tbuckley/cabot-search huggingface dataset:
Optical blood irradiation in improving the effectiveness of neoadjuvant polychemotherapy for breast cancer.
Authors: Elena A. Sheiko, Alla Ivanovna Shikhlyarova, Larisa Nikolaevna Vashchenko, Stella Babieva
Journal: Journal of Clinical Oncology (2017)

e12124 Background: Breast cancer (BC) incidence rates are increasing worldwide. Development of multicomponent programs, in particular polychemotherapy combined with technologies of quantum medicine, can help increase BC treatment effectiveness. The purpose of the study was to assess clinical efficacy of neoadjuvant polychemotherapy (PCT) modified with extracorporeal optical blood processing in BC. Methods: The study included 90 patients, mean age 48 years, with stage IIIB BC: nodular BC with secondary edema – 80 (88.8%) patients, edematous-infiltrative BC – 10 (11.2%) patients. Menstrual function was preserved in 20 (22.3%) patients; the other 70 (77.7%) women were menopausal. The control group (30 patients) received PCT with the total course doses of cytostatics: doxorubicin - 200 mg, 5-fluorouracil - 3000 mg, cyclophosphan - 100 mg, methotrexate - 100 mg. The main group (60 patients): 200 ml of blood from a peripheral vein was obtained into tubes with Glugicir, and then doxorubicin 50 mg/m 2 , methotrexate 25 mg/m 2 , 5-fluorouracil 750 mg/m 2 and cyclophosphan 600 mg/m 2 were added and incubated for 40 min at 37 о C. The blood was continuously irradiated for 3 minutes using red light λ=0.67 µm, W=5 J/cm2. After that, the blood was transfused back to the patient intravenously. Each course included 3 procedures with a 3-day interval, and patients received 2-3 courses with a 3-week interval. Results: The assessment of neoadjuvant chemotherapy modified with extracorporeal optical blood processing showed increased rates of resectable BC by 2.8 times; an objective antitumor effect increased by 20%, and tumor growth rates reduced by 3.5 times. Conclusions: This technology can become an effective additional factor improving the effectiveness of anticancer therapy.
New insights into the mechanisms of venous thrombosis
Authors: Nigel Mackman
Journal: Journal of Clinical Investigation (2012)

In the second paragraph of the Introduction, the final two sentences were incorrect.The correct sentences are below.Finally, individuals with non-type O blood have decreased clearance of von Willebrand factor (vWF).Since FVIII circulates in plasma bound to vWF, an increase in plasma vWF is also associated with increased levels of FVIII.The author regrets the error.
New tool flags randomised controlled trials that may contain false data
Authors: Nigel Hawkes
Journal: BMJ (2017)

Dozens of randomised controlled trials may contain false or fraudulent data, a statistical analysis of more than 5000 papers has shown.1

John Carlisle, a consultant anaesthetist at Torbay Hospital in Devon, has developed a statistical method for assessing whether the baseline data in a reported trial are consistent with the distribution people would expect. The method can be used to identify papers in which demographic data—such as age or body weight—exhibit either too wide or too narrow a distribution to be true.

In earlier papers Carlisle examined the work of Yoshitaka Fujii, a Japanese anaesthetist with more than 190 retractions to his name, and found that his baseline data often failed this test. Carlisle has now searched 5087 randomised controlled trials published from 2000 to 2015 in six anaesthesia journals, as well as in JAMA and the New …
Capecitabine maintenance therapy after docetaxel/capecitabine combination chemotherapy in patients with metastatic breast cancer.
Authors: Pinar Gursoy, Zeki Gokhan Surmeli, Burcu Cakar, Cagatay Arslan, Baha Zengel, Burcak Karaca, Canfeza Sezgin, Bulent Karabulut, Ulus Ali Sanli, Ruchan Uslu
Journal: Journal of Clinical Oncology (2013)

