tbuckley/cabot-search huggingface dataset:
Monitor launches inquiry after NHS trust ran up £29.5m deficit in five months
Authors: Gareth Iacobucci
Journal: BMJ (2015)

England’s health sector regulator Monitor has launched an investigation into the finances of an NHS hospital trust after it forecast a significant deficit by the end of the financial year.

Heart of England NHS Foundation Trust, which provides NHS services for around 1.2 million people in the West Midlands, has recorded a £29.5m (€40m; $45m) deficit in the first five months of 2015-16 and been forced to draw on its …
Abstract 19185: Upregulation of DJ-1 Protein after Prolonged Ischemia in a Murine Model for Myocardial Ischemia and Reperfusion
Authors: Tamas Seres, Jelena Klawitter, Uwe Christians, Tobias Eckle
Journal: Circulation (2014)

Introduction: Upregulation of cardiac DJ-1 protein might be a cardio-protective mechanism under conditions of ischemia or ischemia and reperfusion by regulating mitogen activated protein (MAP) kinases or inducing enzymes for detoxification and glutathione metabolism. We recently observed that significantly elevated DJ-1 protein expression was associated with decreased expression of phosphatase and tensin homolog (PTEN) and increased phosphorylation of the cell protective kinase AKT (protein kinase B) in human heart tissue samples from patients with chronic ischemic cardiomyopathy. Hypothesis: The expression of DJ-1 protein and its interaction with PTEN and AKT during ischemia or ischemia and reperfusion in a murine heart model might play a cardio-protective role. Methods: The level of DJ-1 was analyzed from the area at risk after 30 or 60-minute ischemia or 30-minute ischemia with 30 or 60 minutes of reperfusion using C57BL/6J mice (n=3). The changes in DJ-1 expression were correlated with the expression of PTEN and AKT and phosphorylation of ERK1/2 (extracellular signal regulated kinase) and P38. The protein levels and their phosphorylation were evaluated by Western blot analysis. Results: Expression of DJ-1 increased significantly after 60 minutes of ischemia while PTEN decreased after 30 minutes of ischemia followed by 30 or 60 minutes of reperfusion both were associated with increased phosphorylation of AKT. The phosphorylation of ERK1/2 was increased at all time points of ischemia or ischemia and reperfusion while phosphorylation of P38 was increased only during ischemia and reperfusion. Conclusions: The increased expression of DJ-1 protein is a potential marker for prolonged ischemia. Although, PTEN expression were not decreased with increased DJ-1 levels, a direct inhibiting effect of DJ-1 on PTEN might increase the phosphorylation of the cell protective AKT during 60-minute ischemia. A DJ-1 independent decrease of PTEN expression might contribute to the increased AKT phosphorylation during ischemia reperfusion. Phosphorylation of ERK1/2 was a sensitive marker of early or late ischemia and ischemia and reperfusion. The role of the DJ-1-AKT interaction in preventing P38 phosphorylation during ischemia needs further investigation.
Anti-IgE and airway remodelling: Omalizumab affects reticular basement membrane thickness in severe persistent atopic asthma
Authors: Anna Maria Riccio, Roberto Walter Dal Negro, Laura De Ferrari, Claudio Micheletto, Giorgio Walter Canonica, Chiara Folli, Alessandra Chiappori
Journal: European Respiratory Journal (2011)

Asthma is a complex genetic disorder that is characterized by airway inflammation and reversible airflow obstruction. Severe asthmatics are inadequately controlled despite the use of high-dose inhaled corticosteroids (ICS) and long-acting B2-agonists. Role of IgE mediated inflammation in asthma is esthablished. Allergic inflammatory process underlies the pathogenesis of severe persistent asthma. The most widely used and currently only approved monoclonal antibody against IgE for use in asthma is Omalizumab. The efficacy and safety of omalizumab have been evaluated in several studies which showed a significant drop in asthma exacerbations, and emergency visits. The thickening of subepitelial basement membrane in severe asthmatic is associated to increased bronchial mucosal eosinophils, tipical allergic cellular effectors.  The aim of the study is to investigate the effect of anti-IgE on the basement membrane thickness. Biopsies were obtained from 11 patients with Severe Persistent Allergic Asthma. Before e post (12 months) treatment with omalizumab. RBM thickness was measured by morphometric anaysis by using light microscope image analysis. The analisys proved a significantly statistical difference, p
VEGF pathway therapy: Resampling positive phase III data to assess phase II trial designs and endpoints.
Authors: M. Sharma, T. Karrison, M. L. Maitland, W. M. Stadler, M. J. Ratain
Journal: Journal of Clinical Oncology (2010)

