tbuckley/cabot-search huggingface dataset:
A pharmacokinetic (PK) pharmacodynamic (PD) driven first-in-human study of the oral class I PI3K inhibitor CH5132799, in patients with advanced solid tumors.
Authors: Aurelius Gabriel Omlin, James F. Spicer, Debashis Sarker, David James Pinato, Roshan Agarwal, Philippe Alexandre Cassier, Chara Stavraka, Monsterrat Blanco, Aneta Suder, Suzanne Allan, Simon Heaton, Shaun Decordova, Lorna Pope, Jenny Prince, Kohei Noguchi, Keith Jones, Michiyasu Inatani, Rie Shiokawa, Udai Banerji, Sarah Patricia Blagden
Journal: Journal of Clinical Oncology (2012)

3022 Background: The phosphatidylinositol 3-kinase (PI3K) pathway is a promising target in cancer. CH5132799 is a novel PI3K inhibitor, selectively inhibiting class I PI3Ks (α, β, δ and γ) with no inhibition of class II and III or mTOR, and with potent antitumor activity in preclinical studies (Tanaka et al, Clin Cancer Res; 17; 3272-81, 2011) . First-in-human study objectives were determination of maximum tolerated dose (MTD), safety/tolerability, PK/PD and clinical activity (RECIST). Methods: A 3+3 dose escalation design was used. The initial dosing schedule of CH5132799(schedule A) was once a day (QD). Due to a relatively short half-life, a twice a day (BID) schedule (schedule B) was introduced. PK profiles were studied over 72 hours. PD analyses included quantification of various phosphoproteins in platelet rich plasma (PRP). Tumor assessments were performed at baseline and cycle 3 day 1 (C3D1) and FDG-PET scans at baseline, C1D8 and C3D1. Results: 29 patients (pts) with a variety of solid tumors have been treated (A 23 pts, B 6 pts, the most common tumors were breast, oesophageal, colorectal and ovarian). The starting doses were 2 mg (A) and 48 mg (B). The current doses being explored are 96 mg (A) and 72 mg (B). The most frequently reported drug-related AEs were Grade 1/2 diarrhea, nausea, fatigue, anorexia and anemia. 1 DLT (Grade 3 elevated LFT) was observed in a hepatocellular carcinoma pt at 48 mg BID. MTD has not yet been determined. The preliminary mean ±SD C max and AUC at 96 mg QD were 202±129 ng/ml and 1407±935 ng·hr/ml respectively, which is consistent with an efficacious exposure based on preclinical models. Some patients achieved the expected exposure at over 32 mg. From single dose of 48mg there was a reduction of phosphorylation of AKT in PRP after treatment, consistent with pathway modulation. A patient with clear cell ovarian cancer and a PIK3CA mutation treated at 48 mg BID showed &gt;50% decrease in SUV on a PET scan at C1D8 and a 75% decrease in CA-125 at C2D1. 5 pts exhibited SD (&gt;8 weeks). Conclusions: CH5132799 is well tolerated either QD ≤96 mg or BID ≤48 mg. Dose-escalation continues and updated safety/efficacy/PK/PD data will be presented.
Oral fumaric acid esters for psoriasis: abridged Cochrane systematic review including <scp>GRADE</scp> assessments
Authors: A. Atwan, J.R. Ingram, R. Abbott, M.J. Kelson, T. Pickles, A. Bauer, V. Piguet
Journal: British Journal of Dermatology (2016)

