tbuckley/cabot-search huggingface dataset:
Biopsy for liver cancer: How to balance research needs with evidence‐based clinical practice
Authors: Boris Blechacz, Lopa Mishra
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. To the Editor: The editorials by Torbenson et al.1 and Sherman et al.2 raise important divergent views on liver cancer biopsy in a new era. New treatment strategies based upon genomic data and actionable mutations are urgently needed for hepatocellular carcinoma (HCC). Genomic studies heralded new targeted therapeutics for multiple other malignancies. It is estimated that a pharmacogenomics (PGx)‐mediated 5% increase in response rates results in a 40% cost reduction, compared to conventional clinical trials, and the launch of a drug can be accelerated by at least 2 years.3 PGx can guide drug dosing, decrease adverse events, and improve outcomes and cost‐effectiveness of treatments.4 Sherman et al. point out that, at present, there are no established criteria allowing personalized medicine in HCC patients and that there are currently no molecular, metabolic, or genetic markers that can be targeted in conventional practice. However, the lack of druggable targets in the present does not exclude such targets in the future. Tumor samples will be required to validate the clinical relevance of potential molecular targets. The majority of large trials reported the risk of tumor spread as 0.003‐2.8%. More important, neither the disease course nor mortality was influenced in cases in which tumor spread was associated with a previous biopsy. Sherman et al. point out the high sensitivity and specificity of the radiological diagnosis of HCC in cirrhosis. However, noninvasive identification of cirrhosis is flawed by low accuracy. In addition, chronic hepatitis C virus and nonalcoholic fatty liver disease can predispose to hepatocarcinogenesis, even in the absence of stage IV fibrosis. Orthotopic liver transplantation (OLT) is a potentially curative approach for HCC, but selection criteria are strict. In a recent prospective study, 44% of lesions identified by computed tomography as HCC were found to be false positive.5 Hence, exclusion of patients from OLT based upon radiological stratification might inaccurately exclude patients from potentially curative treatments. The ethical dilemma, if the scientific use of such samples warrants routine biopsy, is valid. However, the confirmation of the correct diagnosis, accurate selection of HCC patients for OLT programs, and therapeutic benefits to future patients have to be weighed against the extremely low complication rate. We commend Hepatology for raising this issue in the field of hepatology and congratulate the authors of both editorials for their excellent discussion of the associated advantages and problems.
Persistence of Aβ seeds in APP null mouse brain
Authors: Lan Ye, Sarah K Fritschi, Juliane Schelle, Ulrike Obermüller, Karoline Degenhardt, Stephan A Kaeser, Yvonne S Eisele, Lary C Walker, Frank Baumann, Matthias Staufenbiel, Mathias Jucker
Journal: Nature Neuroscience (2015)
Antiretroviral Prophylaxis to Reduce Breast-Milk HIV-1 Transmission
Authors: José A Román-Poueriet, Nicole C Kley, Consuelo M Beck-Sagué
Journal: New England Journal of Medicine (2008)

As professionals working in a resource-limited country to prevent the transmission of the human immunodeficiency virus (HIV) from mother to child and to promote child survival and the use of highly active antiretroviral therapy (HAART) we read with interest the articles about abrupt weaning and prophylaxis regimens in infants by Kuhn et al. and Kumwenda et al. (July 10 issue).12 Harm-reduction alternatives for HIV-infected mothers who breast-feed are essential. However in the study by Kuhn et al. the risk of mother-to-child transmission or death among breast-fed infants whether they were abruptly weaned or not was more than 30%.1 Extended antiretroviral prophylaxis was superior to singledose nevirapine but 8.0% of infants were infected at birth; postnatal mother-to-child transmission related to breast-feeding added a 5.2% or 6.4% risk of infection.2 Alternatives should be considered including HAART (which is now available to HIV-infected persons in Zambia3 Malawi4 and the Dominican Republic5) formula and improved access to potable water. From 1999 to 2005 the rate of mother-to-child transmission of HIV among our patients most of whom have low levels of both income and education was 3.3% with the use of multidose antiretroviral treatment and exclusive formula-feeding; 2.8% of uninfected infants died. Pregnant women in developing countries can use HAART prophylaxis regimens for infants formula and home-purified water. The cost is significant but the savings (in lives orphan care and treating infected children) are also significant. (full-text)
SSeCKS/Gravin/AKAP12 suppresses prostate cancer metastasis by inhibiting cell motility and invasion through the inactivation of inside-out Src/FAK/integrin β1-mediated pathways
Authors: Bing Su, Irwin Gelman
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

