tbuckley/cabot-search huggingface dataset:
Randomised comparison of oestrogen versus oestrogen plus progestogen hormone replacement therapy in women with hysterectomy
Authors: T W Meade
Journal: BMJ (1996)

<h3>Abstract</h3> <b>Objective</b>: To compare the acceptability and symptomatic and metabolic effects of two regimens of hormone replacement therapy in women with hysterectomy. <b>Design</b>: Randomised, double blind comparison. <b>Setting</b>: Seven group practices in the Medical Research Council9s general practice research framework. <b>Subjects</b>: 321 women with hysterectomy aged 35-59. <b>Interventions</b>: Hormone replacement therapy with (a) conjugated equine oestrogen 625 µg daily alone or (b) conjugated equine oestrogen 625 µg daily plus the progestogen norgestrel 150 µg daily for the last 12 days of the "cycle." <b>Main outcome measures</b>: Changes in blood pressure, weight, symptoms, and haemostatic and lipid values. <b>Results</b>: After two years 36% (57/158) of women randomly allocated to take oestrogen alone had discontinued treatment as compared with 30% (49/163) of women allocated to take oestrogen plus progestogen. Smokers were more likely to withdraw than non-smokers. There were no clear differences between the two groups in symptoms often attributed to hormone replacement therapy or in blood pressure or weight. At one year low density lipoprotein cholesterol concentrations had fallen substantially in both groups. High density lipoprotein cholesterol concentrations rose to significantly higher values in women taking oestrogen alone compared with those taking oestrogen plus progestogen, though triglyceride concentrations and factor VII activity were also significantly higher in this group. Fibrinogen concentration tended to fall, though not significantly, in both groups, possibly more in women taking oestrogen alone. <b>Conclusions</b>: Oestrogen plus progestogen was no less well tolerated than oestrogen alone. There was a fairly even balance between possibly beneficial and adverse effects of the two regimens on lipid concentrations and coagulability. Concern that the combined regimen may not have the cardioprotective effects ascribed to oestrogen alone can to some extent be allayed, with reassurance for the growing numbers of women with intact uteri using the combined regimen. Misgivings about the combined regimen in women with hysterectomy on the grounds of its acceptability and its effects on lipid values may also be unfounded. <h3>Key messages</h3> Key messages In fact, in hysterectomised women norgestrel containing hormone replacement preparations may be as well tolerated as unopposed oestrogen There may be little difference between norgestrel containing hormone replacement therapy and oestrogen only preparations in their lipid and haemostatic effects Pending the results of clinical end point trials, anxieties about the metabolic effects of norgestrel in hormone replacement therapy can largely be allayed
Circulating tumor DNA before and after surgical resection in patients with peritoneal carcinomatosis.
Authors: Joel Micah Baumgartner, Kimberly C. Banks, Richard Burnham Lanman, Lisa Tran, Kaitlyn J. Kelly, Andrew M. Lowy, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2016)

e13000 Background: Analysis of cell-free DNA (cfDNA) using next generation sequencing (NGS) may be a useful tool for the detection and monitoring of alterations present in circulating tumor DNA (ctDNA). To date, most analyses of ctDNA have been performed on patients with locally advanced or widely metastatic disease. Patients with peritoneal carcinomatosis present unique diagnostic, prognostic and therapeutic challenges. We sought to explore pre- and postoperative ctDNA detection rates and correlation with outcomes in patients with peritoneal carcinomatosis in whom surgery was planned. Methods: Patients referred for surgical resection of peritoneal carcinomatosis underwent pre- and postoperative ctDNA analysis using NGS of plasma cfDNA (68 genes, Guardant Health, a CLIA-licensed lab). Results: Forty-five patients have undergone preoperative ctDNA testing (26 [57.8%] women; median age, 54 years). Diagnoses included: 36 (80.0%) patients with appendix cancer; 6 (13.3%), colorectal; 1 (2.2%) each of small bowel, cholangiocarcinoma, and peritoneal mesothelioma. Thirty-two patients (71.1%) underwent curative-intent tumor resection; while 13 (28.9%) underwent palliative-intent surgery. Fourteen patients (31.1%) had detectable preoperative ctDNA alterations, most frequently in the following genes: TP53 (23.8% of all preoperative alterations detected), KRAS (19.0%), GNAS (9.5%), and TERT(9.5%). Fifty-two percent (12/23) of patients that have undergone postoperative ctDNA testing (median 2.9 weeks after surgery; range, 1.1 to 21.3 weeks) had a detectable postoperative ctDNA alteration. Two patients had different genetic alterations detected than those found preoperatively, and 2 of 14 patients (14.2%) who had preoperative alterations showed no alterations postoperatively. Conclusions: A significant proportion of patients with peritoneal carcinomatosis referred for surgical intervention have detectable ctDNA alterations before and after surgery. Further study of potential association between clinical outcome and quantity of ctDNA and the presence of postoperative ctDNA alterations, as well as correlations with tissue NGS are ongoing and will be included in the final data presentation.
Variations in measured ER, PR, and HER2 status in synchronous and asynchronous paired breast cancer (BC) tumors.
Authors: Clayton Yates, Sherri Z. Millis, Sandeep K. Reddy, Zoran Gatalica, Joyce O'Shaughnessy, Windy Marie Dean-Colomb
Journal: Journal of Clinical Oncology (2015)