2520 Background: The most appropriate phase II design and endpoint for agents with putative growth inhibitory properties is controversial. The VEGFR inhibitor sorafenib significantly improved progression-free survival (PFS) in renal cancer patients in a phase III study (TARGET study). We resampled data from TARGET to simulate one and two-arm phase II designs using endpoints based on CT scan re-evaluation at 6 weeks. Methods: 375 and 374 patients (pts) in TARGET were randomized to placebo or sorafenib, respectively. Tumor size was the sum of unidimensional measurements of RECIST target lesions measured at all time points. Pts were randomly sampled with replacement from this data set to simulate phase II trials, with 5,000 replicates performed (95% CI widths all < ± 1.5%). Designs included a single arm Simon two-stage trial (H0: RR = 0.05, HA: RR = 0.20, one-sided α = 0.10), as well as randomized two-arm trials (one-sided α = 0.10) with n = 20, 25, 30, or 35 patients per arm and an early stopping rule. Endpoints included response rate (RR) by RECIST, RR by modified RECIST (≥ 20% reduction in tumor size), percent change in tumor size from baseline (% change), and change in tumor size on a log scale (log ratio). Results: A Simon two-stage trial (n = 37) with RR by RECIST was positive in 49% of replications, while RR by modified RECIST increased this to 94%. Randomized two-arm trials with 20 pts per arm were positive with RR by RECIST in 55%, RR by modified RECIST in 80%, and % change in 92% of replications. Increasing the sample size to 35 pts per arm increased this to 75%, 93%, and 98%, respectively. The log ratio endpoint yielded results identical to that for % change, and accounted for 54% of the treatment effect (based on PFS). Conclusions: Randomized phase II trials with a feasible number of patients have greater power than a single-arm trial based on RR by RECIST to predict phase III results of sorafenib in renal cancer. Using a lower threshold for a response improves the positive predictive power of both designs. % change (or log ratio) is an early endpoint with greater predictive power than RR by RECIST. These findings may have implications for optimal designs and endpoints of phase II trials with agents predicted to have modest cytotoxic activity. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories, Amgen, Astellas Pharma, Bayer, Biomarin, Daiichi Sankyo, Gilead, Millennium/Takeda Pharmaceuticals, Millennium, Pfizer Actelion, Bayer, Bristol-Myers Squibb, EMD Serono, Genentech, Gilead, Lilly, Pfizer, Roche Patent pending for use of sorafenib to treat pulmonary hypertension
Intragenic expression profile in tissue and plasma for the detection of <i>TMPRSS2</i> rearrangements associated with prostate cancer
Authors: H. R. Sanders, H. Li, K. Z. Qu, Z. J. Zhang, A. D. Sferruzza, M. Albitar
Journal: Journal of Clinical Oncology (2009)

5162 Background: TMPRSS2 gene rearrangements have been reported in 40%-85% of prostate cancer (PCa) patients and have not been found in normal individuals or those with benign prostate hyperplasia (BPH). However, multiple partner genes, including ETS transcription genes, and breakpoints have been reported. We developed an assay based on TMPRSS2 5′ and 3′ intragenic differential expression (IDE) to potentially serve as a diagnostic or prognostic marker for PCa. Methods: We analyzed TMPRSS2 in FFPE tissue from 20 patients (9 PCa and 11 BPH) and plasma from 42 patients (32 PCa and 10 BPH). IDE was expressed as a ratio of 3′:5′ transcript levels which were determined by real-time RT-PCR using distinct primer/probe sets. A normal 3′:5′ ratio (≥30) was established by comparing nonmalignant cells to tumor cells from FFPE tissue. This cutoff was subsequently used to identify abnormal ratios in plasma specimens. Results: In FFPE tissue, 100% of PCa samples had a 3′:5′ratio &lt;30 and 91% of BPH samples were ≥30 ( Table ). RNA in 48% of plasma samples passed our QC criteria for acceptability. The 3′:5′ ratios were &lt;30 in 47% and ≥30 in 6.7% PCa plasma. Conclusions: By measuring IDE, we are not limited to screening for known TMPRSS2/ETS gene translocations. In tissue, this approach enabled us to identify patients with PCa vs. BPH with high specificity. Although work is needed to improve plasma RNA quality, IDE of plasma TMPRSS2 may be a useful non-invasive diagnostic or prognostic tool. [Table: see text] No significant financial relationships to disclose.
Airway epithelial gene expression to detect lung cancer in smokers
Authors: A B Nanguzgambo
Journal: Thorax (2008)

