tbuckley/cabot-search huggingface dataset:
Final results of a phase I study of oral belinostat (PXD101) in patients with lymphoma
Authors: J. M. Zain, F. Foss, W. K. Kelly, J. DeBono, D. Petrylak, A. Narwal, E. Neylon, G. Blumenschein, U. Lassen, O. A. O'Connor
Journal: Journal of Clinical Oncology (2009)

8580 Background: Belinostat (Bel) is a histone deacetylase inhibitor with broad preclinical activity. A phase I of oral Bel in patients (pts) with solid tumors found a recommended dose for day (d) 1–14, q3w, of 750 mg QD, with option for intra-patient dose escalation if limited toxicity. The current study was initiated to assess if the same dose could be utilized in pts with lymphoma. Methods: Objectives included safety and efficacy of oral Bel in cohorts of 3–6 pts (A 750; B 1000; C 1250; mg QD) treated d 1–14, q3w. Pts with relapsed/refractory non-Hodgkin lymphoma (NHL) or Hodgkin's disease (HD) with evaluable disease and acceptable organ functions were eligible. Dose limiting toxicity (DLT) assessed in cycle 1 included: related non-hem grade (gr) 3/4 tox; gr 4 neutropenia &gt; 5 d or with fever &gt; 100.5 °F; gr 4 thrombocytopenia &gt; 7 d. Results: 9 pts (3 per cohort), median age 51 (range 21–92), median 5 (range 2–7) prior regimens (83% had BM transplants, including 1 pt with allogeneic) have been enrolled. Diagnoses include mantle cell lymphoma (MCL; 4 pts), HD (3 pts), other NHL (2 pts). Most frequent adverse events (regardless of attribution or gr) in 7 pts fully evaluable for tox: anorexia (7 pts), fatigue, (6 pts), diarrhea (6 pts), and constipation, fever, and cough (each in 3 pts). Non-hem gr 3 events (no gr 4 noted): diarrhea (1 pt each in cohorts A and B, both in cycle 2), fatigue, anorexia, and leg DVT (each in 1 pt; all after cycle 1). One gr 3, and 1 gr 4 (from baseline gr 2; duration gr 4 &lt;7 d) thrombocytopenia were seen in cohort C. In 6 pts evaluable for efficacy, stable disease have been noted in 5 pts for 3 to +7 cycles, including 3 of 3 pts (one refractory) with MCL and 2 of 2 pts (both refractory) with HD. Tumor shrinkage of 43 to 49% have been found in 1 HD and 2 MCL pts after cycle 2. Conclusions: Oral Bel can be delivered safely with a d 1–14, q3w schedule in pts with lymphoma at a daily dose higher than what has been established for pts with solid tumors. No protocol defined DLTs have yet been encountered in the dose range 750 to 1250 mg QD in pts with lymphoma. Final evaluation will include additional pts and possible dose escalation. The safety profile and early tumor shrinkage noted in MCL and HD warrants continued evaluation of Bel, especially in combination with other active compounds. [Table: see text]
Overall quality of life (QoL) is not meaningfully affected by severity of pegylated liposomal doxorubicin (PLD)-associated palmar-plantar erythrodysesthesia (PPE) among women with metastatic breast cancer
Authors: S. O. Brown, E. Calhoun, C. L. Bennett
Journal: Journal of Clinical Oncology (2005)

788 Background: Chemotherapy-associated toxicities such as anemia and neurotoxicity are evaluated using toxicity-specific instruments such as the FACT-AN and the FACT-NTX. PLD is a new chemotherapeutic agent demonstrated clinical efficacy in metastatic breast cancer both as a first-line agent (O’Brien Ann of Oncology 2004) and for taxane-refractory disease (Keller JCO 2004). Its most common toxicity is PPE (rates of severe [Grade 3–4] toxicity: 17% and 19%, respectively). We evaluated the utility of a commonly used QOL instrument to evaluate PPE impact among metastatic breast cancer patients who participated in recent RCTs with PLD. Methods: All PLD-treated patients in the first-line (n=150) and taxane-refractory (n=254) RCTs completed a general cancer-related QOL instrument, the European Organization for Research and Treatment of Cancer QLQ-30 at baseline and prior to subsequent chemotherapy cycles with PLD during the course of the trial. Results: Mean QLQ-30 scores for PLD-treated patients (1st line and taxane-refractory RCTs) were similar regardless of whether the patient developed severe PPE or not at all. (Table 1, *p<0.05) Conclusions: PPE does not appear to meaningfully impact overall patient reported QoL. Further research is needed to determine if a syndrome specific questionnaire for PLD-associated PPE is needed. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough
Lapatinib and trastuzumab: Molecular effects and efficacy, separately and combined in breast cancer.
Authors: F. A. Holmes, V. A. Espina, L. A. Liotta, Y. M. Nagarwala, J. C. Chang, J. O'Shaughnessy
Journal: Journal of Clinical Oncology (2010)