567 Background: That tumor heterogeneity exists and evolves over time is well appreciated but how often to biopsy patients’ metastatic BC is not well established. Methods: Immunohistochemical (IHC) and in situ hybridization (ISH) analysis of estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), and HER2 in 337 cases with > 1 asynchronous primary/metastatic BC molecular profiles and in 40 cases with > 1 synchronous molecular profiles was performed at a single institution. We evaluated differences in ER, PR and HER2 status in same or contralateral breast, and in primary vs. locally recurrent or metastatic BC’s. Results: We identified a change in ER or HER2 status in 8 (31%) synchronous BCs and in 55 (16%) primary/recurrent BCs, including in biopsies of distinct tumor foci within the same breast or metastatic organ site. Of the 8 synchronous bilateral primary BC’s, 4 (50%) had discordant ER results (ER, PR, and HER2 negative [TN] vs. ER+); 5 of 18 (28%) with two or more metastatic foci tested within the same organ had discordant ER results; 23% of BCs with biopsies of different organ sites had discordant ER results. Of the 55 paired primary/metastatic BCs, 15% of the discordant findings were in cases with biopsies from two different metastatic sites, 19% were in cases with one metastatic and one primary or local recurrent biopsy, and 23% were from 2 primary biopsies or from primary and locally recurrent disease. Discordance was bidirectional from either TN to ER+ or ER+ to TN, and independent of discordance in HER2. Conclusions: Standard systemic treatment of BC relies on reliable assessment by IHC analysis of ER, PR, and HER2. Within a patient, ER and HER2 status are not always concordant between lesions within the same breast, between bilateral BCs, and between distinct foci in a metastatic organ site. Patients are at risk of not being treated for the most clinically important foci of BC if the biopsy(s) obtained are not representative of the more aggressive areas of disease. Profiling should be performed on multiple BC samples both at diagnosis and at each time of recurrence/progression in the cancer continuum, to more accurately reflect the tumor profile at the time of treatment.
Induction of ATF3 and EGR3 by deoxycholate and a singular acid pulse in oesophageal cells
Authors: S Duggan, J Reynolds, D Kelleher
Journal: Endoscopy (2005)

Introduction: The molecular events that allow the progression of the normal oesophageal squamous epithelium to the specialized intestinal metaplasia also known as Barrett's oesophagus are poorly understood. It is known that disease progression is linked to gastro-oesophageal reflux disease and as such it will be invaluable to understand the gene's/molecules involved in both low pH and bile acid signalling.
Early onset breast cancer: Differences in environmental and reproductive factors, tumor phenotype and BRCA1/BRCA2 genotype between the north and south of the Mediterranean Sea.
Authors: Pascal Pujol, Sarra Henouda, Alain Toledano, Dalel Ben Nejima, Hamouda Boussen, Faouzi Habib, Asma Mouhout, Ahmed mohamed Gaballah, Hesham El Ghazaly, Celine Bourgier, Isabelle Coupier, Helena Bertet, Virginie Galibert, Paul Vilquin, Louise Biquard, Jean-Marc Rey, Yazid Belkacemi, Marie Christine Picot, Assia Bensalem, Carole Corsini
Journal: Journal of Clinical Oncology (2016)