The sensitivity of bronchoscopy for detecting lung cancer ranges from 30% for small peripheral lesions to 80% for centrally located endobronchial lesions, necessitating further invasive diagnostic tests to try to establish the diagnosis. To address this diagnostic problem, the authors searched for profiles of gene expression in large airway epithelial cells knowing that cigarette smoke creates a field of injury in all airway epithelial cells exposed to it. In this study of …
Abstract 20063: Mitral Valve Alterations in Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers Without Left Ventricular Hypertrophy
Authors: John D Groarke, Neal Lakdawala, Jens J Thune, Henning Bundgaard, Robert A Levine, Carolyn Y Ho
Journal: Circulation (2014)

Introduction:  Anatomic and imaging studies have shown that abnormal mitral valve (MV) morphology is present in patients with overt hypertrophic cardiomyopathy (HCM) compared to healthy controls. There is much less experience in evaluating the MV in HCM sarcomere mutation carriers without left ventricular hypertrophy (G+/LVH-).   Hypothesis:  Structural abnormalities of the MV are an early phenotypic expression of HCM sarcomere mutations.   Methods:  MV parameters were compared using transthoracic echocardiography in 80 G+/LVH- subjects and 66 healthy controls.   Results:  Anterior leaflet length (ALL) and posterior leaflet length (PLL) were significantly longer in G+/LVH- subjects compared to controls when corrected for body surface area (BSA) or LV size (Table). However, absolute leaflet lengths were not significantly different between the cohorts. MV annular diameter at end-diastole and LV internal diameter at the level of the papillary muscles (LVIDd) were smaller among G+/LVH- subjects. A sarcomere mutation was associated with 0.04 ± 0.02 (p=0.02) and 0.05 ± 0.02 (p=0.001) respective increases in ALL:MV annulus and ALL:LVIDd ratios, after adjusting for age, gender, and BSA. Adjusted analyses did not demonstrate an association between mutation status and similar PLL-based ratios or leaflet thickness. Systolic anterior motion (SAM) of MV apparatus was more frequent among G+/LVH- subjects (15 versus 3%, p=0.02) but no subjects had obstruction.   Conclusion:  MV leaflets are elongated relative to body size and LV cavity size in sarcomere mutation carriers without LVH. ALL is longer relative to MV annular and LV internal dimensions suggesting an intrinsic mismatch in leaflet length to cavity size in G+/LVH- subjects. SAM is also more prevalent compared to controls. These findings provide further support that structural abnormalities of the MV may precede LVH as part of the early phenotypic expression of HCM sarcomere mutations.
Secondary surgical cytoreduction and hyperthermic intraperitoneal chemotherapy: A novel treatment for recurrent endometrial cancer
Authors: C. W. Helm, R. Martin, D. S. Metzinger, R. P. Edwards
Journal: Journal of Clinical Oncology (2005)

5181 Background: Survival with endometrial cancer recurrent within the abdominal cavity is poor. Such patients may benefit from novel approaches such as secondary surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (SSC-HIPEC). To our knowledge, such use of this combined modality treatment has not previously been reported. Methods: We reviewed the single center experience of the use of SSC-HIPEC for recurrent endometrial cancer. After pre-operative evaluation, eligible patients underwent exploratory laparotomy with the aim of resecting gross disease to <5mm maximum dimension followed immediately by intraperitoneal perfusion of cisplatin (100mg/m2) heated to 41–43 0C (105.8–109.40F) for 90 minutes. Data for analysis was extracted from retrospective chart review. Results: Four patients underwent SSC-HIPEC. Original stage and histology were 1A papillary serous, 1A clear cell, 1B endometrioid n=2. Mean age 62 (41–75) years, mean prior laparotomies 1.5 (1–2) and mean chemotherapy agents 2 (2–4). One patient had had prior pelvic irradiation. Mean time from initial treatment to SSC-HIPEC was 42 (29–56) months. Pre-operative workup included PET/CT imaging 3 and CT scan 1. All four patients had disease within the abdomen and pelvis. Mean length of surgery 10.75 (7–13)hours. Three patients had no residual disease at the end of surgery and one had <5mm disease. Post-operative complications included pneumonia, metabolic alkalosis, congestive failure and cardiac arrhythmia. There was no ototoxicity or neuropathy and no peri-operative mortality. Mean maximum post-operative serum creatinine was 0.85 (0.6–1.10) mg/dl. Mean hourly urine output for first 72 hours was 159 (115–220) ml. Bowel function returned in mean of 6.5 (6–8) days and mean duration of hospital stay was 10.75 (6–12) days. Patients have been followed to a maximum of 18 months. Two are alive and disease-free at 12 and 14 months, one is alive with a raised CA125 at 18 months and one died without evidence of cancer at 3 months. Conclusions: Our results with SSC-HIPEC are promising and this approach is worthy of continued research in endometrial cancer recurrent within the abdominal cavity. No significant financial relationships to disclose.
A randomized comparison of haloperidol plus dexamethasone versus prochlorperazine plus dexamethasone in preventing nausea and vomiting in patients receiving chemotherapy for breast cancer.
Authors: L Silvey, J T Carpenter, R H Wheeler, J Lee, C Conolley
Journal: Journal of Clinical Oncology (1988)