Fumaric acid esters (FAEs) are licensed for the treatment of moderate‐to‐severe psoriasis in Germany but are also used off‐label in many other countries. We conducted this systematic review to synthesize the highest‐quality evidence for the benefits and risks of FAEs for psoriasis. Our primary outcomes were change in Psoriasis Area and Severity Index score and dropout rates due to adverse effects. Randomized controlled trials (RCTs) of FAEs or dimethylfumarate were included, with no restriction on age or psoriasis subtype. We searched the Cochrane Skin Group Specialised Register, CENTRAL in the Cochrane Library, Medline, Embase, LILACS and five trials registers, and hand searched six conference proceedings. Six RCTs with a total of 544 participants were included, four of which were published only as abstracts or brief reports, limiting study reporting. Five RCTs compared FAEs with placebo, and all demonstrated benefit in favour of FAEs. However, meta‐analysis was possible only for PASI 50 response after 12–16 weeks, which was achieved by 64% of participants on FAEs compared with 14% on placebo: risk ratio (RR) 4·55, 95% confidence interval (CI) 2·80–7·40; two studies; 247 participants; low‐quality evidence). There was no difference in dropout rates due to adverse effects (RR 5·36, 95% CI 0·28–102·12; one study; 27 participants; very low‐quality evidence and wide CI). More participants experienced nuisance adverse effects with FAEs (76%) than with placebo (16%) (RR 4·72, 95% CI 2·45–9·08; one study; 99 participants; moderate‐quality evidence), mainly abdominal pain, diarrhoea and flushing. One head‐to‐head study of very low‐quality evidence comparing FAEs with methotrexate reported comparable efficacy and dropout rates, although FAEs caused more flushing. The evidence in this review was limited and must be interpreted with caution; studies with better design and outcome reporting are needed.
A Pilot Study Comparing the Effects of Pineal Extract and a Placebo in Patients with Chronic Schizophrenia
Authors: Stanley H. Eldred, Norman W. Bell, Lewis J. Sherman
Journal: New England Journal of Medicine (1960)

SEVERAL authors have reported that pineal extracts cause clinical improvement in schizophrenia.1 Altschule2 corroborated these findings and concluded that "Protein-free extracts made at a pH of about 8.5 and at temperatures between 55 and 70°C. reverse biochemical abnormalities of schizophrenia and cause clinical improvement." He further stated3 that patients hospitalized for fifteen years or more showed only slight to moderate improvement.On the basis of this earlier work indicating that pineal extracts might be useful in schizophrenia a double-blind study was established to compare the effects of pineal extract¶ with a placebo when given to 8 women with chronic schizophrenia . . .
Effects of Anticholinergic Drugs on Pepsin Production and Uropepsinogen Excretion
Authors: Harold M. Silver, Helio Pucci, Thomas P. Almy
Journal: New England Journal of Medicine (1955)

THE effects of anticholinergic drugs on gastric function have usually been measured by radiologic studies to determine decrease in motility and tone, or by intubation technics to determine the decrease in volume and acidity of the gastric juice. The purpose of the present study was to determine the effects of these agents on the secretion of pepsin. Because we were able to show significant depression of pepsin output in acute experiments, we explored the use of uropepsinogen excretion as a measure of long-term anticholinergic effects. The rationale for this method is the fact that the gastric cells producing pepsin secrete . . .
Evidence for a Phosphorus-Depletion Syndrome in Man
Authors: Myron Lotz, Elias Zisman, Frederic C. Bartter
Journal: New England Journal of Medicine (1968)

Antacids can impair phosphorus absorption in man. The long-term results of such impaired absorption are not fully appreciated despite knowledge of the vital role of phosphorus in life processes and the serious results of its depletion in animals. To determine depletion in man, studies were performed in three normal subjects and three patients with parathyroid dysfunction during prolonged treatment with antacids. It was found that a syndrome of phosphorus depletion characterized by hypophosphatemia, hypophosphaturia, increased gastrointestinal absorption of calcium, hypercalciuria, increased resorption of skeletal calcium and phosphorus, and debility, with anorexia, weakness, bone pain and malaise, can be produced by prolonged treatment with nonabsorbable antacids such as magnesium-aluminum hydroxides.
A Novel Mutation in the Cystic Fibrosis Gene in Patients with Pulmonary Disease but Normal Sweat Chloride Concentrations
Authors: W. Edward Highsmith, Lauranell H. Burch, Zhaoqing Zhou, John C. Olsen, Thomas E. Boat, Alexander Spock, Jack D. Gorvoy, Lynne Quittell, Kenneth J. Friedman, Lawrence M. Silverman, Richard C. Boucher, Michael R. Knowles
Journal: New England Journal of Medicine (1994)