2179 

Alterations in cell-extracellular matrix (ECM) adhesion affect tumor cell migration, invasion and metastasis. The SSeCKS/Gravin/AKAP12 gene encodes a cytoskeletal protein with scaffolding activity for regulators of G1->S progression, such as cyclins, PKC and PKA. SSeCKS expression is strongly downregulated by activated forms of Src or Ras and in human prostate cancer (CaP) lesions with Gleason sum ≥6. We previously showed that the tetracycline-regulated re-expression of SSeCKS in MatLyLu (MLL) CaP cells suppressed formation of macroscopic lung metastases in both spontaneous and experimental models of in vivo metastasis, while having minimal inhibitory effects on the growth of primary-site subcutaneous tumors. Part of the metastasis-suppressing activity of SSeCKS is based on its ability to downregulate pro-angiogenic genes such as those encoding VEGF, because the forced re-expression of VEGF rescued SSeCKS-suppressed lung metastasis formation by MLL cells ( Cancer Res. 66(11):5599-607, 2006). Here we demonstrate that while SSeCKS re-expression in MLL cells does not inhibit generic cell motility (e.g.- monolayer wound-healing), it potently inhibits chemotaxis, haptotaxis and Matrigel invasion. SSeCKS re-expression correlates with a delay in the serum-induced activation of the Raf/MEK/ERK pathway and the downregulation of matrix metalloproteinases-2 (MMP-2) expression and secretion. The forced expression of a constitutively-active MEK2 allele rescues SSeCKS-suppressed chemotaxis and Matrigel invasion. In contrast to the effects on motility, SSeCKS re-expression increases cell adhesion to fibronectin (FN) and type I collagen, correlating with an increase in basal and serum-stimulated phospho-FAK Tyr397 levels (up to 180 minutes post serum treatment). In contrast, SSeCKS re-expressing MLL cells exhibit only an initial 30 minute increase in serum-induced Src autophosphorylation (SrcpoY416) and Src substrate (FAKpoY861 and FAKpoY925) levels, followed by a total loss of Src activation. The SSeCKS-enhanced adhesion could be suppressed by the stable expression of FRNK, a dominant-interfering FAK allele, or with an integrin β1-blocking antibody, anti-CD29. Our findings suggest that SSeCKS suppresses oncogenic motility and metastatic invasiveness by suppressing serum-induced ERK activation and MMP-2 secretion, while simultaneously increasing cell-ECM adhesiveness by disengaging Src from an inside-out activated FAK/integrin β1 adhesion complex.
The response to the feeding of cevitamic acid in normal and deficient subjects as measured fay a vitamin C excretory test.
Authors: Elaine P. Ralli, Gerald J. Friedman
Journal: Annals of Internal Medicine (1938)

Excerpt The criterion for the diagnosis of scurvy had been, until recently, the appearance of the symptoms of scurvy. As a result of the experimental work in vitamin C, three new diagnostic procedu...
Results from a randomized study of carboplatin and etoposide (CE) with or without palifosfamide (Pa) in extensive stage small cell lung cancer (ES-SCLC): The MATISSE study.
Authors: Shadia Ibrahim Jalal, Lawrence H. Einhorn, Gregory Lo, Philip Lavin, Francois M. Lebel
Journal: Journal of Clinical Oncology (2015)