e12018 Background: Addition of capecitabine to docetaxel improves survival outcomes compared with single agent docetaxel in metastatic breast cancer (MBC). In this study we analyzed efficacy of maintenance therapy with single agent capecitabine after six cycles of docetaxel/capecitabine chemotherapy in MBC patients. Methods: Patients with metastatic HER2 negative breast cancer were included. Six cycles of docetaxel (75mg/m 2 q3wk) / capecitabine (1650mg/m 2 /day on days 1 to 14) followed by capecitabine (2000 mg/m 2 /day on days 1 to 14) were administered. Demographic features, progression free (PFS) and overall survival (OS) and response to treatment were recorded. Results: Fifty-four patients were included. Thirty-five patients (65%) were postmenopausal, and 40 (74%) were ER/PR positive. Median age was 53 (range 28 – 70). Number of metastatic sites was one in 23 patients, two in 21, three or more in 10 patients. Most common metastatic sites were bone (67%), lymph nodes (33%), lungs (30%), liver (13%); 13 patients (24%) had bone only disease. Forty-four (81.5%) patients received treatment in first-line, 10 (18.5%) received in second line setting. Median number of cycles applied (including docetaxel/capecitabine combination) was 9 (range 2 – 31, total 576). Median PFS was 9 months (10.4 for hormone receptor positive, 7.3 for negative patients) and median OS was 28 months. Objective response was assessable in 38 patients. Overall response rate (partial + complete response) was 42.6% (95% CI 29.6 – 55.6) with 1 complete response. Toxicities were evaluated in 41 patients; grade 3/4 neutropenia was observed in 10% and grade 3/4 hand-foot syndrome was observed in 24% of patients. Dose reduction was performed in capecitabine in 37%, and in docetaxel in 20% of patients. Conclusions: Maintenance with single agent capecitabine therapy after six cycles of docetaxel/capecitabine chemotherapy is an effective and tolerable treatment option for HER2 negative MBC patients.
Abstract P197: Reversible Acetylation of GSK3β Regulates the Development of Cardiac Hypertrophy
Authors: Ravi Sundaresan Nagalingam, Vinodkumar B Pillai, Sadhana Samant, Don Wolfgeher, Madhu Gupta, Mahesh P Gupta
Journal: Circulation Research (2011)

Glycogen synthase kinase 3β (GSK3β) is a critical regulator of diverse cellular functions involved in the maintenance of cellular structure, function and survival. In the heart, GSK3β has been shown to play a key role in antagonizing the development of cardiac hypertrophy. It has been shown that GSK3β activity is inhibited by phosphorylation at Ser9 during the development of cardiac hypertrophy. However, recent studies indicated that blocking the Ser9 phosphorylation alone is not sufficient to protect GSK3β activity, suggesting that alternative mechanisms might be involved in regulation of GSK3β activity. In the present study, we tested the hypothesis whether GSK3β is acetylated in established hypertrophy, which leads to inhibition of GSK3β activity, and thereby promoting progression and maintenance of cardiac hypertrophy. We examined acetylation, phosphorylation and catalytic activity of GSK3β in pressure overload model of cardiac hypertrophy at different stages of hypertrophy development. The results showed that GSK3β catalytic activity was significantly down-regulated throughout the course of hypertrophy development. However, the inhibitory phosphorylation of GSK3β was observed only at initial stages, but not at later stages of pressure overload (4 weeks). Interestingly, we observed a significantly increased acetylation of GSK3β, which corresponded to the reduced activity at this later stage of hypertrophy. We then determined the impact of GSK3β acetylation on its catalytic activity, by measuring the ability of GSK3β to phosphorylate the substrate glycogen synthase. The results showed that acetylation decreased the catalytic activity of the GSK3β by almost 3 fold. Next, we performed mass spectrometry to find out the target lysine residues of GSK3β. Proteomic analysis revealed that multiple lysine residues in different regions of GSK3β were acetylated. By using site directed mutagenesis, we found that acetylation inhibits the catalytic activity of GSK3β by suppressing its substrate binding ability, which is independent of inhibitory-Ser 9 phosphorylation. These studies for the first time show a phosphorylation independent mechanism regulating GSK3β activity during progression and maintenance of cardiac hypertrophy.
The chemotherapeutic selection for pancreatic cancer patients with peritoneal dissemination: A retrospective study from a single center.
Authors: Maiko Mizushima, Tatsuya Ioka, Ryoji Takada, Nobuko Ishida, Hironari Sueyoshi, Nobuyasu Fukutake, Reiko Ashida, Hiroyuki Uehara, Kazuhiro Katayama
Journal: Journal of Clinical Oncology (2014)

