tbuckley/cabot-search huggingface dataset:
The clinical utility of baseline cardiac assessments prior to adjuvant anthracycline chemotherapy in breast cancer: A systematic review and meta-analysis.
Authors: Pierre O'Brien, Kara Matheson, Alwin S. Jeyakumar, Tallal Younis
Journal: Journal of Clinical Oncology (2018)

e12505 Background: Cardiac assessment with MUGA or echocardiography (ECHO) is commonly employed prior to adjuvant anthracycline-based chemotherapy (AA). However, the clinical utility of routine baseline cardiac assessments prior to AA for early-stage breast cancer (EBC) is unknown. We sought to: i) determine the clinical impact of routine baseline cardiac assessments prior to AA for EBC and ii) identify patients in whom baseline cardiac assessments may not be warranted. Methods: A literature search was performed to identify all relevant observational studies involving pre-AA MUGA and/or ECHO in EBC that met predefined criteria. The primary outcomes were: i) the rates of abnormal baseline left ventricular ejection fraction (LVEF) and ii) the rates of change in chemotherapy decisions following LVEF assessments. Results: 8 studies met our predefined criteria. Six (n = 2,545) reported rates of abnormal LVEF and six (n = 1,713) investigated the impact of baseline LVEF assessment on chemotherapy decisions. Overall, 2.5% (95%CI 2.0-4.0%) of patients had abnormal baseline LVEF and 1.6% (95%CI 1.0-3.0%) had a change in chemotherapy decision. In the 4 studies that examined both outcomes (n = 1,080), 35% (7/20) of the patients with abnormal LVEF assessments had a change in chemotherapy decision accordingly. In subset analyses, the underlying imaging modality (Echo vs MUGA) and inclusion of patients with metastatic disease (Yes vs NO) affected the observed rates of abnormal baseline LVEF (4.4% 95%CI 3.0-6.0 % vs 2.0% 95%CI 1.0-3.0%, and 3.2% 95%CI 2.0-6.0% vs 2.0% 95%CI 1.0-4.0%, respectively) and change in chemotherapy decisions (1.6% 95%CI 1.0-3.0% vs 2.2% 95%CI 1.0-4.0%, and 2.6% 95%CI 1.0-11.0% vs 1.1% 95%CI 0.0-3.0%, respectively). There were no consistently identified underlying predictors of abnormal baseline LVEF across studies. Conclusions: Routine baseline cardiac assessments prior to AA in all EBC patients have low yield and infrequently affect clinical management. Future studies should further examine potential predictors of abnormal cardiac functions in an attempt to identify low risk patients in whom routine baseline LVEF assessment may not be warranted.
The Exposome Paradigm and the Complexities of Environmental Research in Psychiatry
Authors: Sinan Guloksuz, Jim van Os, Bart P. F. Rutten
Journal: JAMA Psychiatry (2018)

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 Psychiatry 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 Psychiatry journal
Long-term Results of Stereotactic Body Radiation Therapy in Medically Inoperable Stage I Non–Small Cell Lung Cancer
Authors: Robert D. Timmerman, Chen Hu, Jeff M. Michalski, Jeffrey C. Bradley, James Galvin, David W. Johnstone, Hak Choy
Journal: JAMA Oncology (2018)

Robert D. Timmerman, MD; Rebecca Paulus, BS; Harvey I. Pass, MD; Elizabeth M. Gore, MD; Martin J. Edelman, MD; James Galvin, DSc; William L. Straube, MS; Lucien A. Nedzi, MD; Ronald C. McGarry, MD, PhD; Cliff G. Robinson, MD; Peter B. Schiff, MD; Garrick Chang, MD; Billy W. Loo Jr, MD; Jeffrey D. Bradley, MD; Hak Choy, MD
Patterns of care and predictors of survival among DCIS patients: An NCDB analysis.
Authors: Justine Broecker, Yuan Liu, Toncred Marya Styblo, Theresa Wicklin Gillespie
Journal: Journal of Clinical Oncology (2018)