Many patients with chronic pulmonary disease similar to that seen in cystic fibrosis have normal (or nondiagnostic) sweat chloride values. It has been difficult to make the diagnosis of cystic fibrosis in these patients because no associated mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene has been identified.
Nutritional Defects among Children in Vermont
Authors: Harold B. Pierce, Paul F. Fenton, Walter Wilkins, Milla E. Newland, Pauline S. Budge
Journal: New England Journal of Medicine (1945)

DIET surveys, such as those reported by the National Research Council,1 have revealed that many New Englanders are not eating adequate quantities of protective foods. This condition is reflected by the high incidence of selective service rejections in the area. The object of this study was to determine the nutritional status of a group of Vermont children in the vicinity of Burlington.Experimental Method Selection of Children Children were selected so as to include urban and rural areas, different ages, different economic status and two institutions for child care. A total of 386 were inspected for physical signs, and blood . . .
Zidovudine Alone or in Combination with Didanosine or Zalcitabine in HIV-Infected Patients with the Acquired Immunodeficiency Syndrome or Fewer Than 200 CD4 Cells per Cubic Millimeter
Authors: Louis D. Saravolatz, Dean L. Winslow, Gary Collins, James S. Hodges, Carla Pettinelli, Daniel S. Stein, Norman Markowitz, Randall Reves, Mark O. Loveless, Lawrence Crane, Melanie Thompson, Donald Abrams
Journal: New England Journal of Medicine (1996)

We compared two combinations of nucleosides with zidovudine alone in patients with advanced human immunodeficiency virus (HIV) infection.
<i>PIK3CA</i> mutation, aspirin use after diagnosis, and colorectal cancer survival: A systematic review and meta-analysis of epidemiological studies.
Authors: Laura Paleari, Matteo Puntoni, Matteo Clavarezza, Silvia Caviglia, Davide Corradengo, Eleonora Campazzi, Nicoletta Provinciali, Andrea De Censi
Journal: Journal of Clinical Oncology (2015)

e12594 Background: Regular aspirin (ASA) use has been associated with inhibition of the whole spectrum of colorectal carcinogenesis, including prevention of metastases and reduced total mortality in colorectal cancer (CRC). Preclinical data have demonstrated that ASA down-regulates PI3K signaling activity through COX2 inhibition leading to the hypothesis that the effect of ASA might be different according to PIK3CA mutational status, but epidemiological studies have led to conflicting results. We performed a systematic review and meta-analysis to evaluate the interaction between PIK3CA status and efficacy of post-diagnosis ASA use. Methods: We searched PubMed, ISI Web Science, Embase and Cochrane library electronic databases to identify studies that compared the efficacy of post-diagnosis ASA in CRC patients identified by PIK3CA status. Log HRs for OS were meta-analyzed according to PIK3CA status by inverse variance weighting. A pooled test for treatment by PIK3CA status interaction was performed by weighted linear meta-regression. All statistical tests were two sided. Results: 5 studies were eligible for this meta-analysis for a total of 4589 pts. The mean prevalence of PIK3CA mutation was 14.5%. Overall, the effect of ASA was not significant (HR = 0.82; 95% CI, 0.63-1.08, p = 0.16; I2= 57%). In PIK3CA mutant disease (n = 588) ASA use after diagnosis significantly reduced total mortality by 28% with no heterogeneity (HR = 0.71; 95% CI, 0.51-0.99, p = 0.04; I2= 0%), whereas in PIK3CA wild-type disease (n = 4001), ASA use did not reduce overall mortality (HR = 0.93; 95% CI, 0.61-1.40; P = 0.7; I2= 80%) (p-interaction = 0.39). Sensitivity analyses showed that different PIK3CA assessment methods did not affect overall findings. Conclusions: The benefit of post-diagnosis ASA on total mortality from CRC seems to be restricted to PIK3CA mutated tumors, but the low number of studies prevents definitive conclusions. Adjuvant trials of ASA addressing this issue are warranted.
Priming with Granulocyte Colony-Stimulating Factor — Relation to High-Dose Cytarabine in Acute Myeloid Leukemia
Authors: Thomas Büchner, Wolfgang E. Berdel, Wolfgang Hiddemann
Journal: New England Journal of Medicine (2004)