TPS109 Background: We are examining lapatinib/trastuzumab efficacy in combination and separately, to correlate to in vivo efficacy at the molecular level. Each drug has different modes of action on the HER2/EGFR signal cascade; the mechanism of HER3 block is unclear. We measure therapy effects by phosphoprotein/post-translationally modified protein signaling and gene expression analysis. Molecular profiling allows individualizing therapy separately or together. Changes in compensatory or inter- connected proteins may reveal off-target effects or new combination therapies. This phase II study (USON 05-074/GSK LPT 109096) is the first to monitor signal pathway targets before and after mono or dual therapy. Insights for individualized therapy may be derived by correlating good and poor patient outcomes at the molecular level (gene expression, stem cell data, proteomic signaling pathways) with clinical response at trial completion. The goals are to: 1) identify kinase signal pathway activation states in cancer cells, prior to therapy (biopsy one), or during therapy (biopsy two), which predict later clinical response after standard of care chemotherapy/surgery; 2) identify kinase pathway interconnections in cancer cells that are altered by therapy; 3) evaluate the effect on stem cell populations; and 4) changes in gene expression patterns. Methods: Eligibility are: informed consent; HER2+, Stage II or III invasive breast cancer; adequate cardiac function. Core needle biopsies are collected in a fixative that blocks phosphatase/kinase fluctuations, frozen, subjected to frozen section laser capture microdissection. Using reverse phase protein microarrays in less than 2000 cells, and blinded to outcome, we measured: CD24, CD44, EGFR Y992, EGFR Y1068, EGFR Y1148, EGFR Y1173, EGFR, HER2 Y1248, HER3Tyr1289, AKT Ser473, AKT Thr308, AKT, Actin, ERK Thr202/Y204, GSK3αβ S21/9, GSK3αβ Y279/216, IGF-1R Y1131/1146, MEK 1/2 Ser217/221, mTOR Ser2448, p70S6 Thr389, PI3K, PTEN, and Ser380. At trial end (99 pts) (n=86 to date), the activation state of signal pathways and their interconnections will be compared before and after therapy with the clinical response and correlated with stem cell and transcript microarray data. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
Final Results of the Sunbelt Melanoma Trial: A Multi-Institutional Prospective Randomized Phase III Study Evaluating the Role of Adjuvant High-Dose Interferon Alfa-2b and Completion Lymph Node Dissection for Patients Staged by Sentinel Lymph Node Biopsy
Authors: Kelly M. McMasters, Michael E. Egger, Michael J. Edwards, Merrick I. Ross, Douglas S. Reintgen, R. Dirk Noyes, Robert C.G. Martin, James S. Goydos, Peter D. Beitsch, Marshall M. Urist, Stephan Ariyan, Jeffrey J. Sussman, B. Scott Davidson, Jeffrey E. Gershenwald, Lee J. Hagendoorn, Arnold J. Stromberg, Charles R. Scoggins
Journal: Journal of Clinical Oncology (2016)

The Sunbelt Melanoma Trial is a prospective randomized trial evaluating the role of high-dose interferon alfa-2b therapy (HDI) or completion lymph node dissection (CLND) for patients with melanoma staged by sentinel lymph node (SLN) biopsy.Patients were eligible if they were age 18 to 70 years with primary cutaneous melanoma ≥ 1.0 mm Breslow thickness and underwent SLN biopsy. In Protocol A, patients with a single tumor-positive lymph node after SLN biopsy underwent CLND and were randomly assigned to observation versus HDI. In Protocol B, patients with tumor-negative SLN by standard histopathology and immunohistochemistry underwent molecular staging by reverse transcriptase polymerase chain reaction (RT-PCR). Patients positive by RT-PCR were randomly assigned to observation versus CLND versus CLND+HDI. Primary end points were disease-free survival (DFS) and overall survival (OS).In the Protocol A intention-to-treat analysis, there were no significant differences in DFS (hazard ratio, 0.82; P = .45) or OS (hazard ratio, 1.10; P = .68) for patients randomly assigned to HDI versus observation. In the Protocol B intention-to-treat analysis, there were no significant differences in overall DFS (P = .069) or OS (P = .77) across the three randomized treatment arms. Similarly, efficacy analysis (excluding patients who did not receive the assigned treatment) did not demonstrate significant differences in DFS or OS in Protocol A or Protocol B. Median follow-up time was 71 months.No survival benefit for adjuvant HDI in patients with a single positive SLN was found. Among patients with tumor-negative SLN by conventional pathology but with melanoma detected in the SLN by RT-PCR, there was no OS benefit for CLND or CLND+HDI.
Occupation-induced posttraumatic stress disorders
Authors: R S Schottenfeld, M R Cullen
Journal: American Journal of Psychiatry (1985)