e15195 Background: Pancreatic cancer(PC) patients(pts) with peritoneal dissemination have a poor prognosis. This retrospective study evaluated the prognosis of Gemcitabine(GEM)-based current chemotherapy(G), GEM plus S-1 combination therapy(GS) and single agent of S-1 as 1st line chemotherapy regimen in PC pts with peritoneal dissemination. Methods: This is a retrospective study of PC pts with ascites or peritoneal nodules in the CT or US image who underwent chemotherapy between 2002 and 2011. We collected data regarding age, sex, Performance Status(PS), tumor location, other metastasis location, status of peritoneal dissemination, CA19-9, CEA, albumin, CRP. We classified 1st line chemotherapy regimen in G, GS and S-1, and we evaluated 1-year survival rate, progression free survival(PFS), and overall survival(OS) for the 3 regimens Results: A total of 109 pts were included. The median age was 65 (35-77), males 58.7%, PS 0-1 90.8%. The number of pts treated with G, GS, S-1 was 56, 37, and 16, respectively. The 1-year survival rates of G, GS and S-1 were 23.2%, 21.6% and 50.0%. The median PFS was 112 days, 85 days and 126 days, respectively. The median OS was 196 days, 158 days, 272 days, respectively. The 1-year survival rates of S-1 were significantly better than that of G (P=0.04). Median PFS and median OS of S-1 didn’t demonstrate the superiority compared with that of G (P=0.35, P=0.09). Conclusions: We suggest the use of S-1 as 1st line chemotherapy regimen in PC pts with peritoneal dissemination and we need further investigation.
Obstacles, Opportunities and Priorities for Advancing Metastatic Breast Cancer Research
Authors: Margaret Flowers, Stephanie Birkey Reffey, Shirley A. Mertz, Marc Hurlbert
Journal: Cancer Research (2017)

In January 2016, the Metastatic Breast Cancer Alliance (the Alliance) convened a think tank of stakeholders from academia, government, industry, and patient advocacy to discuss gaps and opportunities in clinical and translational research in metastatic breast cancer. Priorities that emerged from the meeting included the following: the need for innovative preclinical model systems to study metastatic disease; increased sharing of resources and data; collaboration across cancer care teams and scientists; biorepositories for studies to identify biomarkers for treatment response; creation of patient registries to increase access to clinical trials and tissue procurement; and redesign of clinical trials in metastatic breast cancer. Cancer Res; 77(13); 3386-90. ©2017 AACR.
Increasing antimicrobial resistance of Pseudomonas aeruginosa in an intensive care unit in Italy. 14th European Congress of Clinical Microbiology and Infectious Diseases, Prague, 1-4 May 2004. 14th European Congress of Clinical Microbiology and Infectious Diseases, Prague, 1-4 May 2004.
Authors: B. Allegranzi, A. Azzini, A. Luzzani, F. Rapagna, F. Favari, E. Concia, L. Antozzi
Journal: Clinical Microbiology and Infection (2004)
Abstract P072: Blunted β-Adrenergic Response in R92L Cardiac Troponin T Mutant Hearts Occurs via Decreased Accessibility to PKA-Mediated Phosphorylation Sites at Serine 22/23 Residues of Cardiac Troponin I
Authors: Jesus Jimenez, Jil C Tardiff
Journal: Circulation Research (2011)