e12016 Background: Early onset breast cancer ( ≤ 40 years, EOBC) have a particular aggressive phenotype with a high rate of triple negative (TN) tumors and a worse prognosis. It has also been reported that EOBC occurring in North African countries have a more aggressive phenotype and outcome than in occidental countries. This report compares the environmental and reproductive factors, the tumor phenotype and the BRCA1/BRCA2 genotype in EOBC between France and North Africa. Methods: 455 women with invasive EOBC were included from 01/2014 to 06/2015 from 7 participating centers in 5 countries (Algeria, Egypt, France, Morocco, Tunisia). Life factors, tumor phenotype, familial history of BC, BRCA1 and BRCA2 genotype were compared between North Africa (n = 185) and France (n = 270). Results: A younger age at menarche, a higher number of childbearing, a longer duration of breastfeeding, a higher body mass index are found in North African women as compared to French women (p < 0.001). Use of oral contraceptives and consumption of alcohol and tobacco are higher in French women (p < 0.001). TNM stage at diagnosis is higher in North Africa than in France (T3-T4: 44 % vs 10%; N+: 56% vs 42%; M+: 22% vs 4%, respectively, p < 0,001). Conversely, North African women have a lower incidence of TN and proliferative (Ki 67 index > 20%) tumors (p = 0.01 and < 0.01, respectively). We found a lower rate of BRCA1 mutation in North Africa (7 vs 15%, p = 0,02). However, in the subgroup of sporadic BC a higher rate of BRCA1 mutations is observed in North Africa (p = 0.02). Two possible BRCA1/2founder mutations were identified in Algeria and one in Morocco. Conclusions: In women with EOBC, there is a higher incidence of TN and proliferative tumors in France as compared to North Africa. The major differences found in reproductive and environmental factors could thus influence the phenotype of EOBC. The worst prognosis of EOBC previously suggested in North Africa is more likely due to a higher stage at diagnosis than to a more aggressive phenotype. Prevalence and penetrance of BRCA1 mutations appear different between the two shores of the Mediterranean Sea.
Encapsulation of crystalline topotecan in sphingosomes: a formulation suitable for clinical development
Authors: Barbara L.-S. Mui, Quet-Fah Ahkong, Robert Leone, Kim Wong, Kieu Lam, Laurie Chow, Qiang Hu, Michael J. Hope
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

1397 

Topotecan (9-dimethylaminomethyl-10-hydroxy-camptothecin) is a semi-synthetic, water-soluble derivative of camptothecin used for the second-line treatment of metastatic ovarian and small-cell lung cancer. Although topotecan is clinically active, its full potential is compromised by the rapid loss of antitumor activity at physiological pH due to hydrolysis of the closed lactone E ring to form a ring-opened carboxylate moiety. The closed ring configuration is stable at acidic pH; therefore clinically active topotecan can be maintained in the circulation when the drug is encapsulated in liposomes with an acidic interior. Several formulations of this type have been described in the literature and shown to exhibit enhanced antitumor activity compared to free drug in animal models. Here we describe the detailed characterization of a novel liposomal topotecan formulation. The drug is encapsulated to high concentration into preformed egg sphingomyelin/cholesterol (ESM/CH, 55:45 mol ratio) vesicles (sphingosomes) using a chemical gradient of Mg2+ or Mn2+ and the divalent cation/H+ ionophore A23187 to generate a pH gradient (inside acidic). Greater than 90 % encapsulation of topotecan occurs after 40 minutes at pH 6 and 60oC employing incubation volumes ranging from 1 ml to 20 L. Topotecan is highly membrane permeable and difficult to retain inside conventional liposomes. However, sphingosomes provide a rigid bilayer structure, which is less permeable to drug than conventional phospholipid bilayers, and is very stable in blood. Using cryo electron microscopy and 1H-NMR we show that >98 % of the encapsulated drug is in the form of solid, needle-like crystals. Increasing drug retention increases efficacy and the pharmacokinetics and greatly enhanced antitumor activity of this formulation are described in an accompanying abstract.
The Clinical Trial
Authors: A. Bradford Hill
Journal: New England Journal of Medicine (1952)