7504 Background: Extensive stage small cell lung cancer (ES-SCLC) is a disease with high mortality. SCLC is initially exquisitely sensitive to chemotherapy with carboplatin and etoposide (CE), considered the standard first-line regimen in ES-SCLC in the US. In a previous phase III trial, the combination of cisplatin, etoposide, and ifosfamide (VIP) improved overall survival (OS) as compared to cisplatin and etoposide in ES-SCLC but with increased toxicity (JCO 13: 2594-2599,1995). Palifosfamide (Pa), a bi-functional DNA alkylator is the active metabolite of Ifosfamide that does not generate toxic metabolites facilitating its combination with CE. This trial was therefore pursued comparing CE with or without Pa in ES SCLC. Methods: This was a multi-center, open-label trial in chemotherapy-naive patients (pts) with ES SCLC with planned enrollment of 548 pts. Pts were randomized 1:1 to receive CE (C at AUC 5mg/mL/min day 1 with E 100mg/m2/day days 1-3) or PaCE (Pa at 130mg/m2/day, E at 100mg/m2/day both on days 1-3 and C at AUC 4mg/mL/min day 1). The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival, objective response rate, and quality of life assessment. Pts were stratified based on age, gender, and Eastern Cooperative Oncology Group (ECOG) performance status. Results: The MATISSE trial closed prematurely in light of the negative phase III trial evaluating the addition of Pa to doxorubicin in sarcoma (PICASSO). ES-SCLC pts (N = 188) were randomized to CE (n = 94) or PaCE (n = 94). Pt characteristics were well balanced with median age of 61 and the majority of pts having an ECOG PS of 0-1. Median OS in the Intent to treat population was 10.0 months (95% CI: 7.7-10.5) with PaCE and 10.4 months (95% CI: 8.7-13.4) with CE (p value 0.096). Serious treatment-related adverse events were observed in 28.3% pts receiving PaCE and 27.5% pts receiving CE with febrile neutropenia occurring in 4.3% of pts on PaCE arm and 5.5% of pts on CE arm. Conclusions: The addition of Pa to CE did not improve survival in ES-SCLC. The safety profile was as anticipated and the addition of Pa did not lead to increased toxicity. Clinical trial information: NCT01555710.
Restenosis: do we need to understand it to treat it?**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: David Faxon
Journal: Journal of the American College of Cardiology (2002)

“There is, we believe, both in pathogenesis and in therapeutics: much remedy, little cure; much theory, little truth.” —Pierre Marie, 1883, Archive de Neurologique

Restenosis has been the major therapeutic challenge of interventional cardiology over the past two decades. Andreas Gruentzig
Phase II study of the progesterone antagonist mifepristone in patients with untreated metastatic breast carcinoma: a National Cancer Institute of Canada Clinical Trials Group study.
Authors: D Perrault, E A Eisenhauer, K I Pritchard, L Panasci, B Norris, T Vandenberg, B Fisher
Journal: Journal of Clinical Oncology (1996)

PURPOSE Mifepristone (RU486) is a progesterone receptor (PgR) antagonist that has been shown to be active in some preclinical hormone-dependent breast cancer tumor models and to produce a few responses in patients with pretreated metastatic disease in two small trials. This trial was designed to assess the response rate and toxic effects of mifepristone in a favorable group of women with PgR-positive recurrent breast cancer who had received no prior therapy. METHODS Postmenopausal patients with PgR-positive, bidimensionally measurable disease were eligible provided they had received no other therapy for recurrence. Prior adjuvant hormonal treatment was permitted if a disease-free interval of at least 24 months had been observed. Mifepristone 200 mg was given daily and disease was reassessed every 4 weeks. Standard criteria for tumor response and toxic effects were used. RESULTS A total of 28 patients were registered in the trial: all were eligible and assessable. Three partial responses were noted for an overall response rate of 10.7% (95% confidence interval [CI], 2% to 28%). Toxic effects were generally mild to moderate and consisted primarily of nausea, lethargy, anorexia, and hot flashes. CONCLUSION Mifepristone had minimal activity in this optimal group of patients. While there may be reason to conduct some clinical studies with it in combination with antiestrogens on the basis of some preclinical work, our data do not support its use as a single agent in the management of breast cancer.
Abstract 9515: ATP Synthase Subunit Alpha and Left Ventricular Hypertrophy in Ischemic Cardiomyopathy: A Mitochondrial Proteomic Approach Using Human Cardiac Tissue
Authors: Miguel Rivera, Esther Rosello, Maria Eugenia Barderas, Estefania Tarazon, Ana Ortega, Luis Rodriguez Padial, Antonio Salvador, Manuel Portoles
Journal: Circulation (2014)