The antiemetic effectiveness of haloperidol plus dexamethasone was compared with that of prochlorperazine plus dexamethasone in a prospective study of patients receiving chemotherapy for breast cancer. Chemotherapy consisted of cyclophosphamide, doxorubicin or methotrexate, and fluorouracil in all patients. Patients who received the doxorubicin-containing combination experience significantly more nausea and vomiting than those who received the chemotherapy combination containing methotrexate. There was no significant difference between the two antiemetic regimens in the overall incidence of post-chemotherapy nausea and vomiting, but patients who received haloperidol and dexamethasone did have a lower incidence of severe vomiting. Neither regimen is highly effective, especially for the combination containing doxorubicin, and cannot be recommended as standard antiemetic therapy for this population of patients.
A phase I clinical and pharmacokinetic study of weekly docetaxel followed by flavopiridol: promising activity in metastatic pancreatic cancer
Authors: D. Rathkopf, M. Fornier, M. A. Shah, J. Kortmansky, E. O’Reilly, J. Winkelmann, L. Balzano, D. P. Kelsen, G. K. Schwartz
Journal: Journal of Clinical Oncology (2005)

4096 Background: Flavopiridol (F), a potent cyclin dependent kinase inhibitor, potentiates docetaxel (Doc) induced apoptosis at nanomolar concentrations (300 nm). Significant tumor regression has been seen in tumor xenografts when Doc is given 3–7 hours before F. Methods: In view of this finding, we designed an ongoing phase I trial in advanced solid tumors with fixed dose Doc (35 mg/m2 ), followed 4 hours later by escalating doses of F (20–80 mg/m2) administered weekly over one hour, for 3 weeks out of every 4. Standard phase I eligibility criteria apply. Prior Taxane therapy is allowed. Results: Median characteristics of 27 evaluable patients: age 57 (39–77), KPS 90% (70–90), 11 males/ 16 females, 2 prior regimens (range 0–8). The combination has been well-tolerated, with 1 dose limiting toxicity (DLT) occurring at 70 mg/m2 (grade 3 mucositis), and 1 DLT at 80 mg/m2 (grade 4 neutropenia). Pharmacokinetic (PK) studies demonstrate Cmax ranging from 1.342±0.646 μM (F 20 mg/m2) to 4.167±0.016 μM (F 60 mg/m2). Due to wide interpatient variability, no relationship between dose and Cmax has been seen. There is no appreciable difference in Cmax between cycles 1 and 2. We have observed 5 partial responses (PR) to treatment in pancreatic (2), breast (2), and ovarian (1) cancers. Stable disease (SD) has been seen in 10 patients, including 4 with pancreatic cancer previously treated with gemcitabine (3,4,6, and 2+ months). Conclusions: The combination is safe and effective with PK data exceeding the 300 nm of F needed to enhance apoptosis at all dose levels. Significant activity is seen in gemcitabine refractory metastatic pancreatic cancer (10 patients treated: 2 PR, 4 SD) for which a phase II trial is currently planned. No significant financial relationships to disclose.
First-line treatment with lapatinib plus paclitaxel versus paclitaxel alone for patients with HER2+ metastatic breast cancer (MBC): Quality-of-life (QOL) analysis using repeated measures and pattern mixture models
Authors: B. Sherrill, Y. Wu, M. Amonkar, M. Arbushites, A. DiLeo
Journal: Journal of Clinical Oncology (2009)

