tbuckley/cabot-search huggingface dataset:
Are ulcerated breast cancers biologically more aggressive compared to their non-ulcerated counterparts?
Authors: Muy-Kheng Maria Tea, Kamil Pohlodek, Christine Staudigl, Nadja Fritzer, Michaela Bartova, Christian F. Singer
Journal: Journal of Clinical Oncology (2012)

21 Background: Ulcerated breast carcinomas belong to the group of locally advanced breast cancers. In this study, the authors analyzed the biological presentation of ulcerated breast cancers (ULBC), examined their histo-pathological characteristics, and addressed the question whether T4b carcinomas have more aggressive phenotypes compared to their non-ulcerated counterparts (NULBC). Methods: In this case-control study the histo-pathologies of 66 patients with ulcerated locally advanced breast cancer were evaluated and compared with 132 consecutive non-ulcerated age-matched breast malignancies at the Medical University of Vienna and Comenius University School of Medicine of Bratislava. Results: The mean age in the ULBC and NULBC group was 64,86 (SD +/- 15,54) and 64,70 (SD +/- 14,11), respectively. The average tumor size at diagnosis in the ULBC group was 54.12 mm, 55% larger than in the NULBC group (p=&lt;0.001). Furthermore, we detected statistical significantly more poorly differentiated (G3) tumors in the ULBC collection (p=0.003) and more Her-2-neu positive (p=0.035) breast cancers. In contrast, more hormone receptor positive (ER +/- PR positive) breast cancers were detected in the NULBC group (p=0.04). In addition, a total of 37.3% (n=25) patients with ULBC were diagnosed with primary metastasis. Conclusions: To our knowledge this is the first direct comparison between ULBC and NULBC.We could demonstrate that ulcerated breast cancers are characterized by more aggressive phenotypes. The observed differences of more unfavorable prognostic factors might contribute to the generally known poor prognosis of ULBC.
Comparison of the intermediate risk 21-gene recurrence score (RS) with the 70-gene signature (GS) as a continuous variable, Magee equations, and Adjuvant! Online (AOL).
Authors: Hanh P. Mai, Stephanie Kliethermes, Zulfia McCroskey, Cagatay Ersahin, Ellen R. Gaynor, Patricia A. Robinson, Kathy S. Albain, Shelly S. Lo
Journal: Journal of Clinical Oncology (2014)

47 Background: Multigene assays and risk-prediction models are used to provide prognostic information in the management of patients with estrogen receptor positive (ER+) lymph node negative (LN-) breast cancer (BC). Some have predictive utility in determining the value of chemotherapy added to endocrine therapy. We previously reported a mix of high and low risk 70-GS within the intermediate risk 21-gene RS. The Magee equations provide an estimate of the 21-gene RS using standard pathological findings. AOL provides a 10-year risk of BC recurrence or death. The objective of this study is to evaluate correlations between the 70-GS as a nondichotomous continuous variable, the Magee equations, and AOL within patients (pts) with 21-gene intermediate RS. Methods: The 70-GS as a continuous variable (highest risk of -1 to lowest risk of +1) was obtained on all consecutive ER+LN- BC cases with an intermediate 21-gene RS at Loyola U Med Ctr from 1/2005 to 9/2012. AOL recurrence risk and the Magee equations were calculated from clinical-pathologic findings. Pearson pairwise correlations among all four recurrence measures were generated. Results: Results of the 70-GS as a continuous variable and the 21-gene RS were available in 89 cases. A higher risk 70-GS correlates with a higher 21-gene RS (r = -0.31; p = 0.003). A higher risk of recurrence as estimated by AOL is associated with a higher 21-gene RS (r = 0.22; p = 0.036), higher Magee equation 1 (r = 0.36; p = 0.001) and 2 (r = 0.32; p = 0.004), and a higher risk 70-GS (r = -0.40; p &lt; 0.001). Magee equations 1 and 2 are statistically correlated to the 21-gene RS (r = 0.24; p = 0.028 and r = 0.23; p = 0.036 respectively), but not to the 70-GS (p = 0.064 and p = 0.057 respectively). Magee equation 3 is not statistically correlated with 70-GS, 21-gene RS or AOL. Conclusions: There is a continuum of highest to lowest risk 70-GS among LN- ER+ BC within intermediate risk RS. The prospective PROMIS study will assess if the 70-GS adds clinical utility regarding adjuvant therapy choice for these pts.
Pharmacologic therapy of mild to moderate hypertension
Authors: P R Hebert, J E Manson, C H Hennekens
Journal: Journal of the American Society of Nephrology (1992)