While diastolic dysfunction due to impaired relaxation is a classic finding in patients with Familial Hypertrophic Cardiomyopathy (FHC), the primary cellular mechanisms remain undefined. We have previously demonstrated impaired relaxation in our transgenic mouse models of FHC carrying the cTnT R92L mutation. We hypothesize that the impaired relaxation in RL is a result of an allosterically mediated, diminished structural accessibility to the PKA phosphorylation sites on cTnI. Protein levels of phosphorylated TnI at baseline and following stimulation with isoproterenol were significantly lower for RL compared to non-transgenic (NT) mice while protein levels of phosphorylated phospholamban (PLB), TnI, and PLB were the same between both groups. These results indicate that PKA signaling is intact and uncoupling occurs at the myofilament level. Next, we crossed RL mice with phosphomimetic mice that have had their cTnI residues S 22 S 23 changed to D 22 D 23 to generate the double transgenic RL/DD. Preliminary isovolumic studies demonstrated improved contractility and relaxation for RL/DD compared to RL alone but did not reach levels observed for NT following graded doses of dobutamine (Figures A and B). In Ca 2+ transient measurements of isolated adult cardiac myocytes, DD cells demonstrated enhanced peak rates of Ca 2+ rise and fall as well as accelerated times to 50% and 90% Ca 2+ declines compared to NT and RL. However, RL/DD mice did not show improvement in any of these parameters. Collectively, these results indicate that the diastolic dysfunction observed in R92L is caused by direct impairment of the myofilament axis in the beta adrenergic signaling cascade.
Diagnostic accuracy of core needle biopsy by image guidance and vacuum assistance.
Authors: Firas M Dabbous, Sarah M. Friedewald, Ellen O'Meara, Donald L. Weaver, Karen Wernli, Kimberly Ray, Garth H Rauscher
Journal: Journal of Clinical Oncology (2017)

e12081 Background: Half of the women in the US undergoing annual screening mammography over 10 years require at least one additional imaging study. Of these women, 7%-17% undergo biopsies, the majority of which (77%) are benign. We sought to estimate the accuracy of core needle biopsy (CNB) by method of imaging guidance and use of vacuum assistance (VA). Methods: Data were pooled from four registries participating in the Breast Cancer Surveillance Consortium (bcsc-research.org) including facilities that perform both VA and non-VA CNB. Each registry collects data on screening mammography and breast pathology reports linked to their state cancer registries or regional Surveillance, Epidemiology and End Results registry. Sensitivity was defined as the proportion of positive biopsies among all cancers diagnosed within 12 months of biopsy. PPV3 was defined as the percentage of all biopsies performed that were positive for cancer. We estimated the adjusted average population risks/rates by modality using marginal standardization with logistic regression in STATA.Results: : Among the 37,270 CNBs, breast malignancy was found in 9,241 women (28.6%), of which 2,276 (25%) were ductal carcinoma in-situ. Sensitivity was 90.5% (95% CI 82.6-98.4) for non-VA Stereotactic (n = 415), 95.4% (95% CI 94.7-96.1) for VA Stereotactic (n = 18,733), 96.1% (95% CI 95.4-96.7) for non-VA ultrasound (n = 14,803), 95.1% (95% CI 93.7-96.5) for VA Ultrasound (n = 3,271) and 82.3% (95% CI 59.9-104.6) for non-VA MRI (n = 48). PPV3 was 12.2% (95% CI 9.0, 15.3), 17.7% (95% CI 17.2, 18.3), 28.6% (95% CI 27.8-29.4), 32.1% (95% CI 30.4-33.8) and 16.9% (95% CI 5.3, 28.5), respectively. For stereotactic biopsies, VA was associated with improved PPV3 (p = 0.01) without any change in sensitivity compared to non-VA Stereotactic biopsies.Conclusions: Our multicenter data confirm that VA-stereotactic CNB and ultrasound CNB with or without VA have high sensitivity and thus represent effective alternatives to open surgical biopsy.
Could the Adoption of Unleaded Gasoline in the 1970s Play a Role in the Precipitous Decline in Dementia Prevalence?
Authors: Esme Fuller-Thomson, Sydney A. Jopling
Journal: JAMA Internal Medicine (2017)