Introduction: Mitochondrial dysfunction plays a critical role in the development of ischemic cardiomyopathy (ICM). In this study, the mitochondrial proteome in the cardiac tissue of ICM patients was analyzed for the first time to identify potential molecular targets for therapeutic intervention in this cardiomyopathy. Methods: We isolated mitochondria from left ventricular (LV) samples of explanted hearts of ICM patients (n=10) and control donors (n=10) and we used a proteomic approach to investigate the variations in mitochondrial protein expression. Results: We found that most of the altered proteins were involved in cardiac energy metabolism (82%). We focused on ATPA, which is involved in energy production, and DLDH, implicated in substrate utilization, and observed that these molecules were overexpressed and that the changes detected in the processes mediated by these proteins were closely related. Notably, we found that ATPA overexpression was associated with reduction in LV mass (r=-0.74, P<0.01). W...
Abstract 16285: Routine Use of 3D Mapping and Irrigated Ablation Improves Outcomes of Pulmonary Vein Antral Isolation Among Patients With Persistent AF
Authors: Pouria Alipour, Yaariv Khaykin, Meysam Pirbaglou, Alfredo Pantano, Paul Ritvo, Patrick E Brown, Shelby Olesovsky, Lauren Chun, Atul Verma
Journal: Circulation (2015)

Bckground: Pulmonary Vein Antrum Isolation (PVAI) is a widely accepted treatment option in Atrial Fibrillation (AF). However, despite procedural advancements, post-PVAI AF recurrences remain a common challenge. We thought to investigate whether the addition of routine 3D electroanatomical mapping and routine use of irrigated ablation catheters (IC) vs 8 mm tip catheters made an impact on the outcomes of PVAI guided by intracardiac echocardiography (ICE) and a decapolar circular mapping catheter (CMC) alone. Methods: Patient and procedural data were collected for 884 AF consecutive patients undergoing PVI at a single Canadian center during 2004 - 2014 (469 patients in 2004-2009, Group 1vs. 415 patients in 2010-2014, Group 2). Group 1 patients received PVAI guided by ICE and CMC. All Group 2 patients had PVAI guided by ICE, CMC and 3D mapping with the use of irrigated tip ablation catheters. Mean ages for Groups 1 and 2 were = 58.6 ± 10.0 and 61.0 ± 10.7 years respectively (p= 0.001). Mean follow up time was 17.1 ± 18.8 months for Group 1 and 14.1± 9.7 months for Group 2 (p=0.003). ECG and ambulatory monitoring was performed at 1, 3, 6, and 12 months. Recurrences ≤ 3 months post-PVI were considered Early (ER), while recurrences after 3 months post-PVI were considered Late (LR). Using survival analysis, rates of LR stratified by AF type [Paroxysmal AF (PAF) vs. Non-PAF (NPAF)] were compared between the two cohorts Results: ER rate was lower in Group 2 vs. Group 1 (36.8% vs. 44.7%, P=0.05) in patients with PAF and for those with NPAF (54.8% vs. 66.9%, P=0.03). LR rates did not differ between the Groups among PAF patients (62.5% in Group 1 vs. 57.3% in Group 2, P=0.16), but improved significantly for the NPAF patients (55.6% in Group 1 vs. 37.9% in Group 2 , P=0.002). Conclusion: Late recurrence of AF post-PVI has dramatically improved since 2010 for patients with persistent AF following routine addition of 3D mapping to ICE and CMC, while substituting an irrigated for an 8mm ablation catheter.
A phase II study of vinoreline (VNR) and carboplatin (CBDCA) in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: H. Takatani, A. Kinoshita, M. Fukuda, Y. Soejima, S. Nagashima, F. Narasaki, H. Soda, M. Oka, S. Kohno
Journal: Journal of Clinical Oncology (2006)