This article reviews the evidence on pharmacologic therapy of hypertension in reducing morbidity and mortality from stroke and coronary heart disease (CHD) and considers the possible generalizability of these findings to diabetics. For malignant hypertension, benefits are large and obvious from uncontrolled case series. For severe hypertension, conclusive benefits have been shown in several randomized trials. For mild to moderate hypertension, however, it is necessary to consider meta-analyses of all individual trials. The most comprehensive of these shows reductions of 42% for total stroke (95% Cl, -33 to -50%; P < 0.0001) and 14% for all CHD (95% Cl, -4 to -22%; P < 0.01). The applicability to diabetics is unclear because they were excluded from most of the trials. The Hypertension Detection and Follow-Up Program included diabetics and reported subgroup analyses. The reduction in mortality among the actively treated diabetics of 5% was less than the 17% achieved in nondiabetics. It is unclear, however, whether the mortality reductions are truly different or reflect the play of chance. Because of the higher incidence of CHD events among diabetics with hypertension, a similar relative benefit would result in a much greater absolute risk reduction. Further, the drugs used adversely affect lipid and glucose metabolism. New antihypertensive drugs without these side effects may further improve the risk-to-benefit ratio of antihypertensive treatment, especially in diabetics, who are at a several-fold absolute increased risk or cardiovascular disease.(ABSTRACT TRUNCATED AT 250 WORDS)
IL-11 is a parietal cell cytokine that induces atrophic gastritis
Authors: Meegan Howlett, Heather V. Chalinor, Jon N. Buzzelli, Nhung Nguyen, Ian R. van Driel, Katrina M. Bell, Eva Dimitriadis, Trevelyan R. Menheniott, Andrew S. Giraud, Louise M. Judd, James G. Fox
Journal: BMJ (2011)

Additional supplementary materials are published online only. To view these files please
visit the journal online (http://gut.bmj.com/content/early/recent).
Invasion of the human albumin-alpha-fetoprotein gene family by Alu, Kpn, and two novel repetitive DNA elements.
Authors: D E Ruffner, C N Sprung, P P Minghetti, P E Gibbs, A Dugaiczyk
Journal: Molecular Biology and Evolution (1987)

The human albumin-alpha-fetoprotein genomic domain contains 13 repetitive DNA elements randomly distributed throughout the symmetrical structures of these genes. These repeated sequences are located at different sites within the two genes. The human albumin gene contains five Alu elements within four of its 14 intervening sequences. Two of these repeats are located in intron 2, and the remaining three are located in introns 7, 8, and 11. The human alpha-fetoprotein gene contains three of these Alu elements, one in intron 4 and the remaining two in the 3'-untranslated region. In addition, the human alpha-fetoprotein gene contains a Kpn repeat and two classes of novel repeats that are absent from the human albumin gene. Six of the Alu elements within the two genes are bound by short direct repeats that harbor five base substitutions in 120 possible positions (60 bp times 2 termini). The absence of Alu repeats from analogous positions in rodents indicates that these repeats invaded the albumin-alpha-fetoprotein domain less than 85 Myr ago (the time of mammalian radiation). Furthermore, considering the conservation of terminal repeats flanking the Alu sequences of the albumin-alpha-fetoprotein domain (0.042 changes per site), we submit that the average time of Alu insertion into this gene family could have been as recently as 15-30 Myr ago.
IMP321 and weekly paclitaxel as first-line chemoimmunotherapy for metastatic breast cancer (MBC)
Authors: F. Triebel, C. Brignone, C. Grygar, M. Marcu, M. Gutierez
Journal: Journal of Clinical Oncology (2008)

