 patients evaluated. Conclusions: Cabozantinib demonstrated limited efficacy in an unselected population of pts with advanced CCA. Despite close monitoring, a high rate of ≥ grade 3 toxicities was observed at the 60 mg daily dosing. Pharmacodynamic changes in plasma levels of VEGF, PlGF and sVEGFR2 were consistent with anti-VEGFR activity of cabozantinib. A more detailed biomarker analysis will be presented at the meeting. Clinical trial information: NCT01954745.
Treatment utilization trends and outcomes in renal liposarcoma (RLS): A National Cancer Database (NCDB) analysis.
Authors: Midhun Malla, Abhishek Tripathi, Ying Zhang, Sanjay Patel, Vipul Pareek
Journal: Journal of Clinical Oncology (2019)

559 Background: RLS is an extremely rare neoplasm with only few case reports documented in the literature. Due to the rarity of this disease, level 1 evidence guiding optimal patient management is lacking. Utilizing the NCDB, we analyzed the current treatment patterns and outcomes in patients with RLS in the United States. Methods: The NCDB was queried from 2004- 2015 for patients diagnosed with T1-4N0-1M0 RLS. Baseline patient characteristics were summarized using descriptive statistics. Impact of baseline demographic, clinicopathologic variables and treatment on overall survival (OS) was evaluated using univariate (UV) and multivariable (MV) cox proportional hazards analysis. Results: 136 patients diagnosed with non-metastatic RLS between 2004- 2015 were included in this analysis. Median age at diagnosis was 64.7 years. Males and females had equal preponderance (50% each). 89% (n = 121) were Caucasian, while only 6% were African American. T staging was based on AJCC 8th edition. 20% of patients had T1 disease, 17% had T2, while T3 and T4 stage was present in 26% and 37% of cases respectively. Only 7% (n = 10) had lymph node (LN) involvement. Dedifferentiated RLS was the most common histology (44%). 59% (n = 80) had radical nephrectomy, 12% (n = 17) had partial nephrectomy, and 17% had nephrectomy NOS. Adjuvant radiation and chemotherapy were used in 15% (n = 20) and 3.6% (n = 5) of patients respectively. Median OS was 41 months (20-76 mos). On UV analysis age ≤ 70 years and sex had a statistically significant effect on OS (HR: 0.387 and 0.549, p &lt; 0.001 and 0.04 respectively). On MV analysis adjusting for age and sex, female patients had a significantly improved OS compared to males (47 vs 36.7mos, HR-0.45, CI: 0.250-0.804 p &lt; 0.05). Conclusions: RLS is a rare and aggressive malignancy with poor outcomes even at localized stage. Age at diagnosis and sex had a statistically significant impact on OS. Given the lack of prospective data, our study provides insights into the prognosis of this rare disease. Additional studies are needed to better guide the optimal management of this rare disease.
Preliminary results of patients with advanced ovarian carcinoma treated with paclitaxel associated to nanoemulsions.
Authors: Silvia Regina Graziani, Carolina Graziani Vital, Brigitte M. Van Eyll, Aleksandra Tiemi Morikawa, Carlos Elias Fristachi, Marisa Nosralla, Alvaro Peres Neto, Raul Cavalcante Maranhão
Journal: Journal of Clinical Oncology (2015)

e16539 Background: Ovarian cancer is often diagnosed at advanced stages and is poorly responsive. First-line treatment consists in schemes including platin and taxane derivatives and second-line regimens are based in gemcitabine and liposomal doxorubicin. Thereafter, the disease progresses rapidly and chemotherapy is no longer indicated for lack of response together with high toxicity. We showed that non-protein nanoemulsions resembling LDL associated with antineoplastic agents, after injection into the bloodstream, can target neoplastic cells through the internalized by the LDL receptors that are up-regulated in cancer cells, and reduces toxicity. We tested the hypothesis whether paclitaxel associated to the nanoemulsion could be safely benefit patients with advanced ovarian cancer refractory to previous treatments, thus not eligible for further conventional chemotherapy. Methods: Twelve women with advanced ovarian cancer aged 63±9yrs were included, with Stage IV (TNM scale) ovarian carcinomas that were unresponsive for second line chemotherapy treatments. Treatment consisted with paclitaxel associated to the nanoemulsion at 175mg/m2 body surface dose, every 3 weeks. The patients were submitted to clinical examination three days before each chemotherapy cycle. Serum biochemistry determinations and ultrasound imaging were performed at each cycle and CT imaging every 3 cycles. Treatment should be discontinued whenever disease progression or grade 3-4 toxicity would be diagnosed. Results: Total 59 cycles was performed, and in none of them clinical and laboratorial toxicities were observed. In all patients, the quality of life improved (SF36 questionnaire). In none of the patients disease progression occurred < 9 weeks after treatment commencement. The mean time without disease progression was 30 weeks, but two patients were dropped for surgery, without presenting disease progression; they are still alive 2 years after treatment ending. Conclusions: Treatment with paclitaxel-nanoemulsion achieved longer periods of progression-free disease and improved life-quality with non-observable toxicity. Thus, the novel preparation is candidate for future larger clinical studies.
Comparative Risk of Serious Infections With Biologic and/or Immunosuppressive Therapy in Patients With Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis
Authors: Siddharth Singh, Antonio Facciorusso, Parambir S. Dulai, Vipul Jairath, William J. Sandborn
Journal: Clinical Gastroenterology and Hepatology (2019)
cRGD-decorated biodegradable polytyrosine nanoparticles for robust encapsulation and targeted delivery of doxorubicin to colorectal cancer in vivo
Authors: Xiaolei Gu, Yaohua Wei, Qianyi Fan, Huanli Sun, Ru Cheng, Zhiyuan Zhong, Chao Deng
Journal: Journal of Controlled Release (2019)