IT IS with mixed feelings that I stand, a layman, before the medical faculty of one of the world's most famous universities. In the past century, or more, statisticians have, it is true, been recognized as having a right of entry to the field of public health, and to its related sciences of epidemiology and preventive medicine. They have been closely associated with medical officers of health. They have worked with all who have been concerned with the promotion and maintenance of the well-being of the community. But it is clear that the health of the community — the group . . .
Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice
Authors: Bérengère Benoit, Emmanuelle Meugnier, Martina Castelli, Stéphanie Chanon, Aurélie Vieille-Marchiset, Christine Durand, Nadia Bendridi, Sandra Pesenti, Pierre-Axel Monternier, Anne-Cécile Durieux, Damien Freyssenet, Jennifer Rieusset, Etienne Lefai, Hubert Vidal, Jérôme Ruzzin
Journal: Nature Medicine (2017)
The relationship between cardiac endothelium and fibroblasts: it’s complicated
Authors: Ravi Karra, Agoston O. Walter, Sean M. Wu
Journal: Journal of Clinical Investigation (2017)

Coronary revascularization is an effective means of treating ischemic heart disease; however, current therapeutic revascularization strategies are limited to large caliber vessels. Because the mammalian heart scars following cardiac injury, recent work showing that cardiac fibroblasts can transdifferentiate into new coronary endothelium raises a new and exciting approach to promoting endogenous revascularization following cardiac injury. In this issue of the JCI, He et al. report on their employment of a battery of lineage-tracing tools to address the developmental origins of fibroblasts that give rise to new endothelial cells. Surprisingly, cardiac fibroblasts did not appear to contribute appreciably to regeneration of cardiac endothelium. Instead, cardiac endothelial cells were likely to proliferate and generate new endothelium following injury. As these conclusions diverge from prior findings, additional work will be required to understand the sources that generate cardiac endothelium in new blood vessels after injury. Clarification of the origins of coronary endothelial cells during cardiac repair is essential for identifying improved approaches to revascularizing damaged myocardium in patients with ischemic heart disease.
First-in-Human Study of AMG 820, a Monoclonal Anti-Colony-Stimulating Factor 1 Receptor Antibody, in Patients with Advanced Solid Tumors
Authors: Kyriakos P. Papadopoulos, Larry Gluck, Lainie P. Martin, Anthony J. Olszanski, Anthony W. Tolcher, Gataree Ngarmchamnanrith, Erik Rasmussen, Benny M. Amore, Dirk Nagorsen, John S. Hill, Joe Stephenson
Journal: Clinical Cancer Research (2017)

Purpose: Binding of colony-stimulating factor 1 (CSF1) ligand to the CSF1 receptor (CSF1R) regulates survival of tumor-associated macrophages, which generally promote an immunosuppressive tumor microenvironment. AMG 820 is an investigational, fully human CSF1R antibody that inhibits binding of the ligands CSF1 and IL34 and subsequent ligand-mediated receptor activation. This first-in-human phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 820.Experimental Design: Adult patients with relapsed or refractory advanced solid tumors received intravenous AMG 820 0.5 mg/kg once weekly or 1.5 to 20 mg/kg every 2 weeks until disease progression, adverse event (AE), or consent withdrawal.Results: Twenty-five patients received ≥1 dose of AMG 820. AMG 820 was tolerated up to 20 mg/kg; the MTD was not reached. One dose-limiting toxicity was observed (20 mg/kg; nonreversible grade 3 deafness). Most patients (76%) had treatment-related AEs; the most common were periorbital edema (44%), increased aspartate aminotransferase (AST; 28%), fatigue (24%), nausea (16%), increased blood alkaline phosphatase (12%), and blurred vision (12%). No patients had serious or fatal treatment-related AEs; 28% had grade ≥3 treatment-related AEs. Grade 3 AST elevations resolved when treatment was withheld. AMG 820 showed linear pharmacokinetics, with minimal accumulation (<2-fold) after repeated dosing. Pharmacodynamic increases in serum CSF1 concentrations and reduced numbers of skin macrophages were observed. Best response was stable disease in 8 patients (32%).Conclusions: AMG 820 was tolerated with manageable toxicities up to 20 mg/kg every 2 weeks. Pharmacodynamic response was demonstrated, and limited antitumor activity was observed. Clin Cancer Res; 23(19); 5703-10. ©2017 AACR.
Abstract 109: Characterization of Secretome From C-kit+ Cells Derived From Neonate and Adult Heart Patients
Authors: Sudhish Sharma, Rachana Mishra, Young A Goo, Brody P Wehman, Yin Guo, Srinivasa R Datla, Keerti Balachandran, Osama T Siddiqi, Sunjay Kaushal
Journal: Circulation Research (2015)