The authors describe a variant of posttraumatic stress disorder that presents as a somatoform disorder. Applying clearly specified diagnostic criteria, they found that seven of 21 patients who were severely disabled by medically unexplained symptoms following occupational exposure to toxic substances had atypical posttraumatic stress disorder, while three patients had typical posttraumatic stress disorder and the remainder suffered from somatoform disorders. Analysis of these cases revealed specific exposure factors and personality characteristics that favor the development of atypical posttraumatic stress disorder. The authors discuss the theoretical, clinical, and therapeutic advantages of this diagnosis.
Abstract 17944: Increased Susceptibility to β-amyloid Toxicity In Rat Brain Microvascular Endothelial Cells Under Hyperglycemic Conditions
Authors: Cristina I Carvalho, Paige S Katz, Somhrita Dutta, Prasad V Katakam, Paula I Moreira, David W Busija
Journal: Circulation (2012)

β-amyloid peptide (Aβ) accumulation is the hallmark of Alzheimer9s Disease (AD), but the mechanisms underlying its cellular toxicity are unclear. Evidence shows a close association between Type 2 diabetes (DM) and AD. DM also promotes impaired function of cerebrovascular endothelium that constitutes the blood-brain barrier. We hypothesized that hyperglycemia-induced mitochondrial dysfunction and oxidative stress promote Aβ toxicity in endothelial cells.   Methods.  Rat brain microvascular endothelial cells (RBMEC) were isolated from adult Sprague-Dawley rats and cultured in normoglycemic and hyperglycemic media followed by exposure to Aβ peptide or Aβ 40-1. Cell viability was measured by the Alamar blue assay and mitochondrial membrane potential (Ψ mito ) was measured by confocal microscopy and microplate reader (rhodamine 123). Also, mitochondrial superoxide (mitoSO) was measured by fluorescence microscopy (MitoSOX) and Hydrogen peroxide (H 2 O 2 ) levels by microplate reader (Amplex Red). RBMECs were treated with antioxidants (MitoTempo and PEG-SOD) to study the role of oxidative stress in Aβ-toxicity.   Results.  Hyperglycemia, mannitol, Aβ or Aβ 40-1 alone did not affect cell viability. However, during hyperglycemia, Aβ reduced the cell viability compared to normoglycemic conditions. Baseline Ψ mito  and depolarization in response to ionophore were not different among all treatment groups. Aβ and hyperglycemia together induced a reduction in Ψ mito , promoted mitochondrial fission and enhanced mitoSO production and H 2 O 2  levels. Only MitoTempo and PEG-SOD treatments were able to counteract Aβ toxicity by increasing cell viability and recovering Ψ mito response.   Conclusion.  Hyperglycemia increases RBMEC susceptibility to Aβ toxicity leading to cell death by promoting the alterations of mitochondrial morphology, electromotive force and enhanced oxidative stress. The effect of hyperglycemia to promote Aβ toxicity appears to be mediated by mitoSO.
An early non-invasive detection of the patient inspiratory effort for patient-ventilator synchronization
Authors: Miodrag Vukcevic, Bosko Bojovic, Marija Petrovic, Goran Simic, Aleksandar Danicic, Jovana Petrovic, Ljupco Hadzievski
Journal: European Respiratory Journal (2013)

Background: In ICU NIV setting, patient-ventilator asynchrony imposes an additional burden on the respiratory system and may lead to NIV failure. Breath triggering using pneumatic variables (pressure, flow or volume) may be affected by air leaks, contributing to patient-ventilator asynchrony. LPG sensors (Long-Period Grating-fiber optic sensing) may be used to measure curvature of the rib cage, allowing measurement of breathing movements and volumes, providing a trigger variable independent on air leaks. Timing of the LPG breathing signal compared to the pneumatic signal is essential for triggering.

