tbuckley/cabot-search huggingface dataset:
Tannic acid prevents angiogenesis in vivo by inhibiting CXCR4/SDF-1 alpha binding in breast cancer cells
Authors: Devin D. Twitchell, Nyall R. London, David P. Tomer, Steve Tomer, Byron K. Murray, Kim L. O’Neill
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

51 

The migration of cancer cells from the primary tumor to a secondary site is a complex process involving invasion, trafficking, localization, growth and angiogenesis. How tumors are able to grow and create new blood vessels is still unknown. However, new evidence has demonstrated a strong correlation between CXC chemokine receptor-4 (CXCR4) and its ligand stromal cell-derived factor-1 alpha (CXCL12), suggesting that they have a pivotal role in the angiogenesis, migration, and localization of cancer cells. Recent studies have shown that these chemoattractants can regulate vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP). Blocking the binding of CXCR4 with SDF-1 alpha may inhibit the development of new blood vessels to tumors. Tannic acid, found in nuts, wines, and wood extracts, is a water-soluble polyphenol known to inhibit the proliferation of various cancer cell lines, induce apoptosis, and increase life expectancy in tumor bearing mice. We hypothesized that tannic acid may reduce angiogenesis induced by metastatic breast cancer cell lines, MDA-MB-231 and MDA-MB-435 (which have been demonstrated to express CXCR4), by inhibiting the binding of CXCR4 with SDF-1 alpha. Dimethyl-cellulose patches containing different concentrations of SDF-1 alpha and tannic acid were added to the chorioallantoic membrane (CAM) of a chick embryo. Concentrations of tannic acid ranged from 5uM to 25uM and 5x10^5 cells were then placed on top of the each patch and allowed to diffuse. Angiogenesis inhibition was quantified using a novel computer-analyzing program. This program allowed us to count the density percentage, the branching points, and the total length of developing vessels. We report that MDA-MB-231 and dimethyl-cellulose patches on the CAM produced 788.69mm of vessel length, 260 branching points, and 76.08% of vessel density. SDF-1 alpha added to the membrane created 888.05mm, 367 branching points, and 80.78% density. Tannic acid at 25uM reduced angiogenesis to 589.45mm, 163 branching points, and 75.2% density. In MDA-MB-435, 25uM of tannic acid decreased the vessel length by 397.28mm, 275 branching points, and the density percentage by 1.96. Tannic acid has shown to reduce angiogenesis and may be a potential inhibitor of the binding of CXCR4 and SDF-1 alpha. Further research is required to demonstrate the mechanisms of tannic acid inhibition of angiogenesis and to confirm if it inhibits the binding of SDF-1 alpha to CXCR4.
18F-FDG Superscan Caused by Extensive Bone Marrow Involvement in Hemophagocytic Lymphohistiocytosis
Authors: W. Phillip Law, Shannon Emmett, Peter Jackson
Journal: Clinical Nuclear Medicine (2017)

An 82-year-old woman who initially presented with pulmonary infection had persistent pancytopenia, which presented a diagnostic dilemma requiring multiple bone marrow biopsies for eventual diagnosis of hemophagocytic lymphohistiocytosis. This case highlights the utility of FDG PET in (a) focusing attention on the bone marrow and reticuloendothelial system as the primary site of pathology and (b) excluding underlying malignancy and infection in this rare but potentially fatal hyperinflammatory condition caused by a highly stimulated but ineffective immune response.
Clinical utility and therapeutic implications of oncotype analysis in patients with breast cancer.
Authors: Stephanie A. Williams, Talar Tatarian, Christine B. Teal, Anita P. McSwain, Robert S. Siegel, Martin Ojong-Ntui, Ashima Saini, Imad A. Tabbara, Rebecca Davidson Kaltman
Journal: Journal of Clinical Oncology (2012)