To the Editor: Granulocyte colony-stimulating factor (G-CSF) given concurrently with chemotherapy was recently shown to improve disease-free and overall survival in patients 18 to 60 years of age w...
Effect of a Chemically Defined Diet in Liquid Form on Colon Carcinogenesis in Rats2
Authors: Masaharu Tatsuta, Hisako Yamamura, Hiroyasu Iishi, Makoto Ichii, Sanai Noguchi, Miyako Baba, Haruo Taniguchi
Journal: JNCI Journal of the National Cancer Institute (1985)

The effects of ad libitum feeding of a chemically defined diet in liquid form on the incidence and histology of colon cancer induced by 10 weekly sc injections of 7.4 mg/kg of azoxymethane [(AOM) CAS: 25843-45-2] were investigated in W-rats. The chemically defined diet was adjusted once every 24 hours from 4 weeks before injection of the carcinogen to the end of the experiment at week 40. Oral administration of the defined diet resulted in significant increase in the incidence of colon cancer at week 40. Histologic examination showed that unlike adenocarcinomas with high mucin-producing activity, which were common in rats on pellet diet, most of the adenocarcinomas that developed in rats fed on defined diet were highly or well differentiated, with a typical glandular pattern. Administration of the chemically defined diet also resulted in marked colon mucosal hypoplasia and reduced gastrin levels in the serum at weeks 4 and 40.
Escalated as Compared with Standard Doses of Doxorubicin in BACOP Therapy for Patients with Non-Hodgkin's Lymphoma
Authors: Ralph M. Meyer, Ian C. Quirt, Jamey R. Skillings, M.C. Cripps, Vivien Bramwell, Brian H. Weinerman, Mary K. Gospodarowicz, Bruce F. Burns, Ann Marie Sargeant, Lois E. Shepherd, Benny Zee, William M. Hryniuk
Journal: New England Journal of Medicine (1993)

In 1981 the Clinical Trials Group of the National Cancer Institute of Canada completed a pilot study in patients with advanced-stage non-Hodgkin's lymphoma with aggressive tumor histology. That study demonstrated the potential efficacy of escalating the dose of doxorubicin used in a regimen of bleomycin, doxorubicin, cyclophosphamide, vincristine, and prednisone (BACOP). In the present study, we compared standard BACOP (s-BACOP) with BACOP that included escalated doses of doxorubicin (esc-BACOP) in 238 patients 16 to 70 years old with previously untreated, advanced-stage intermediate- or high-grade non-Hodgkin's lymphoma. During the first 28-day cycle all patients received doxorubicin in a dose of 25 mg per square meter of body-surface area on days 1 and 8. Patients randomly assigned to receive s-BACOP subsequently received five identical cycles, whereas those assigned to receive esc-BACOP received 40 mg of doxorubicin per square meter on days 1 and 8 of five subsequent cycles if granulocytopenia (<1000 cells per cubic millimeter) had not developed during the first cycle.
P214 Arrhythmias in pneumonia: a review of incidence, outcomes and management
Authors: DR Cox
Journal: Thorax (2015)