Goal: Compare the timing of the breathing volume signals obtained by pneumotachograph (by flow signal integration) and LPG sensor (calculated from torso curvature measurement).

Methods: Silicon rubber encapsulated LPG sensor patches were used for the movement/volume measurements. The self-adhesive sensor (1.4x6cm) was attached to the subject’s lower ribs. All measurements lasted 60 sec, with subjects in supine position and an ICU ventilator pneumotachometer (PTM) used for comparisson.

Results: Measurements were done in 9 healthy volunteers (4 male, 5 female). A systematic delay was observed in PTM with respect to LPG signal. The mean delay (by crosscorrelation method) of the PTM with respect to LPG sensor volume curves was 156±59 ms, while the mean delay during breath initiation (first 200 ms of each breath) was 166±66 ms.

Conclusions: LPG sensors provide a robust and non-invasive detection of the patient inspiratory effort significantly earlier than that provided by PTM method, which is independent of air leaks and can be used to substantially improve the triggering algorithms.
A review of national guidelines for management of COPD in Europe
Authors: Marc Miravitlles, Claus Vogelmeier, Nicolas Roche, David Halpin, João Cardoso, Alexander G. Chuchalin, Hannu Kankaanranta, Thomas Sandström, Paweł Śliwiński, Jaromir Zatloukal, Francesco Blasi
Journal: European Respiratory Journal (2016)

The quality of care can be improved by the development and implementation of evidence-based treatment guidelines. Different national guidelines for chronic obstructive pulmonary disease (COPD) exist in Europe and relevant differences may exist among them. This was an evaluation of COPD treatment guidelines published in Europe and Russia in the past 7 years. Each guideline was reviewed in detail and information about the most important aspects of patient diagnosis, risk stratification and pharmacotherapy was extracted following a standardised process. Guidelines were available from the Czech Republic, England and Wales, Finland, France, Germany, Italy, Poland, Portugal, Russia, Spain and Sweden. The treatment goals, criteria for COPD diagnosis, consideration of comorbidities in treatment selection and support for use of long-acting bronchodilators, were similar across treatment guidelines. There were differences in measures used for stratification of disease severity, consideration of patient phenotypes, criteria for the use of inhaled corticosteroids and recommendations for other medications ( e.g. theophylline and mucolytics) in addition to bronchodilators. There is generally good agreement on treatment goals, criteria for diagnosis of COPD and use of long-acting bronchodilators as the cornerstone of treatment among guidelines for COPD management in Europe and Russia. However, there are differences in the definitions of patient subgroups and other recommended treatments.
A randomized trial for the treatment of high-grade soft-tissue sarcomas of the extremities: preliminary observations.
Authors: F Gherlinzoni, G Bacci, P Picci, R Capanna, P Calderoni, E G Lorenzi, M Bernini, E Emiliani, E Barbieri, A Normand
Journal: Journal of Clinical Oncology (1986)

A new trial for evaluating the effectiveness of adjuvant chemotherapy in high-grade soft-tissue sarcomas of the extremities in adult patients is presented. All patients after local treatment were randomized into two arms, one without further therapy and the other to receive adjuvant chemotherapy (Adriamycin [Farmitalia-Carlo Erba, Milan, Italy], 450 mg/m2). The preliminary results of the study are reported at a median observation period of 27.6 months. Of the 59 patients who entered the study, 79.1% in the chemotherapy group are without sign of disease, whereas the corresponding figure in the nonadjuvant chemotherapy group is 54.3%. The difference between the two groups is statistically significant (P less than .005, log rank test). These preliminary observations encourage continuation of the study.
High-dose cyclophosphamide in small-cell carcinoma of the lung.
Authors: R L Souhami, G Finn, W M Gregory, B G Birkhead, R Buckman, D Edwards, A H Goldstone, P G Harper, S G Spiro, J S Tobias
Journal: Journal of Clinical Oncology (1985)