17108 Background: VNR is one of standard drugs for elderly NSCLC. The role of platinum- based combination chemotherapy for elderly pts is controversial. Methods: Based on our phase I study (Fukuda, et al, abstract 2763, ASCO 2002), we conducted a phase II single arm study of VNR combined with CBDCA for elderly NSCLC pts. Primary endpoints were response and toxicity. Eligibility criteria included: chemotherapy-naïve, good performance status (PS: 0–2), age ≥75, stage IIIB-IV, and adequate hematological, hepatic and renal function, written informed consent. Treatment consisted of VNR 20 mg/m 2 i.v. on days 1 and 8 and CBDCA target AUC = 4 (Chatelut formula, Jaffe method) on day 1 of every 4 weeks. Planned sample size was 40. Results: A total of 40 pts were enrolled. Pts characteristics: male/female = 30/10, PS 0/1 = 18/22, median age (range) = 78 (75–86), Ad/Sq/Others = 30/9/1, stage IIIB/IV = 14/26. Forty pts were eligible and assessable for toxicity and survival, and 37 pts were assessable for response on the submission of this abstract. Thirty-three pts were treated with two or more courses of treatment. Overall response rate was 13.5% (95% CI, 4.5%-28.8%); CR= 0, PR= 5, SD = 23, PD = 9. Grade 3 or 4 leukopenia, neutropenia, and anemia were observed in 31.6%, 50.0%, and 7.1%, respectively. Treatment-related death did not occurred. Non-hematological toxicity was mild. The median survival time was 392 days (95% CI, 311–474) and the median time to progression was 114 days. Conclusions: This combination is well-tolerated and modest activity in pts with elderly NSCLC. No significant financial relationships to disclose.
Hypertension detection, treatment and control
Authors: Daniel Levy, C.Noel Bairey Merz, Robert J Cody, Fetnat M Fouad-Tarazi, Charles K Francis, Marc A Pfeffer, Neal A Scott, H.J.C Swan, Malcolm P Taylor, Myron H Weinberger
Journal: Journal of the American College of Cardiology (1999)

Hypertension affects about 25% of the adult population in the United States, or about 50 million people [(1,2)][1]. Over the past 30 years great strides have been made in improving awareness, treatment and control of high blood pressure [(1)][1]. These advances in blood pressure control have
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors for Treatment of High Cholesterol Levels
Authors: Jeffrey A. Tice, Dhruv S. Kazi, Steven D. Pearson
Journal: JAMA Internal Medicine (2015)

Source of Review The Institute for Clinical and Economic Review developed an evidence report, including a systematic reviewof the literature, a costeffectiveness model, and a budget impact assessment, to support a public meeting of the New EnglandComparativeEffectiveness Public Advisory Council (CEPAC) on October 27, 2015.1 The report evaluates the comparative clinical effectiveness and comparative value of proprotein convertase subtilisin/ kexin type9 (PCSK9) inhibitors as a class for the treatmentof adults with familial hypercholesterolemiaor cardiovascular disease (CVD) who require additional lowering of low-density lipoprotein cholesterol (LDL-C) levels.
Mesh use in surgery for pelvic organ prolapse
Authors: M. D. Barber
Journal: BMJ (2015)

Despite many advances, outcomes after surgery remain far from perfect

By age 80 years, one in eight women will undergo surgery for pelvic organ prolapse (POP), a condition where the pelvic organs descend into or through the vaginal canal.1 In the United States, about 80% of procedures are performed transvaginally.2 3 4 Building on the experience of general surgeons and the treatment of abdominal hernias, pelvic surgeons began using synthetic mesh to augment prolapse repairs to reduce prolapse recurrence seen frequently after native tissue (non-mesh) repairs. However, use of synthetic mesh also results in increased adverse events, in some cases with serious consequences.2 5 As a result, the use of mesh for transvaginal POP surgery has been the source of much scrutiny, including two public health notifications from the US Food and Drug Administration (FDA), a change in the US regulatory process for mesh devices, and substantial litigation.2 6

In a linked article (doi:10.1136/bmj.h2685), Chughtai and colleagues report on mesh use and risk of complications and reintervention of POP surgeries from a large, population based cohort from New York state between 2008 and 2011. Overall, 26% of the 27 991 patients in the cohort received mesh as part of their …
Neurology Advocacy 2.0
Authors: Nicholas E. Johnson, Amy Kaloides, Elaine Jones
Journal: JAMA Neurology (2015)

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Functional properties of patient-derived melanoma cancer stem cells
Authors: Gabriel Nistor, Aleksandra Poole, Hans Keirstead
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Caladrius Biosciences has recently identified biomarkers that may predict clinical efficacy in immunotherapy treatments for melanoma. While numerous clinical trials demonstrated success in long-term survival using immunotherapy agents in various types of malignancies, very few