e11084 Background: Oncotype DX is a 21-gene assay developed for early stage, hormone receptor positive breast cancer that generates a Recurrence Score which estimates response to chemotherapy and the likelihood of systemic recurrence at 10 years. It differentiates between patients who would benefit from chemotherapy plus hormonal therapy versus hormonal therapy alone. This study’s goal was to determine if the Recurrence Score affected clinical management at our institution and physicians’ accuracy at predicting Recurrence Scores. Methods: A retrospective review was conducted of 116 breast cancer patients treated over a 7 year period. Clinic notes, pathology reports, and additional relevant information were presented to breast surgeons, oncologists, radiation oncologists, and surgical pathologists. Individual physicians estimated recurrence risks and recommended treatment based on those estimates. The Recurrence Score was revealed and changes in therapeutic recommendations were recorded. Results: Treatment recommendations changed in 43% of patients. 29% had a change from chemotherapy followed by hormone therapy to hormone therapy alone due to a low recurrence score, while 14% initially recommended hormonal therapy were changed to chemotherapy plus hormonal therapy due to an intermediate range score. Surgical oncologists accurately predicted Recurrence Scores 52% of the time, medical oncologists 46%, radiation oncologists 45%, and surgical pathologists 15%. A nested mixed model showed that pathologists were statistically significantly worse at predicting recurrence scores than surgical oncologists, medical oncologists, and radiation oncologists. Conclusions: The Oncotype DX assay changes management of breast cancer patients at our institution, frequently downgrading the intensity of systemic therapy. Clinicians were able to accurately estimate recurrence categories about 50% of the time. We recommend the use of Oncotype DX assay along with assessment of clinicopathologic features of an individual’s disease in eligible patients to enhance the selection of appropriate adjuvant therapy.
Response to: Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis by Kremer and Weinblatt
Authors: Jenny H Humphreys, Ruth Costello, Suzanne MM Verstappen, William G Dixon
Journal: Annals of the Rheumatic Diseases (2017)

We thank Drs Kremer and Weinblatt for their interest in our study.1 We agree and acknowledge that lack of biopsies and detailed histology is a limitation of our study.2 Unfortunately good quality data on liver biopsies and ultrasound scans were not available in this retrospective observational study and would not have been systematically performed in all patients, necessitating the use of serum liver function tests (LFTs). However this limitation is balanced against our ability to study a rare outcome in a large number of people. The strengths of observational data are that they reflect ‘real-life’ usage versus a carefully monitored research cohort, and this …
A mouse-human phase I co-clinical trial of taselisib in combination with TDM1 in advanced HER2-positive breast cancer (MBC).
Authors: Otto Metzger Filho, Shom Goel, William Thomas Barry, Erika Paige Hamilton, Sara M. Tolaney, Denise A. Yardley, Rebecca Rees, Michelle Demeo, Caitlin Mills, Marc Hafner, Eric P. Winer, Jean Zhao, Ian E. Krop
Journal: Journal of Clinical Oncology (2017)

1030 Background: PI3K blockade has the potential to revert resistance to anti-HER2 therapies. Methods: Pre-clinical experiments were conducted in parallel to a phase Ib study with the PI3-kinase inhibitor Taselisib + T-DM1 in HER2+ MBC. Results: Pre-clinically, HER2+ cell lines (HCC1954, MDA-MB-361, MDA-MB453) treated with T-DM1 until resistance had decreased HER2 expression. Tx with Taselisib restored HER2 levels in T-DM1 resistant cells. In vivo, the combination of T-DM1 + Taselisib was superior to either agent alone in transgenic mammary carcinomas driven by HER2 with or without a PIK3CA H1047R transgene. The phase Ib study enrolled 26 pts with HER2+ MBC. Median age was 57 (38-95), ER+ (58%), ER- (42%). PIK3CA wild type (35%) mutant (23%) pending results (42%). Pts had a median of 2 lines of prior tx for MBC. Prior T-DM1 was given to 38.5% of pts. Median duration of tx among 18 pts was 4 cycles (2-19). 8 pts remain on tx. No DLTs were observed in the 2 dose levels explored: T-DM1 (3.6mg/Kg) q3 wk with either Taselisib 2mg QD or Taselisib 4mg QD. 20 patients were included in the expansion phase. Most common G3 G4 AEs were thrombocytopenia (19.2%), diarrhea (15.4%), vomiting (7.7%), lipase increase (7.7%) and hyperglycemia (7.7%). Pneumonitis was reported in 4 cases (3 G1, 1 G2); further evaluation revealed elevated beta-glucan in 3 of the 4 cases raising suspicion for pneumocystis pneumonia (PJP). 24/26 pts were evaluable for confirmed response: (4% CR, 29% PR, 50% SD). Confirmed PR/CR according to prior TMD1 (yes 30% no 36%) and PIK3CA mut status (40% mut, 22% wild type; 9/23 PIK3CA results pending). Median PFS was 7.6 mos (95% CI 2.9 to NR). Conclusions: The combination of Taselisib + T-DM1 is superior to either agent alone in mouse models of HER2+ BC. In the phase Ib study, T-DM1 + Taselisib had an acceptable safety profile although PJP prophylaxis should be considered for this regimen. Thrombocytopenia was reversible with no bleeding events. Preliminary evidence of efficacy was observed regardless of PIK3CA status or prior tx with T-DM1. This co-clinical trial allowed for the rapid translation of lab observations to the clinical setting and provided data to facilitate interpretation of the clinical results. Clinical trial information: NCT02390427.
Abstract B36: Rab25 aggravates cancer cell invasion through Snail expression
Authors: Bo Young Jeong, Kyung Hwa Cho, Seung Hwa Kim, Yu Na Kim, Chang Gyo Park, Hoi Young Lee
Journal: Cancer Research (2016)