1045 Background: IMP321 (hLAG-3Ig), a novel immunomodulator:derived from the natural human protein LAG-3 (CD223), a ligand for MHC class II molecules, in the form of a soluble fusion protein; acts indirectly on T cell responses by MHC class II+APC activation. Two intended clinical settings: low dose (250 μg) as T-cell adjuvant for therapeutic vaccines and high dose (>1 mg) as monotherapy (i.e. without antigen) or combined with standard chemotherapy. Pharmacokinetics study on patient's plasma shows systemic exposure to IMP321 for at least 24 hr following s.c. injection of doses above 1 mg. Chemoimmunotherapy protocol rationale: boosting the DC network when it is loaded with tumour antigens for the several days following chemotherapy (secondary to tumour cell apoptosis) with repeated s.c. injection of the APC-specific activator IMP321 may increase cytotoxic CD8 T cell responses. Direct and prolonged activation of APC such as monocytes may also occur. Methods: This is an open label fixed dose-escalation phase I study, performed in ambulatory setting in patients receiving as a first-line chemotherapy for MBC the standard 6 cycles of weekly paclitaxel (80 mg/m² at D1, D8 and D15 of a 4-week cycle. Two IMP321 doses, 0.25 and 1.25 mg given s.c., are being tested, given at D2 and D16 of this 4-week cycle, for 6 courses. Results: IMP321 was very well tolerated. Twelve pts have been treated to date with no grade III or IV adverse events related to the product. A three-fold increase in MHC class II+ monocyte blood counts was observed two weeks after the last injection. In addition, a two-fold increase in activated CD8+ circulating T cells was observed in these pts that mimics in vivo the in vitro effect of IMP321 on human PBMCs. Conclusions: IMP321 in MBC patients treated with first-line chemotherapy was well tolerated when given s.c. over 6 months and this low IMP321 dose (i.e. for systemic exposure) was already efficacious at enhancing significantly the number of effector cytotoxic cells in vivo. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Immutep Immutep
G18 : The FXR agonist PX20606 reduces liver damage, fibrosis and portal hypertension in cirrhotic rats
Authors: P. Schwabl, E. Hambruch, B.A. Payer, T.L. Schubert, B. Strobel, S. Fida, M. Wagner, L. Garnys, M. Trauner, M. Peck-Radosavljevic, C. Kremoser, T. Reiberger
Journal: Journal of Hepatology (2015)
CD8 <sup>+</sup> T Cells Regulate Monopoiesis and Circulating Ly6C <sup>high</sup> Monocyte Levels in Atherosclerosis in Mice
Authors: Clément Cochain, Miriam Koch, Sweena M. Chaudhari, Martin Busch, Jaroslav Pelisek, Louis Boon, Alma Zernecke
Journal: Circulation Research (2015)

Rationale: Proinflammatory adaptive immune responses are recognized as major drivers of atherosclerotic lesion formation. Although CD8 + T cells have recently been proposed as a proatherogenic cell subset, their full scope of actions remains to be elucidated. Objective: We here addressed the contribution of CD8 + T cells to monocyte trafficking in atherosclerosis. Method and Results: We observed that CD8 + T cells express proinflammatory cytokines (interferon-γ, tumor necrosis factor-α, and interleukin-12) within atherosclerotic lesions and spleens of high-fat diet–fed low-density lipoprotein receptor–deficient ( Ldlr −/− ) mice. Antibody-mediated CD8 + T-cell depletion in high-fat diet–fed Ldlr −/− mice decreased atherosclerotic plaque formation, associated with decreased macrophage accumulation within lesions. Despite a reduction in vascular chemokine (CC-motif) ligand 2 and chemokine (CXC-motif) ligand 1 expression, CD8 + T-cell depletion did not directly affect monocyte recruitment to inflamed vessels. However, CD8 + T-cell depletion decreased chemokine (CC-motif) ligand serum concentrations and circulating Ly6C high monocyte counts. We further evidenced that CD8 + T-cell depletion decreased levels of mature monocytes and myeloid granulocyte–monocyte progenitors in the bone marrow and spleen of hypercholesterolemic mice, effects that were partially reproduced by interferon-γ neutralization, showing a role for interferon-γ. Conclusions: These data suggest that CD8 + T cells promote atherosclerosis by controlling monopoiesis and circulating monocyte levels, which ultimately contributes to plaque macrophage burden without affecting direct monocyte recruitment, identifying this cell subset as a critical regulator of proatherogenic innate immune cell responses in atherosclerosis.
Benefit of the serum-effusion albumin gradient in congestive heart failure patients
Authors: Piamlarp Sangsayunh, Boonjong Saejueng
Journal: European Respiratory Journal (2011)