e12515 Background: The optimal treatment of ductal carcinoma in situ (DCIS) remains controversial. The aims of this study were to: 1) evaluate patterns of treatment, and 2) identify predictors of survival among patients diagnosed with DCIS. Methods: The National Cancer Database (NCDB) was queried to identify all patients diagnosed with DCIS between 2004-2013. After applying exclusion criteria, Cox proportional hazards and Kaplan-Meier analyses were performed to compare treatment groups and estimate risk of death stratified by demographics, clinical features, and treatment delivered. Propensity-score matching (PSM) was utilized to match three treatment cohorts of interest: lumpectomy alone, lumpectomy with radiation/mastectomy without hormonal therapy (local therapy group), and lumpectomy with radiation/mastectomy with hormonal therapy (systemic therapy group). Results: Among 57,960 patients diagnosed with DCIS who met inclusion criteria, the mean age at diagnosis was 59. Patients who received lumpectomy alone were older, and had smaller, more well-differentiated, ER/PR negative tumors compared to other treatment cohorts(p < 0.001). After PSM, lumpectomy alone(HR = 1.88, 95%CI:1.62-2.18) and local therapy(HR = 1.33, 95%CI:1.14-1.55) were associated with decreased overall survival compared to the addition of systemic therapy(p < 0.001). Additional predictors of reduced survival on MVA included African-American race(HR = 1.31, 95%CI:1.17-1.46), increased Charlson-Deyo score(HR = 3.18, 95%CI:2.72-3.73), older age at diagnosis(HR = 1.08 95%CI:1.07-1.08), and Medicaid insurance(HR = 1.76, 95%CI:1.43-2.16)(all p < 0.001). Conclusions: Among patients diagnosed with DCIS, significantly better overall survival was observed with the addition of hormonal therapy compared to extended local therapy or lumpectomy alone. Although the NCDB does not capture recurrence or breast-cancer specific mortality, these results suggest that DCIS may have metastatic potential for some patients.
Contributing factors of early breast cancer mortality reduction by molecular subtypes from 2000 to 2014: A single institute experience.
Authors: Shin-Cheh Chen, Hsiu-Pei Tsai, Hsien-Kun Chang, Yung-Chang Lin, Shih Che Shen, Wen-Lin Kuo, Chi-Chang Yu, Hsu-Huan Chou, Chia-Hui Chu, Yi-Ting Huang, Shir-Hwa Ueng
Journal: Journal of Clinical Oncology (2018)

e12506 Background: To clarify whether the Asia-Pacific breast cancer patients get small decline mortality in comparison to American white, we compared the survival differences between 2 decades(2000-2014) of T1-2N0 breast cancer by molecular subtypes and analysis the contributing factors. Methods: A total of 4478 patients with T1-2N0 breast cancer who received curative breast surgery at Chang Gung Memorial Hospital, Linkou, and divided into two period cohorts according to their surgical date (earlier cohort 2000 - 2008, n = 2397; recent cohort 2009-2014, n = 2081). The trends of clinicopathologic characteristics, treatment strategies and outcome between two cohorts were reviewed retrospectively. Mortality reduction was compared between the ER/HER2 subtypes. The effect of treatment factors on disease free survival (DFS), distant metastasis free survival (DMFS) and overall survival (OS) were determined using a stepwise Cox regression model. Results: The median follow up duration was 73 months. There was a trend of older mean age, smaller tumor size, more patients received conserving surgery and more ER (+) patients (71%) in recent cohort was found. The HER2(+) subtype was the poorest of 7-year DFS,DMFS and OS (p< 0.0001)in comparison to others. The 7-year DFS were 90.9%, 85.2%,84.1% and 81.0% in luminal A,luminal B, triple negative and HER2(+) subtypes, 7-year OS were 97.1%, 94.4%, 90.8% and 91.5% in those subtypes, respectively. The differences of survival data in earlier and recent cohort by the four subtypes are summarized in the table. In HER2(+) subtype, targeted therapy was the only contributing factor for survival benefit both in DFS and OS, and no significant specific treatment factor found in other subtypes. Conclusions: The estimated survival improvement was largest in HER2(+) subtype and targeted therapy was the only contributing factor. 5-year DFS 5-year DMFS 5-year OS earlier recent p earlier recent p earlier recent p Luminal A 92.4 94.9 0.021 96.3 97.7 N.S 98.4 98.5 N.S Luminal B 86.4 90.5 N.S 92.6 98.2 0.023 96.7 99.1 N.S HER2(+) 82.4 89.1 0.037 90.1 96.4 0.005 92.7 97.2 0.012 Triple negative 85.8 88.8 N.S 90.6 96.0 0.037 92.3 93.0 N.S
Metabolic therapy with PEG-arginase induces a sustained complete remission in immunotherapy-resistant melanoma
Authors: Carmela De Santo, Paul Cheng, Andrew Beggs, Sharon Egan, Alberto Bessudo, Francis Mussai
Journal: Journal of Hematology & Oncology (2018)