Abstract Background: Rab25 is a member of the Rab11 subfamily and exclusively expressed in epithelial cells. As a small GTP-binding protein, Rab25 has been known to mediate recycling of proteins from the endosome to the plasma membrane. Cancer metastasis is multi-step events including epithelial-to-mesenchymal transition (EMT). Various transcription factors mediate EMT through downregulation of E-cadherin. In the present study, we investigate whether Rab25 induces EMT transcription factors, thereby increasing cancer invasiveness. Methods: Immunoblotting, quantitative RT-PCR and immunofluorescence assay were used to examine the expression of Rab25 and EMT factors. siRNAs of Rab25 and Snail were transfected to determine their role in Rab25-induced cancer cell EMT and invasiveness. Transwell invasion assay were used to determine cancer cell invasiveness. Results: Ectopic expression of Rab25 marked reduced E-cadherin expression, while Snail expression was upregulated. In addition, Rab25 significantly aggravated cancer cell invasiveness. However, silencing Snail expression by utilizing specific siRNA significantly attenuated cancer cell invasion. In addition, Rab25 induced phosphorylation of Akt and GSK-3beta. However, pharmacological inhibition of Akt and GSK-3beta marked attenuated Rab25-induced Snail expression. Further, we observed that a beta1integrin located upstream of an Akt/GSK-3beta signaling is important for Rab25-induced Snail expression and cancer cell invasion. Conclusion: Our results show for the first time that Snail mediates Rab25-induced cancer cell EMT and invasiveness through a beta1 integrin /Akt/GSK-3beta signaling cascade, providing novel biomarkers, and potential therapeutic targets for deadly cancers. Citation Format: Bo Young Jeong, Kyung Hwa Cho, Seung Hwa Kim, Yu Na Kim, Chang Gyo Park, Hoi Young Lee. Rab25 aggravates cancer cell invasion through Snail expression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B36.
TARGIT E(lderly): Prospective phase II study of intraoperative radiotherapy (IORT) in elderly patients with small breast cancer—3 year local control and overall survival.
Authors: Frederik K. Wenz
Journal: Journal of Clinical Oncology (2017)

e12105 Background: To investigate the efficacy of a single intraoperative radiotherapy treatment within elderly low risk patients with breast cancer (≥ 70 years, &lt;3.5cm, cN0, cM0, invasive-ductal histology) which is followed by whole breast radiotherapy (WBRT) only when risk factors are present. This prospective, multicentric single arm phase II study (NCT01299987) is based on the experimental arm of the randomized protocol of the international TARGIT A study. Here we present 3 year data on local control and overall survival after a median follow-up of 24 months. Methods: 541 patients from 28 international centers were recruited between February 2011 and September 2014. Sixty-three patients were excluded from the analysis because of screening failure, drop-out or loss to follow-up. During breast conserving surgery a single dose of 20 Gy of intraoperative radiotherapy was given using the INTRABEAM system (Carl Zeiss Meditec, Germany). Additional postoperative WBRT (46 – 50 Gy) was prescribed only in patients with risk factors (larger size, other histology, small free margin, lymphvessel invasion, positive nodes, multifocality/multicentricity, extensive intraductal component (EIC)). Systemic therapy was given according to international standards. The primary outcome was local relapse. Overall survival was a secondary outcome. Discontinuation of the trial was scheduled if rates of local relapse rates rise to 3/4/6% after 2.5/5/7.5 years. Results: After a median follow-up of 24.0 months (120 pts with 3 year f/u), one ipsilateral in-breast recurrence and nine deaths were observed resulting in an actuarial local relapse free survival of 99.7% and actuarial overall survival of 96.6% after 3 years. Conclusions: The results of the prospective TARGIT E trial consolidate earlier reports from the randomized TARGIT A trial supporting the use of accelerated partial breast radiotherapy (APBI) in selected patients. The observed local relapse rate after 3 years is well below the prospectively defined stopping rules (Neumaier et al. BMC Cancer 2012). Further follow-up will be performed. Clinical trial information: NCT01299987.
Noninvasive EGFR testing in plasma circulating free DNA (cfDNA) by a new diagnostic method to detect point mutations, deletions and insertions associated to non small cell lung cancer: CLART CMA EGFR LB.
Authors: Marta Sanchez, Maria Jesus Sanz, Ana Aragon, Nuria Manjon, Jaime Carrillo, Atocha Romero, Mariano Provencio, Vanesa García-Barberán, Trinidad Caldes, Jose Luis Rodriguez-Peralto, Javier Hernandez-Losa, Rosario Cospedal, Maria Luisa Villahermosa
Journal: Journal of Clinical Oncology (2017)