1049 Background: A phase III randomized, multicenter, double-blind, placebo-controlled study compared first-line therapy with lapatinib and paclitaxel (L+P) versus paclitaxel alone (P) for MBC. In a sub-group analysis of HER2+ patients, time to tumor progression for L+P was significantly improved, with an emerging trend for survival benefit. This analysis models the QOL data in the subset of the randomized ITT population that overexpressed HER2 (FISH+ or IHC3+). Methods: QOL was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. Outcome measures included FACT-B total score, trial outcome index (TOI) score and breast cancer subscale (BCS). Higher scores represent better QOL. Patients completed the FACT-B at the screening visit, week 9, every 12 weeks thereafter, and at discontinuation of therapy. The assessment at discontinuation was applied to the next scheduled visit for analyses. Changes from baseline were analyzed using repeated measures models with baseline score as a covariate. Pattern mixture modeling was implemented as a sensitivity analysis. Results: Of 579 randomized patients, 86 were HER-2+ and 85 completed at least one item from the FACT-B (n = 48 L+P; n = 37 P). The baseline characteristics of this subset were well-matched with regard to age, ECOG status, and prior anthracycline use. More patients in the L+P group than in the P group had visceral disease (69% vs 51%) and more were at stage IV (88% vs 78%).Over the first year, the L+P arm demonstrated stable FACT-B scores over time, whereas average scores for patients on paclitaxel monotherapy decreased (change from baseline: L+P p = 0.99; P p = 0.01). Statistically significant differences were observed between treatment arms on the FACT-B (p = 0.05), TOI (p = 0.03), and BCS (p = 0.01). Pattern mixture models suggested more QOL differentiation between treatments among patients who progressed or withdrew within 6 months of study start. Conclusions: Among patients with HER2+ MBC, treatment with L+P resulted in more stable QOL than with P monotherapy. These findings represent clinically important differences between treatment groups. [Table: see text]
Clinical and molecular characteristics of advanced non-small cell lung cancer (NSCLC) patients (pts) with rapid progressive disease (RPD) on gefitinib therapy (G)
Authors: M. J. Fidler, L. Buckingham, M. Gale, J. Coon, A. Mauer, V. Villaflor, K. A. Kaiser, S. McCormack, L. Morrison, P. Bonomi
Journal: Journal of Clinical Oncology (2007)

7592 Background: Prognostic factors associated with better outcomes (EGFR mutations (mut), high EGFR gene copy number, never smoking) can be used to select pts for EGFR tyrosine kinase inhibitor (TKI) combination trials, but would exclude the majority of NSCLC pts. Excluding pts with the worst likely outcomes is another strategy that may result in more pts who could benefit from the combination of a TKI with other agents. Our objective was to identify clinical and molecular characteristics associated with RPD (=70 days) and shorter progression-free survival (PFS) in previously treated NSCLC pts receiving G. Methods: Consecutive Expanded Access Trial pts with &gt;1 week G were included for analysis. Tissue from 87 pts was evaluated for EGFR, pAKT and PTEN protein expression by immunohistochemistry; 58 tumors were analyzed for mut and sum of CA dinucliotide repeats (ΣCA rpts) by SSCP, PCR and sequencing. Results: There were 150 pts; 77 female, median (md) age 67. Md follow-up was 5.8 months (mo). Objective response was 8% (2CR, 10PR, 56 SD, 82 RPD). Md Kaplan-Meier PFS and survival were 2.0 and 5.8 mo, respectively. See table for univariate results. Smoking, Mut - PTEN - , EGFR - PTEN - and EGFR - pAKT - tumors were associated with shorter PFS. Separate clinical and molecular multivariate models were developed. In logistic regressions, non-adenocarcinoma histology (N- A), p=0.004, =12 mo from diagnosis to G (dx-G =12 mo), p=0.0009, lack of mut (p=0.0298) and ΣCA rpts &lt;34 (p=0.0622) were associated with RPD. In Cox regressions, N-A (p=0.0256), dx-G =12 mo (p=0.0166) and lack of mut (p=0.0298) were associated with shorter PFS. Conclusions: N-A, dx-G =12 mo and lack of mut were associated with RPD and shorter PFS in univariate and multivariate analyses. ΣCA rpts &lt;34 and double-negative molecular combinations were also related to worse outcome. These clinical and molecular characteristics may warrant further study as exclusion criteria for TKI combination clinical trials. [Table: see text] [Table: see text]