Background: Despite the regenerative benefit reported in recent human clinical trials (SCIPIO trial) using human cardiac stem cells (CSCs) (identified by ckit+CD45-/lin-), low retention and differentiation of transplanted hCSCs into cardiomyocytes are insufficient to explain the myocardial regeneration. This discrepancy has led to the paracrine hypothesis of stem cell action that indicates communication between newly transplanted stem cells and reparative native cells, essentially jumpstarting the repair process. Methods: We derived CSCs from the biopsies of right atrial appendage (RAA) of neonatal human subjects (nCSCs, age &lt; 2 months) and from adult human subjects (aCSCs, age &gt;50 years). CSCs were grown upto 90% confluency and incubated with basal medium (Ham’s/F12) for 72 hours. Conditioned medium (CM) was collected and further analyzed. Results: The expression levels of various key cytokines were analyzed using ELISA and data showed nCSCs secrete higher levels of the angiogenic cytokines like SDF1, VEGF-A, ANG, SCF, PDGB, and FGF2 compared to over 20 other cytokines we examined as compared to aCSCs. CM derived from nCSCs showed more angiogeneic potential as compared to CM derived from aCSCs as analyzed by HuVEC tube assay formation. We also did a comparative analysis of CM from nCSCs and aCSCs using mass spectrometry. Molecular distribution of lead proteins revealed that the yhCSCs has more angiogenic, anti-inflammatory and proliferative proteins while ahCSCs have more of apoptotic proteins Conclusion: These data provide preliminary evidence that there is a difference in the cytokine secretion by the nCSCs as compared to aCSCs and implicates highly expressed cytokines as the key to myocardial recovery.
Primary Renal Paragangliomas and Renal Neoplasia Associated with Pheochromocytoma/Paraganglioma: Analysis of von Hippel–Lindau (VHL), Succinate Dehydrogenase (SDHX) and Transmembrane Protein 127 (TMEM127)
Authors: Sounak Gupta, Jun Zhang, Dragana Milosevic, John R. Mills, Stefan K. Grebe, Steven C. Smith, Lori A. Erickson
Journal: Endocrine Pathology (2017)
The association between antihypertensive medications and breast cancer characteristics.
Authors: Hadar Goldvaser, Shulamith Rizel, Daniel Hendler, Victoria Neiman, Daniel Shepshelovich, Tzipora Shohat, Baruch Brenner, Aaron Sulkes, Rinat Yerushalmi
Journal: Journal of Clinical Oncology (2016)

e12000 Background: Data regarding the impact of antihypertensive medications on breast cancer are inconsistent. We evaluated the association between antihypertensive medications on tumor characteristics and outcome for patients with estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2) negative early breast cancer, whose tumors were sent to Oncotype DX analysis. Methods: This was a retrospective, single center study. Patients' Charts were reviewed for demographics, clinicopathological parameters, chronic medications, treatment and outcome. Patients were grouped according to antihypertensive medications usage during the time of breast cancer diagnosis. Every group was compared to the rest of the cohort. Results: A total of 671 patients were included. Treatment with β-blockers (BB), angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and mineralocorticoid receptor antagonists (MRA) were recorded in 17.5%, 14.2%, 7%, and 2.1% of the study population, respectively. Patients treated with ARB had different histological subtype distribution (p = 0.009), higher incidence of macroscopic nodal involvement (p < 0.001) and more advanced stage (p < 0.001). Interestingly, mean Ki67 was lower for these patients (p = 0.005). ACEI usage was associated with larger tumors (p = 0.004). Patients treated with either ARB or ACEI had larger tumors (p < 0.001), more macroscopic lymph node involvement (p = 0.03) and presented with more advanced stage (p < 0.001). They also had less intense progesterone receptor staining (p = 0.04) and different histological subtype distribution (p = 0.007). Patients treated with BB had higher incidence of angiolymphatic invasion (p = 0.002). MRA usage had no impact on examined characteristics. None of the medications evaluated in the study influenced disease free survival. Conclusions: ARB and ACEI usage was associated with worse tumor characteristics at presentation for patients with ER positive, HER2 negative early breast cancer. Further research is needed to validate our finding and to elucidate the effect of anti-hypertensive treatment in breast cancer.