Objective: To compare between light's criteria and serum-effusion (S-E)albumin gradient in diagnosis of transudate effusion in CHF patients.

Material and method: Eighty-six patients who had pleural effussion and suspected CHF were enrolled in this study between October 2008-September 2010. Suspected CHF was defined by clinical or echocardiography. Inform consents were done in all volunteers. Exclusion criteria was previous thoracotomy or coronary by pass graft 3 month before study. Thoracocentesis was done to evaluate transudate effusion by light's criteria and S-E albumin gradient > 1.2 mg/dl. Definite diagnosis of pure CHF was no effusion after treatment with diuresis and pleural ProBNP > 4000 ng/dl. Combination of pleural disease and CHF were defined by confirmed pleural disease with pleural biopsy and/or VAT, partial response with diuresis and high pleural ProBNP

Result: 12 (13.95%), 56 (65.11%), 17 (19.76%) of all were pure pleural disease, pure CHF, combination of pleural disease and CHF. Sensitivity/specificity/accuracy of S-E albumin gradients and light's criteria and in diagnosis of CHF (both pure and combined) were 90.1/33.3/80.2%, 64.7/80.0/67.4%. No correlation between amount of diuretic drug and “exudate” criteria from lights' (p=.66).25 (27.2%) patients were previous post thoracotomy or coronary bypass graft. 7 of 25 patients had loculated effusion. There was correlation between previous surgery with loculated effusion and effusion from combination of pleural disease and CHF (p=.22).

Conclusion: There is benefit to use S-E albumin gradient > 1.2 mg/dl to diagnosis patients who suspected CHF with or without pleural disease. No correlation between diuresis and exudate from Light's criteria.
Abstract 17979: Left Atrial Cross Sectional Area is a Novel Echocardiographic Measure Which Improves the Predictive Value of Chads2 Score in Risk Stratification of Cardioembolic Strokes
Authors: Timothy C Tan, Mark Handschumacher, Octavio M Pontes-Neto, Maria C Nunes, Yong H Park, Cashel O’Brien, Victoria Piro, Yuan Jiao, Xin Zeng, Gyeong M Kim, Johanna Helenius, Ross Avery, Karen Furie, Hakan Ay, Judy Hung
Journal: Circulation (2014)