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Phase II trial of neoadjuvant (neo) palbociclib (Palbo) plus anastrozole (ana) in endocrine resistant clinical stage 2/3 estrogen receptor positive and HER2 negative (ER+ HER2-) breast cancer (BC).
Authors: Nusayba Ali Bagegni, Feng Gao, Matthew P. Goetz, Donald W. Northfelt, Andres Forero-Torres, Jill Anderson, Kiran R. Vij, Souzan Sanati, Matthew J Ellis, Cynthia X. Ma
Journal: Journal of Clinical Oncology (2017)

TPS592 Background: Persistent cell proliferation (Ki67 &gt; 10%) on tumor biopsies as early as 2-4 weeks (wks) on neo endocrine therapy (ET) identifies resistant tumors in ~20% patients (pts) with early stage ER+ HER2- BC who are at high risk of relapse. Palbo plus ET significantly improves progression free survival in pts with ET naïve or resistant advanced ER+ HER2- BC, and is being evaluated in the adjuvant setting. However, biomarkers predictive of palbo sensitivity are unknown. Ki67 analysis of serial tumor biopsies in the neo palbo and ana (NeoPalAna) trial demonstrated that 2 wks of palbo plus ana potently inhibited Ki67 and induced complete cell cycle arrest (CCCA, Ki67≤2.7%) in tumors with high Ki67 post 4 wks ana run-in. This study is therefore aimed to prospectively investigate the biological activity of palbo plus ana in ET resistant ER+ HER2- BC. Methods: The primary objective is to assess the rate of CCCA (central Ki67 ≤2.7%) after 2 wks of neo palbo and ana. Secondary objectives include analysis of tumor biopsies to explore response biomarkers. Key inclusions include women with clinical stage 2/3 ER+ HER2- BC, central Ki67 &gt; 10% after ≥2 wks of any neo ET, adequate organ function. Key exclusions include prior CDK 4/6 inhibitor, treatment of BC except ET, concomitant use of strong CYP3A4 inhibitor. Pts receive palbo (125mg PO daily, days 1-21, 28-day cycle), ana (1 mg PO daily) and goserelin (if premenopausal). Pts with C1D15 Ki67 &gt; 10% will discontinue study. If C1D15 Ki67 ≤10%, pt will receive 4 cycles of treatment, and additional 10-12 days of palbo if counts normalized within 3 wks post C4D28. Following surgery, pts are eligible for 2 years of adjuvant palbo. A sample size of 37 (stage 1, n = 12, stage 2 n = 25) by simon optimal two stage phase II design will be employed to assess whether the rate of CCCA is ≤5% vs ≥20% (90% power, alpha 0.1). Stage 2 will proceed if ≥1 had CCCA in stage 1. If ≤3 of 37 had CCCA, this regimen will be considered ineffective. The study is active and has enrolled 4 pts. Clinical trial information: NCT01723774.
Whole exome sequencing of metaplastic breast cancer (MpBC): Effect of mutation status on survival.
Authors: Luis Baez Vallecillo, Jeffrey T Chang, Ken Chen, Tyler J. Moss, Kenna Rael Shaw, Funda Meric-Bernstam, Agda Karina Eterovic, Gordon B. Mills, Sendurai Mani, Xiaoxian (Bill) Li, Michael Gilcrease, Stacy L. Moulder
Journal: Journal of Clinical Oncology (2017)