Eighteen patients with untreated small-cell cancer of the lung have been treated with cyclophosphamide 200 mg/kg on two occasions at an interval of four weeks. An additional eight patients received etoposide in addition to cyclophosphamide. Measurements of tumor volume were made by thoracic computed tomographic (CT) scan before and after each cycle. When compared with our previous study in which only one cycle of cyclophosphamide was given, the double procedure did not increase response rate, decrease the incidence of local relapse, or prolong the relapse-free interval. Survival after relapse was shorter with two cycles of chemotherapy mainly due to greater difficulty in administering further chemotherapy. The CT scans showed a decrease in tumor volume from 99.2 cc to 21 cc after the first cycle, but a smaller decrease to 14.1 cc after the second. These results show that the rapid emergence of drug resistance imposes limitations on the use of very high-dose cytotoxic chemotherapy.
The Macronutrients, Appetite, and Energy Intake
Authors: Alicia L. Carreiro, Jaapna Dhillon, Susannah Gordon, Kelly A. Higgins, Ashley G. Jacobs, Breanna M. McArthur, Benjamin W. Redan, Rebecca L. Rivera, Leigh R. Schmidt, Richard D. Mattes
Journal: Annual Review of Nutrition (2016)

Each of the macronutrients—carbohydrate, protein, and fat—has a unique set of properties that influences health, but all are a source of energy. The optimal balance of their contribution to the diet has been a long-standing matter of debate. Over the past half century, thinking has progressed regarding the mechanisms by which each macronutrient may contribute to energy balance. At the beginning of this period, metabolic signals that initiated eating events (i.e., determined eating frequency) were emphasized. This was followed by an orientation to gut endocrine signals that purportedly modulate the size of eating events (i.e., determined portion size). Most recently, research attention has been directed to the brain, where the reward signals elicited by the macronutrients are viewed as potentially problematic (e.g., contribute to disordered eating). At this point, the predictive power of the macronutrients for energy intake remains limited.
The influence of mammaplasty in axillary lymphatic drainage patterns and sentinel lymph node detection.
Authors: C. Bouteille, C. Soler, A. Steiner, B. Geissler, E. Gremillet
Journal: Journal of Clinical Oncology (2010)

609 Background: Controlateral mammaplasty is often necessary during the procedure of breast reconstruction after mastectomy. However the impact of these surgery on axillary lymphatic drainage and sentinel node (SN) detection remains controversial. The American Society of Clinical Oncology (ASCO) published a guideline in 2005 that recommended that SN biopsy should not be performed in patients with previous mammaplasty or axillary surgery. However, because of insufficient evidence and lack of scientific studies, mammaplasty cannot be considered an absolute contraindication for SN biopsy procedure, therefore, the same panelists of the ASCO guideline suggested that a preliminary LSG examination could be done when considering a SN biopsy in patients with previous mammapasty, with the objective of verifying the integrity of the mammary and axillary lymphatics areas. The aim of our study was to evaluate the lymphatic patterns and SN detection rates after mammaplasty by using lymphoSPECT-CT (LS). Methods: Twenty patients who underwent mammaplasty were evaluated by LSG immediately after periareolar injections of Tc 99m labelled sulphur colloid (NanoCIS*) at too time points: before mammaplasty (pre-LS) and between 40 to 60 days after mammaplasty (post-LS). Results: All breasts drained primarily to the axillary SN. The binomial test did not show statistical differences in lymphatic drainage patterns between pre-LSG and post-LSG. The average number of hot SN was 1.28 in pre-LS, 1.14 in post-LS. The localisation of hot SN was evaluated by: (1) antero-posterior distance was estimated in centimeter from SN region to dorsal vertebrae spine center; and (2) SN's coronal position was compared to grill rib. The preservation of axillary lymphatic drainage after mammaplasty was allowed for SN detection in all studied breasts and the localisation of the sentinel node was the same after surgery than before. Conclusions: After evaluating the impact of the previous mammaplasty surgery on the accuracy of SLN biopsy, we observed that this surgery does not significantly affect the accuracy of lymphatic mapping and that it will be possible to propose sentinel node biopsy after mammaplasty. No significant financial relationships to disclose.
New Appliances
Authors: J H FERRIS
Journal: BMJ (1965)

Y& .W-M possible at greater rih e In my own p ic A t sets will functi ,uiings for up to 3 miles (4.8 kmi) and in the open air`for pto5miles (8km.).Servicing.-An&Aquate service network is essential, particu- larly in the -early months.Most doctors have 'ad no real difficulties, but "those in isolated ar may find servicing a 'Problem.Mi'ufacturers quote a fault rate of -one a year for a modern -traysistorized set, but the older valve equipment was less 'relive.Progress iif design continues to be made.