Metastatic melanoma is an aggressive skin cancer with a poor prognosis. Current treatment strategies for high-stage melanoma are based around the use of immunotherapy with immune checkpoint inhibitors such as anti-PDL1 or anti-CTLA4 antibodies to stimulate anti-cancer T cell responses, yet a number of patients will relapse and die of disease. Here, we report the first sustained complete remission in a patient with metastatic melanoma who failed two immunotherapy strategies, by targeting tumour arginine metabolism. A 65-year-old patient with metastatic melanoma who progressed through two immunotherapy strategies with immune checkpoint inhibitor antibodies was enrolled in a phase I study (NCT02285101) and treated with 2 mg/kg intravenously, weekly pegylated recombinant arginase (BCT-100). The patient experienced no toxicities > grade 2 and entered a complete remission which is sustained for over 30 months. RNA-sequencing identified a number of transcriptomic pathway alterations compared to control samples. The tumour had absent expression of the recycling enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC) indicating a state of arginine auxotrophy, which was reconfirmed by immunohistochemistry, and validation in a larger cohort of melanoma tumour samples. Targeting arginine metabolism with therapeutic arginase in arginine auxotrophic melanoma can be an effective salvage for the treatment of patients who fail immunotherapy.
A cytoplasmic long noncoding RNA LINC00470 as a new AKT activator to mediate glioblastoma cell autophagy
Authors: Changhong Liu, Yan Zhang, Xiaoling She, Li Fan, Peiyao Li, Jianbo Feng, Haijuan Fu, Qing Liu, Qiang Liu, Chunhua Zhao, Yingnan Sun, Minghua Wu
Journal: Journal of Hematology & Oncology (2018)

Despite the overwhelming number of investigations on AKT, little is known about lncRNA on AKT regulation, especially in GBM cells. RNA-binding protein immunoprecipitation assay (RIP) and RNA pulldown were used to confirm the binding of LINC00470 and fused in sarcoma (FUS). Confocal imaging, co-immunoprecipitation (Co-IP) and GST pulldown assays were used to detect the interaction between FUS and AKT. EdU assay, CCK-8 assay, and intracranial xenograft assays were performed to demonstrate the effect of LINC00470 on the malignant phenotype of GBM cells. RT-qPCR and Western blotting were performed to test the effect of LINC00470 on AKT and pAKT. In this study, we demonstrated that LINC00470 was a positive regulator for AKT activation in GBM. LINC00470 bound to FUS and AKT to form a ternary complex, anchoring FUS in the cytoplasm to increase AKT activity. Higher pAKT activated by LINC00470 inhibited ubiquitination of HK1, which affected glycolysis, and inhibited cell autophagy. Furthermore, higher LINC00470 expression was associated with GBM tumorigenesis and poor patient prognosis. Our findings revealed a noncanonical AKT activation signaling pathway, i.e., LINC00470 directly interacts with FUS, serving as an AKT activator to promote GBM progression. LINC00470 has an important referential significance to evaluate the prognosis of patients.
Immunohistochemical expression and prognostic value of PD-L1 in Extrapulmonary small cell carcinoma: a single institution experience
Authors: Mohammed Salhab, Yazan Migdady, Melanie Donahue, Yiqin Xiong, Karen Dresser, William Walsh, Benjamin J. Chen, James Liebmann
Journal: Journal for ImmunoTherapy of Cancer (2018)