e20008 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are current treatments for advanced non-small cell lung cancer (NSCLC) with activating EGFR gene mutations. Histological samples are the standard tumor materials for EGFR mutation analysis. However, the accessibility of tumor samples is not always possible in advanced NSCLC patients. Moreover, a high percentage of EGFR mutated NSCLC patients will develop resistance to EGFR-TKIs such as T790M mutation. CLART CMA EGFR LB is a novel diagnostic assay able to detect 39 high-prevalence mutations associated with sensitivity or resistance to tyrosine kinase inhibitor treatment. Methods: A highly sensitive and specific method was developed for detection of EGFR mutations (G719X, T790M, L858R, L861Q, insertions in exon 20, and deletions in exon 19) in plasma samples (cfDNA). CLART CMA EGFR LB is based on a preamplification step with a multiplex ARMS-PCR and microarray detection system. Clinical testing was performed using 51 clinical plasma samples: 27 contained L858R, T790M, and deletions in exon 19; 24 contained wild type alleles. 20 samples were cross checked by next generation sequencing performed on the PGM platform (Ion Ampliseq™ Custom, deep-coverage 15000x). Results: Analytical sensitivity was assessed using recombinant plasmids, results ranged between 10-1000 copies/5µl for all mutations. cfDNA from cell lines with the mutations L858R, T790M and deletions in exon 19 at different frequencies (cfDNA Reference Standard, Horizon) were assessed. The system was able to detect the mutations present in a frequency of 2%. The analysis of 51 samples allowed establishing the diagnostic sensitivity and specificity in 93.33% and 100% respectively. CLART CMA EGFR LB showed similar analytical and diagnostic sensitivity than NGS for detecting L858R, T790M and deletions in exon 19. Conclusions: Our data support the use of CLART CMA EGFR LB for clinical testing prior to the selection of the appropriate treatment in NSCLC, monitoring the patient evolution and the emergence of resistance mutations such as T790M in plasma samples.
Clinical utilization of Breast Cancer Index (BCI) for late recurrence risk assessment and prediction of extended endocrine therapy (EET) benefit in early stage HR+ breast cancer.
Authors: Reshma L. Mahtani, Vijayakrishna K. Gadi, Theresa N. Operana, Harris S Soifer, Brock Schroeder, Catherine A. Schnabel, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2017)