Background: Cardioembolic (CE) stroke carries significant morbidity and mortality. Current risk stratification tools such as CHADS2 score do not include any imaging parameters and are based on clinical features, which have limitations. Left atrial (LA) enlargement and remodeling may be associated with CE risk due to predisposition for atrial arrhythmias and thrombus formation. Left atrial cross sectional area (LACSA), a novel echo measure which reflects both LA size and shape, may improve CE stroke risk assessment. Aim: This study examined the value of LACSA in predicting CE stroke risk and the improvement in risk prediction when added to CHADS2 score. Methods: Clinical and echo parameters were examined in a prospective cohort of 1275 consecutive patients with ischemic stroke. Strokes were classified using the Causative Classification of Strokes and 259 (20%) were classified as CE stroke. LACSA was calculated using the formula: π/4*largest measured LA diameter*smallest measured LA diameter where mid LA diameter was measured in the parasternal long axis, 4 chamber and 2 chamber views. Results: Patients with CE stroke had greater LACSA (8.6 ± 2.3 vs 6.4 ± 1.8 cm2/m2; p&lt;0.001) and mean CHADS2 score (2.25 ± 1.28 vs 1.87 ± 1.40; p&lt;0.0001) compared to non-CE stroke patients. LACSA was independently associated with CE strokes (OR 1.21; 95% CI 1.08-1.34; p=0.001) in a multivariable model adjusted for CHADS2, gender, score, BMI, atrial fibrillation, anti-platelet and anti-coagulant use, E/E’ and LVEF. The addition of LACSA to CHADS2 score improved the prediction of CE stroke (c-statistic for predicting CE stroke using CHADS2 alone was 0.59 (95% CI 0.55-0.63) vs CHADS2 and LACSA 0.78 (95% CI 0.72-0.80) (p&lt;0.001). Conclusion: LACSA is a novel measure of LA remodeling and associated with CE stroke. LACSA, an imaging parameter, enhances the risk prediction of the CHADS2 score, a clinical measure of risk, improving risk stratification for CE stroke and impacting therapeutic strategies.
Endoscopically inserted nasobiliary catheters for high dose-rate brachytherapy as part of neoadjuvant therapy for perihilar cholangiocarcinoma
Authors: Saurabh Mukewar, Arjun Gupta, Todd Baron, Gregory Gores, Keith Furutani, Michael Haddock, Christopher Hallemeier
Journal: Endoscopy (2015)

<b>Background and aim:</b> Selected patients with unresectable perihilar cholangiocarcinoma can undergo neoadjuvant chemoradiotherapy followed by liver transplantation, which has been shown to improve survival. The aim of this study was to determine the feasibility and safety of endoscopic transpapillary insertion of nasobiliary tubes (NBTs) and brachytherapy catheters for high dose-rate (HDR) brachytherapy as part of this neoadjuvant chemoradiotherapy. <b>Patients and methods:</b> Medical records of patients undergoing biliary brachytherapy for hilar cholangiocarcinoma at the Mayo Clinic, Rochester were reviewed. Patients were treated with curative intent using external beam radiotherapy (4500 cGy), chemotherapy (5-FU or capecitabine), and HDR brachytherapy (930 – 1600 cGy in one to four fractions delivered over 1 – 2 days) prior to planned liver transplantation. <b>Results:</b> Between 2009 and 2013, 40 patients underwent biliary HDR brachytherapy via endoscopically placed NBTs (8.5 – 10 Fr). Patients had a median age of 55 years (range 28 – 68); 25 patients (62.5 %) had primary sclerosing cholangitis. Prior to therapy, 29 patients (72.5 %) had plastic stents, two (5 %) had metal stents, and nine (22.5 %) had no stents. Bilateral NBTs were placed in five patients (12.5 %). NBT/brachytherapy catheter displacement was seen in eight patients (20 %) – five intraprocedure and three post-procedure. A radiotherapy error and NBT kinking each occurred once. Post-procedure adverse events included: cholangitis (n = 5; 12.5 %), severe abdominal pain (n = 3; 7.5 %), duodenopathy (n = 3; 7.5 %), gastropathy (n = 3; 7.5 %), and both duodenopathy and gastropathy (n = 2; 5 %). <b>Conclusion:</b> HDR biliary brachytherapy administered via endoscopically placed NBTs and brachytherapy catheters is technically feasible and appears reasonably safe in selected patients with unresectable perihilar cholangiocarcinoma.
ALCHEMIST Trials: A Golden Opportunity to Transform Outcomes in Early-Stage Non–Small Cell Lung Cancer
Authors: Ramaswamy Govindan, Sumithra J. Mandrekar, David E. Gerber, Geoffrey R. Oxnard, Suzanne E. Dahlberg, Jamie Chaft, Shakun Malik, Margaret Mooney, Jeffrey S. Abrams, Pasi A. Jänne, David R. Gandara, Suresh S. Ramalingam, Everett E. Vokes
Journal: Clinical Cancer Research (2015)