Extrapulmonary small cell carcinomas (ESCC) are rare but aggressive tumors. Relapses are common despite treatment with chemotherapy and/or radiotherapy. Prospective data for treatment of ESCC are lacking; treatment of these cancers usually incorporates lung small cell carcinoma treatment recommendations. Cancer staging remains the most important prognostic factor. Cancer immunotherapy targeting the PD-1/PD-L1 pathway has shown efficacy in multiple tumor types, and could be an appealing treatment strategy for these rare tumors.We investigated PD-L1 expression by immunochemistry (IHC) in ESCCs diagnosed at University of Massachusetts Medical Center, from 1999 to 2016. 34 cases with sufficient material were selected for PD-L1 IHC analysis using clone E1L3N. PD-L1 expression was evaluated using the combined positive score (CPS). Retrospective chart review was performed. We evaluated the incidence and prognostic value of PD-L1 expression in ESCC at our institution.Twelve out 34 cases (35%) had PD-L1 CPS scores ≥1. Ten cases had CPS scores ranging 1-5, whereas 2 cases had CPS scores > 80. The overall response rate to the standard chemotherapy with/without radiotherapy in the PD-L1 positive group was 80% versus 67% for the PDL-1 negative group (p-value 0.67). The median overall survival for the PD-L1 positive group, regardless of stage, was 11.5 months versus 7 months for PD-L1 negative group (p-value 0.34). Patients with limited stage disease with positive PD-L1 had a median survival of 53 months compared to 15 months for patients with PD-L1 negative limited stage (p-value 0.80).This study showed that at least one third of our ESCC tissue samples expressed PD-L1. There was a trend for higher response rates to the standard chemotherapy with/without radiotherapy and improved survival in PD-L1 positive patients. Further studies are required to understand the implications of immune dysregulation in these aggressive tumors. PD-L1/PD-1 inhibitors should be investigated in this group of patients.
Regulation of superoxide dismutase by Cdc-like-kinase (LAMMER kinase) in Drosophila Melanogaster and human tumor cells
Authors: B. James, W. Staatz, S. Wilkinson, E Meuillet, G. Powis
Journal: Cancer Research (2008)

1748  The antioxidant defense enzyme, superoxide dismutase (SOD), plays a critical role in the prevention of damage by reactive oxygen species (ROS). The in vitro activation of SOD can increase cell differentiation, decrease cell proliferation and in Drosophila melanogaster increase life span. In the fission yeast, S. pombe, SOD expression is regulated by the yeast Lkh1 gene, a homolog of Cdc-2-like kinases (CLKs) or LAMMER kinases. CLKs are a family of ubiquitously expressed dual-specificity kinases involved in pre-mRNA splicing, and the splicing associated activity of CLK1 has been successfully targeted by the CLK inhibitor TG003. We examined the regulation of the SOD by CLKs in Drosophila melanogaster and human tumor cells and found that CLKs negatively regulate SOD protein and activity. We have observed that loss of function mutations in the Drosophila CLK gene, Darkener of apricot (Doa) increase mitochondrial SOD (Mn-SOD) and cytoplasmic SOD (CuZn-SOD) activity approximately 2 fold in adult Drosophila. In addition, this increase in activity corresponds with an increase in the protein levels of both Mn-SOD and CuZn-SOD. Since an increase in SOD activity is expected to increase resistance to oxidative stress, we asked if loss of CLK function in Drosophila can increase resistance to oxidative stress by determining if Doa mutants were more resistant to the ROS generator, paraquat, as compared to wild type flies. We found flies heterozygous for a loss of function allele of Doa showed an increased survival in the presence of paraquat when compared to wild-type flies. In HeLa and MCF7 human cancer cell lines we have found that treating cells with the CLK inhibitor TG003 leads to an increase in SOD activity. To confirm that CLK is responsible for the increase in SOD activity seen when cells are treated with TG003 we tested siRNAs targeted against CLK1, CLK2, and CLK3. We show that knock down of CLK2 and CLK3 has no significant effect on SOD activity but that knock down of CLK1 leads to a significant increase in CuZn-SOD activity, transcript and protein. Thus, the data suggest that SOD is negatively regulated by CLKs in Drosophila and human cancer cell lines affecting the response to ROS and that this regulation may be conserved during evolution.
Abstract 16086: A Genomic Blueprint of Human Endothelial Cell Differentiation From Pluripotent Stem Cells Identifies Unique Epigenetic Signatures and Anti-Osteogenic Responses to Laminar Shear Stress
Authors: Christina V Theodoris, Molong Li, Mark P White, Lei Liu, Daniel He, Katherine S Pollard, Benoit G Bruneau, Deepak Srivastava
Journal: Circulation (2014)