<h3>Background</h3> Community-acquired pneumonia (CAP) has high mortality, from 5 to 18.3%.<sup>1</sup> Arrhythmias are a recognised significant complication. Growing evidence associates this treatable complication with increases in mortality. No review has summated data on mortality or ways to improve outcome. <h3>Aims</h3> This review aimed to define the extent of the problem, collate and appraise evidence regarding outcomes and management, and identify gaps in understanding. <h3>Methods</h3> Narrative review using a systematic protocol. Medline, ProQuest, Web of Science were searched for papers reporting adults with CAP complicated by arrhythmia. 382 articles were assessed and excluded based on title (348), abstract (27) and full text (6), leaving 11. Review of bibliographies added 3, totalling 14. These were appraised and coded, with Newcastle-Ottawa scores assigned. <h3>Results</h3> Three reviews and 11 primary studies were included: 10 Cohorts (4 prospective, 6 retrospective) and one case series. One meta-analysis of cardiac events identified a pooled incidence of 4.7% for CAP inpatients developing arrhythmia.<sup>2</sup> N-O scores ranged from 5 to 9, Median 7.5. Outcomes reported: Incidence; 30 and 90 day mortality; Re-hospitalisation; predisposing factors. Only one paper commented on treatment. <h3>Discussion</h3> There is high quality evidence of a link between CAP and arrhythmogenesis. Data linking it to mortality suggest a strong association with worse outcome. This review was limited by its single reviewer. Some evidence was limited by retrospective study designs and biassed populations. The strengths of this review lie in its reproducible systematic methods and clear outlining of gaps in our understanding of this phenomenon, particularly regarding best management. <h3>Conclusion</h3> New arrhythmia complicating CAP is a recognised phenomenon that carries morbidity and mortality. Notably, no research has been reported on how best to manage this complication – reflected by the guidelines for the respective diseases in isolation. The next step is to look at how this complication is managed and identify the best approach to improve patient outcomes. <h3>References</h3> 1 Lim WS, Woodhead M. BTS adult CAP audit 2009/10.<i> Thorax</i> 2011;<b>66</b>(6):548–549 2 Corrales-Medina VF, <i>et al</i>. Cardiac complications in patients with community-acquired pneumonia: a systematic review and meta-analysis of observational studies. <i>PLoS Med</i>. 2011;<b>8</b>(6):779
PTU-204 The prevalence and significance of anaemia in patients receiving chemoradiotherapy treatment for squamous cell carcinoma of the anus
Authors: R Bulla, D Humes, J Scholefield, CJ Walter
Journal: Gut (2015)

<h3>Introduction</h3> Anaemia at disease presentation is known to be associated with worse outcomes in a number of cancers. In squamous cell carcinoma of the anus some of this effect may result from the relative radioresistance offered by anaemia-induced tumour hypoxia.<sup>1</sup> This study aimed to examine the relationship between pretreatment anaemia and survival in patients undergoing chemoradiotherapy treatment of squamous cell carcinoma of the anus. <h3>Method</h3> All patients diagnosed with squamous cell carcinoma of the anus between 2005–2012 at Nottingham University Hospitals NHS Trust (NUH) were identified from the multidisciplinary team database. Retrospective data collection was undertaken using the electronic and case note records of those patients whose primary treatment was with chemoradiotherapy. The patients were divided into 2 groups: the anaemic group (Haemoglobin (Hb) &lt;120 g/L and non-anaemic group (Hb ≥ 120 g/L). Their baseline demographics and clinical outcomes were compared. <h3>Results</h3> Seventy-six patients (50 female and 26 male) with a median age of 63 years (IQR 52–74) were treated at NUH for squamous cell carcinoma of the anus with chemoradiotherapy over the 8-year study period. Of these 21 (28%) were anaemic at presentation, 2 of these patients received blood transfusions during their treatment but their Hbs remained below 120 g/L. There was no significant difference in follow-up times between the anaemic and non-anaemic groups with median clinical follow-up of 39 months (IQR 11–68) and 35 months (IQR 25–48) (p = 0.8) respectively. Anaemia was associated with increased mortality with a hazard ratio (HR) of 2.52 (95% CI 1.05–6.05). Multivariate analysis of mortality adjusting for the known confounders of age, sex and stage of disease demonstrated a HR of 2.06 (95% CI 0.80–5.35). <h3>Conclusion</h3> In this study over a quarter of patients with squamous cell carcinoma of the anus were anaemic at presentation. Anaemia was associated with increased mortality. This association weakened when adjusting for stage of disease at presentation. Further research examining the role of correcting pretreatment anaemia prior to radiotherapy treatment is required in order to understand how best to optimise patient outcomes following chemoradiotherapy. <h3>Disclosure of interest</h3> None Declared. <h3>Reference</h3> Vaupel P, Thews O, Hoecke M. Treatment resistance of solid tumors: role of hypoxia and anaemia. Med Oncol. 2001;18:243–59
Phase I study of OGX-011, a second generation antisense oligonucleotide (ASO) to clusterin, combined with cisplatin and gemcitabine as first-line treatment for patients with stage IIB/IV non-small cell lung cancer (NSCLC)
Authors: J. J. Laskin, K. N. Chi, B. Melosky, K. Sill, D. Hao, C. M. Canil, M. Gleave, N. Murray
Journal: Journal of Clinical Oncology (2006)