551 Background: Randomized trials demonstrated a modest (3-5%) absolute benefit from EET in patients (pts) with early stage HR+ breast cancer (BC), but also a risk of toxicities. BCI is a validated gene expression-based assay that provides 2 results: BCI Prognostic, based on the algorithmic combination of HoxB13/IL17BR (H/I ratio) and a set of proliferation-based genes, reports individualized risk of late distant recurrence (DR); BCI Predictive, based on H/I alone, reports a prediction of high vs low likelihood of benefit from EET. The objective of this study was to assess clinical and pathologic patient characteristics, prognostic and predictive assay results, and physician testing patterns in &gt;14,000 clinical cases. Methods: The BCI Clinical Database for Correlative Studies is a de-identified database developed under an IRB approved protocol that contains &gt;50 clinicopathologic and molecular variables from cases submitted for BCI in clinical practice. Clinicopathologic variables were abstracted from pathology reports, and were available for a subset of cases. Results: Across all pts (N=14,463), median age was 58.2y (range: 23-92y; 73.9% ≥50y). The majority were Stage I (47.3% IA, 3.5% IB, 29.1% IIA, 14.1% IIB, 6% III). Cases were 29%, 51%, and 20% Grade 1, 2, and 3, respectively. Most pts were ER+/PR+ (87.7%) or ER+/PR- (11.3%); 11.3% were HER2+. The majority of cases (55.7%) were ordered 4-6y postdiagnosis, with 23.1% &gt;6y, 14.4% between 1-4y, and 6.8% &lt;1y postdiagnosis. In LN- pts (n=3395), BCI Prognostic identified 50.6% as low risk for late DR vs 49.4% as high risk, while BCI Predictive (H/I) classified 41.0% as high vs 59.0% as low likelihood of benefit. In LN+ pts tested with the BCIN+ Prognostic algorithm (BCI + size/grade, n=818), 77.3% were classified as high risk vs 22.7% as low risk, while BCI Predictive (H/I) classified 44.6% and 55.4% as high vs low likelihood of benefit. Conclusions: Findings from this large cohort characterize utilization of BCI in clinical practice for pts with early-stage, HR+ BC. BCI stratification of pts with high risk and high likelihood of benefit from EET may facilitate selection of pts for prolonged regimens.
Downregulation of miR-503 Promotes ESCC Cell Proliferation, Migration, and Invasion by Targeting <i>Cyclin D1</i>
Authors: Lanfang Jiang, Zitong Zhao, Leilei Zheng, Liyan Xue, Qimin Zhan, Yongmei Song
Journal: Genomics Proteomics & Bioinformatics (2017)

Abstract Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers in China, but the underlying molecular mechanism of ESCC is still unclear. Involvement of microRNAs has been demonstrated in cancer initiation and progression. Despite the reported function of miR-503 in several human cancers, its detailed anti-oncogenic role and clinical significance in ESCC remain undefined. In this study, we examined miR-503 expression by qPCR and found the downregulation of miR-503 expression in ESCC tissue relative to adjacent normal tissues. Further investigation in the effect of miR-503 on ESCC cell proliferation, migration, and invasion showed that enhanced expression of miR-503 inhibited ESCC aggressive phenotype and overexpression of CCND1 reversed the effect of miR-503-mediated ESCC cell aggressive phenotype. Our study further identified CCND1 as the target gene of miR-503. Thus, miR-503 functions as a tumor suppressor and has an important role in ESCC by targeting CCND1.
Sorafenib (SFB) treated elderly patients (E) with hepatocellular carcinoma (HCC): Chromogranine A (CGA) plus vascular endothelial growth factor (VEGF) as predicting factors (PF) of treatment outcome.
Authors: Ignazio Ugo Carreca, Dario Piazza, Bruno Castagneto, Giovanni Condemi, Dario Cova, Antonio Gambardella, Paolo Foa
Journal: Journal of Clinical Oncology (2012)

e14676 Background: HCC accounts for approximately 90% of all primary liver cancers, and is the fifth most common cancer in the world and prognosis is so far very poor,particularly in E patients.Between all tentative of treatment till know SFB seems to be the most promising drug in patients with advanced or metastatic HCC.Aim of the study is to investigate if SFB is efficient and safe also in E HCC patients despite the comorbidities and other problems. Objectives: To investigate if CgA and VEGF work as predicting factors of Sorafenib treatment outcomes. Methods: 51 patients, mean age 68,9 (65-85) with HCC were enrolled . Serum CgA, VEGF and αFP were evaluated at baseline and after end of treatment (SFB 400mg p.o. bid), until disease progression. Clinical response (RECIST), Comprehensive Geriatric Assessment and PFS were considered as well. Results: CgA mean value (baseline: 77.9 – after treatment: 26.25 UI/L) and VEGF levels (baseline: 67.3 – after treatment 47.2 pg/ml) seems to have a predictive role in clinical benefit. A correlation between lower values of CgA and VEGF was noted in pts with longer PFS. Furthermore 3-4 toxicity was not observed in these pts. OS median was 11 months. Conclusions: The most relevant data in this study refer to the role of serum CgA and VEGF levels, for prediction of tumor response. If these findings were confirmed in future largest studies, it could be sufficient to measure these markers levels for identification of those HCC patients who have more probability of obtaining clinical benefit from a sorafenib treatment.