Endothelial cells (ECs) sense hemodynamic shear stress and transduce these signals to direct vascular development and to prevent calcification in adults. Here, we studied a time-course of EC differentiation from human pluripotent cells to understand the transcriptional and epigenetic mechanisms governing endothelial cell specification. We then exposed the ECs to either static or laminar shear stress conditions to understand how hemodynamic flow protects vessels and valves from calcification. We found that stage-specific gene expression was enriched for processes including WNT signaling at the mesodermal stage, angiogenesis at the EC precursor stage, and matrix metalloproteinases at the EC stage, the latter of which may prevent calcification via extracellular matrix degradation. We used a random forest machine-learning algorithm to identify stage-predictive transcription factors such as SOX2, a known cell fate determinant, which was predictive for the pluripotent stage. STAT6 or SMAD6 expression was predictive of static or shear-stress conditions respectively. In addition, immune response or inhibition of the TGFβ osteogenic pathways was enriched in static or shear-specific gene expression respectively. Taken together, this suggests an anti-inflammatory and anti-osteogenic EC response to shear-stress. We also identified stage-specific epigenetic states. For instance, those genes expressed specifically at the mesodermal stage showed a unique epigenetic signature with expression being most correlated with loss of the repressive histone modification H3K27me3 and residence in regions of DNA hypomethylation. This signature was more pronounced in developmental genes compared to non-developmental genes. Our findings represent the first comprehensive transcriptional and epigenetic analysis of human EC differentiation and provide a blueprint for the gene networks involved in formation and maintenance of ECs. Specifically, we found that human ECs have an anti-osteogenic and anti-inflammatory response to shear-stress providing a basis for understanding endothelial cell dysfunction in disease states.
Association between adaptive immune signature and outcome in HER2-positive breast cancer treated with trastuzumab and lapatinib in the NCCTG-N9831 (Alliance) and NeoALTTO trials.
Authors: Saranya Chumsri, Daniel Serie, Afshin Mashadi-Hossein, Jennifer M. Kachergus, Sarah Warren, Gerardo Colon-Otero, Ann H. Partridge, Lisa A. Carey, Florentine Hilbers, Veerle Van Dooren, Eileen Holmes, Serena Di Cosimo, Olena Werner, Jens Bodo Huober, Jose Baselga, Christos Sotiriou, Edith A. Perez, Amylou C. Dueck, Alvaro Moreno-Aspitia, E Aubrey Thompson
Journal: Journal of Clinical Oncology (2018)

577 Background: Trastuzumab (H) acts in part through adaptive immune system, whereas lapatinib (L) acts through inhibition of HER2 signaling. Previous studies showed that enrichment of immune-related genes was associated with improved outcome. However, the role of immune system in response to L or LH is not fully understood. Methods: NanoString was used to quantify mRNA in 1,378 samples from N9831 trial: Arm A chemotherapy alone, arm B sequential H, and arm C concurrent H. Enrichment analysis was performed on genes with significant HR to generate a signature. RNA-seq data was analyzed from 193 samples from NeoALLTO trial: Arm A L, arm B H, and arm C LH. Cox models for RFS and EFS were analyzed. Results: In N9831, enrichment of the 17 gene adaptive immune signature (AIS) was found to be significantly associated with improved RFS in arm C (HR 0.71, 95%CI 0.56-0.90; p = 0.005). Further validation was performed in arm A and B with similar associations observed in arm B (HR 0.76, 95%CI 0.62-0.92; p = 0.006) and arm A (HR 0.84, 95%CI 0.72-0.99; p = 0.04). Enrichment of this signature was significantly associated with higher sTIL (p < 0.0001), ER negativity (p = 0.047), and larger tumor size (p < 0.0001) but not lymph node status or tumor grade. In NeoALTTO, 134 out of 244 (54.9%) patients were considered deficient AIS (dAIS). NeoALTTO patients with dAIS had significantly lower pathologic complete response (pCR) rate, compared to patients with enriched AIS (eAIS). In arm B, pCR was observed in 43% with eAIS compared to 8% with dAIS (OR = 9.12, 2.25-54.42, p = 0.0004). pCR was observed in 17% with dAIS in arm A and in 52% in arm C . Among dAIS patients, 6 year-EFS was longer in L (68%, 95%CI 0.55-0.85) or combination HL (73%, 95%CI 0.60-0.88), compared to H alone, (63%, 95%CI 0.49-0.80). Conclusions: Patients with dAIS had poor outcome despite receiving H likely due to inability to mount proper immune response. However, these patients appear to benefit from L and the combination of LH. Further studies are needed to validate this signature to identify patients who will benefit from dual anti-HER2 therapy. Clinical trial information: NCT00898898 and NCT00553358. %pCR %6-yr EFS dAIS eAIS dAIS eAIS L 17% 21% 68% 65% H 8% 43% 63% 74% LH 52% 44% 73% 85%