17078 Background: The clusterin gene is frequently expressed in NSCLC and encodes a cytoprotective chaperone protein that promotes cell survival and is upregulated in response to apoptotic stimuli such as chemotherapy. OGX-011 is an ASO that binds to clusterin mRNA thus potently regulating expression and chemosensitizing cancer cells. Previous Phase I studies of OGX-011 identified biologically active doses of 480mg to 640mg. The objective of this multi-center Phase I study was to define the Phase 2 dose of OGX-011 in combination with standard chemotherapy. Methods: Patients (pts) with chemotherapy-naive advanced stage IIIB/IV NSCLC were potentially eligible. OGX-011 is given as a 2hr IV infusion weekly after 3 loading doses (days -7, -5, and -3). OGX-011 dose escalation was planned to a maximum of 640mg. Cisplatin was given at 75 mg/m 2 IV day 1 and gemcitabine 1250mg/m 2 IV days 1 and 8, on a 21-day schedule up to 6 cycles. Pharmacokinetic profiling was done in cycle 1. Results: Between Jan 2004 and Apr 2005, 10 patients were enrolled. Median age 62 yrs (49–75); 4 female. ECOG 0/1: 3/7. Stage IIIB/IV: 1/9. 9 of 10 pts completed at least one cycle; 1 withdrew after one dose of OGX-011 due to progressive disease (PD). Of the 9 pts, 6 received ≥ 5 cycles and 3 received 2–4 cycles (2 patients discontinued due to PD and 1 at the pts request). Median follow-up: 5.0m (1.6 - 6.7m). As of Jan 2006, 2 pts had a PR; 5 had SD; 2 had PD. 4 pts had 5 serious adverse events: elevated creatinine, hypoxia, pneumonia, pleural effusion, and febrile neutropenia. 3 pts had Gr 3 hyponatremia. Gr 3/4 hematological toxicities in 10–40% and 10–20%, respectively. No dose-limiting toxicities noted; 7 pts received OGX-011 at 640 mg. A proportional increase in OGX-011exposure (C max and AUC 0-inf ) from 480 to the 640 mg was noted with no apparent effect on GEM/CIS. Conclusions: OGX-011 was well tolerated and can be given at biologically active doses (640 mg) with standard GEM/CIS chemotherapy for patients with advanced NSCLC. A multicenter Phase II trial of this combination is underway. Sponsored by OncoGenex Technologies, Inc. with Isis Pharmaceuticals Inc. [Table: see text]
Activation of Coagulation after Administration of Tumor Necrosis Factor to Normal Subjects
Authors: Tom van der Poll, Harry R. Büller, Hugo ten Cate, Cornelis H. Wortel, Kenneth A. Bauer, Sander J.H. van Deventer, C. Erik Hack, Hans P. Sauerwein, Robert D. Rosenberg, Jan W. ten Cate
Journal: New England Journal of Medicine (1990)

Tumor necrosis factor has been implicated in the activation of blood coagulation in septicemia, a condition commonly associated with intravascular coagulation and disturbances of hemostasis. To evaluate the early dynamics and the route of the in vivo coagulative response to tumor necrosis factor, we performed a controlled study in six healthy men, monitoring the activation of the common and intrinsic pathways of coagulation with highly sensitive and specific radioimmunoassays.