1090 Background: Metaplastic Breast Cancer (MpBC) is considered a chemo-refractory, aggressive subtype that is characterized by squamous and/or mesenchymal differentiation and associated with a high rate of molecular aberrations that activate the PI3K pathway. The goal of this study was to correlate outcomes data with underlying genomic aberrations in MpBC. Methods: A cohort of 52 archived samples of MpBC collected from 1986 and 2016 that had clinical outcomes data available for central review underwent hybrid capture sequencing of 202 cancer-related genes (n = 52) and, when sufficient material was available, whole exome sequencing (n = 21). Relapse free (RFS) and overall (OS) survival analyses at 5 years were compared between patients having mutation vs. wild-type (WT) in the whole genome using Kaplan-Meier statistics. Results: The variant allele frequency (VAF) was relatively low with most mutations having a VAF of &lt; 50%. TP53 mutation was found in 33 tumors (63%) and was associated with improved RFS (HR = 2.4; p = 0.03) and OS (HR = 3.7; p = 0.006) compared to WT. Aberrations in the PI3K/AKT/mTOR pathway were present in 29% of tumors and associated with diminished OS (HR = 0.27; p = 0.02) but not RFS (HR = 0.67; p = 0.32). Though uncommon, the presence of an AKT1 (6%) mutation was associated with worse RFS (HR = 0.006; p = 0.006) and OS (HR = 0.0005; p &lt; 0.0001). Conclusions: Surprisingly, TP53 mutation was associated with better prognosis in MpBC with increased RFS and OS. Mutations in AKT1 were uncommon but associated with a significantly worse RFS and OS. Notably, all patients harboring an AKT1 mutation died within a year of diagnosis. Mutations activating the PI3K/AKT/mTOR pathway were associated with worse OS.
Tumor profiling of 1,306 gastric and esophageal carcinomas and different treatment options.
Authors: John Thomas Miura, Joanne Xiu, Fabian McCartney Johnston, Kiran Turaga, T. Clark Gamblin
Journal: Journal of Clinical Oncology (2014)

4017 Background: NCCN guidelines state that chemotherapies for esophageal and gastric carcinomas may be used interchangeably. We interrogated biomarkers from a large cohort of gastroesophageal cancer patients to identify similar and different alterations with therapeutic implications for gastric and esophageal cancers. Methods: 666 gastric adenocarcinoma (GA) and 640 esophageal (553 adenocarcinoma, or EA, and 87 others) cases were evaluated by a combination of sequencing (Sanger, NGS), protein expression (IHC) and gene amplification (CISH/FISH). Results: In the complete cohort of 1306 patients, 30 of 45 (66%) genes tested had mutations, with the highest rates seen in TP53 (54%), APC (10%), SMAD4 (5.9%), KRAS (5.9%) and PIK3CA (5.1%). Elevated IHC of TOP2A was seen in 76% of cases, TOPO1 in 51% and SPARC in 25%; decreased IHC of ERCC1 was seen in 65%, RRM1 in 62%, TS in 61% and MGMT in 45%, indicating benefit from epirubicin, irinotecan, nab-paclitaxel, platinums, gemcitabine, 5FU/capecitabine and temozolomide, respectively. In the HER2-positive cases, additional alterations were seen including low TS (50%), ERCC1 (63%), RRM1 (55%) and high TOPO1 (53%), indicating potential benefit from combining trastuzumab with 5FU/capecitabine, cisplatin, gemcitabine and irinotecan, respectively. When comparing EA to GA, select biomarkers showed a differential pattern between cancer types (Table), suggesting potential variability in efficacy of available therapeutic agents. Conclusions: A multiplatform biomarker analysis identified common actionable targets in gastric and esophageal cancer as well as significant biomarker differences in EA and GA. This indicates the potential clinical impact of molecular profiling and highlights the need for separation of the two cancer entities for therapeutics. Biomarker comparison of gastric (GA) and esophageal adenocarcinoma (EA). Target biomarker Associated therapeutic agent EA (%) GA (%) p-value IHC HER2 trastuzumab 13 4.6 <0.01 SPARC nab-paclitaxel 34 15 <0.01 TOP2A epirubicin 86 67 <0.01 TOPO1 irinotecan 55 46 0.01 FISH HER2 trastuzumab 22 9 <0.01 EGFR cetuximab 33 16 <0.01 SEQ KRAS cetuximab* 3.8 8.4 <0.01 PIK3CA mTOR inhibitors 2.4 7.8 0.04 *Lack of benefit.