Abstract The treatment of patients with metastatic non–small cell lung cancer (NSCLC) is slowly evolving from empirical cytotoxic chemotherapy to personalized treatment based on specific molecular alterations. Despite this 10-year evolution, targeted therapies have not been studied adequately in patients with resected NSCLC who have clearly defined actionable mutations. The advent of next-generation sequencing has now made it possible to characterize genomic alterations in unprecedented detail. The efforts begun by The Cancer Genome Atlas project to understand the complexities of the genomic landscape of lung cancer will be supplemented further by studying a large number of tumor specimens. The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) is an NCI-sponsored national clinical trials network (NCTN) initiative to address the needs to refine therapy for early-stage NSCLC. This program will screen several thousand patients with operable lung adenocarcinoma to determine whether their tumors contain specific molecular alterations [epidermal growth factor receptor mutation (EGFR) and anaplastic lymphoma kinase rearrangement (ALK)], making them eligible for treatment trials that target these alterations. Patients with EGFR mutation or ALK gene rearrangement in their tumor will be randomized to placebo versus erlotinib or crizotinib, respectively, after completion of their standard adjuvant therapy. ALCHEMIST will also contain a large discovery component that will provide an opportunity to incorporate genomic studies to fully understand the clonal architecture, clonal evolution, and mechanisms of resistance to therapy. In this review, we describe the concept, rationale, and outline of ALCHEMIST and the plan for genomic studies in patients with lung adenocarcinoma. Clin Cancer Res; 21(24); 5439–44. ©2015 AACR.
Zoledronic acid affects the expression of VEGF in breast cancer cells and in bone marrow stromal cells through direct and indirect mechanisms
Authors: Antonella De Luca, Marianna Gallo, Monica Maiello, Rachiglio Annamaria, Luana Lamura, Amelia D'Alessio, Antonio Pinto, Donatella Aldinucci, Nicola Normanno
Journal: Cancer Research (2008)

294   Bone metastases occur in approximately 50% of breast cancer patients with advanced disease. Biphosphonates such as zoledronic acid (ZA) represent the mainstay of current treatment of bone metastases in cancer patients. Reduction of serum VEGF in patients with advanced breast cancer treated with ZA has been described. Therefore, we investigated the effects of this compound on paracrine circuits involved in neo-angiogenesis within the bone marrow. The anti-proliferative effect of ZA was assessed in a small panel of human breast cancer cell lines. We found that two cell lines, MCF-7 and MDA-MB-435 cells, were sensitive to the drug with IC50s below 20 μM. Treatment with ZA significantly reduced activation of both MAPK and AKT in breast cancer cells. Furthermore, the levels of secreted VEGF by both MCF-7 and MDA-MB-435 cells was reduced by approximately 50% following treatment with ZA. No significant effects of ZA on the levels of VEGF mRNA in breast cancer cells was observed, suggesting that ZA regulates VEGF expression through post-transcriptional mechanisms. Treatment of breast cancer cells with ZA also produced a significant reduction in the secretion of the EGFR-ligand transforming growth factor α (TGFα), that was associated with a reduction in the levels of TGFα mRNA. Recombinant TGFα induced a significant increase in the levels of secretion of VEGF in different models of human bone marrow stromal cells (BMSC): human bone marrow derived-mesenchymal stem cells (MSC); the human MSC-like HDS-2 cell line that was derived from a patient with Hodgkin disease; the human osteoblastic cell line hFOB. Such increase was prevented by simultaneous treatment with the EGFR tyrosine kinase inhibitor gefitinib. Finally, treatment of MSC-like HDS-2 cells with ZA produced a significant reduction of AKT phosphorylation, of VEGF secretion and of VEGF mRNA levels as compared to untreated cells. Taken together, these findings suggest that ZA might reduce the levels of expression of VEGF within the bone marrow microenvironment by inhibiting the secretion of VEGF in breast cancer cells and in BMSC, and by affecting TGFα-mediated paracrine circuits between tumor cells and BMSC.