tbuckley/cabot-search huggingface dataset:
Phase I study of oral CP-4126, a gemcitabine analog, in patients with advanced solid tumors.
Authors: A. Hendlisz, E. E. Voest, J. Schellens, A. Awada, P. Witteveen, R. Stuurman, W. Rasch, P. Hals
Journal: Journal of Clinical Oncology (2010)

e13078 Background: CP-4126 (gemcitabine-5′-elaidic acid ester) is a novel nucleoside analogue with preclinical antitumor activity. CP-4126 has been solubilized in a lipid-based formulation and encapsulated in nongelatine hard shell capsules. This dose- escalating study assesses the pharmacokinetics (PK), safety and preliminary antitumor activity of the oral formulation and determines the recommended dose (RD) for phases II. Methods: Patients with advanced refractory solid tumors, performance status ECOG ≤ 2, adequate hematologic, renal, and hepatic function are enrolling. The study has a two- step design; a nonrandomized dose-escalating step I with oral CP-4126 alone, followed by a randomized, cross-over step II comparing oral CP-4126 with IV gemcitabine (gem). In step I CP-4126 is given on days (d) 1, 8, 15 q4w in increasing doses until MTD and RD are established. Step II involves a cross-over design with oral CP-4126 at RD on d1 or d8 and IV gemcitabine (1000 mg/m2) on d1 or d8. Further in step II, from day 15 and all subsequent cycles, all patients will receive oral CP-4126. Serial blood samples are collected for PK analysis on d1 in step I and on d1 and 8 in step II. Results: The study is ongoing. 25 (m=8; f=17) patients (45-80 years age range) have been enrolled in step I at 7 dose levels (100–3000 mg), and have received 1 to 5 treatment cycles. Most had pancreatic, colon, breast, or ovarian carcinoma. Most frequent AEs are fatigue and AST/ALT increases, the majority being grade 1-2. One DLT was reported at 1300 mg: γGT grade 4, and ALT/AST and fatigue grade 3. Two patients showed disease stabilisation according to RECIST evaluation (23-25% reduction from baseline). RD has not yet been established. No CP-4126 was detected in plasma up to 1300 mg and only trace amounts appeared at higher dose levels. dFdC concentrations (Cmax) and exposure (AUC) increased linearly with CP-4126 dose, indicating that oral CP-4126 acts as a prodrug for gemcitabine. Conclusions: Oral CP-4126 is a prodrug for gemcitabine in humans. It is well tolerated at doses up to 3000 mg in a d1, 8, 15 q4w schedule and shows a good safety profile and an early efficacy signal compared with gemcitabine historical data. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Clavis Pharma Clavis Pharma
Investigation of selective JAK1 inhibitor GSK2586184 for the treatment of psoriasis in a randomized placebo-controlled phase IIa study
Authors: V.J. Ludbrook, K.J. Hicks, K.E. Hanrott, J.S. Patel, M.H. Binks, M.R. Wyres, J. Watson, P. Wilson, M. Simeoni, L.A. Schifano, K. Reich, C.E.M. Griffiths
Journal: British Journal of Dermatology (2016)

GSK2586184 is a selective oral Janus kinase (JAK)1 inhibitor being evaluated as a treatment for moderate-to-severe plaque-type psoriasis.To assess the relationship between dose of GSK2586184 and clinical response, primarily by the Psoriasis Area Severity Index (PASI).Sixty patients with moderate-to-severe plaque psoriasis were randomized to cohort A: 100 mg, 200 mg or 400 mg GSK2586184 twice daily or placebo; and eight were randomized to open-label cohort B, a small exploratory cohort treated with 400 mg GSK2586184 twice daily, to explore differential gene expression.At week 12, a 75% reduction in PASI (PASI 75) response rates in the intent-to-treat population were 0% in the placebo group compared with 13%, 25% and 57% in the 100 mg, 200 mg and 400 mg GSK2586184 twice-daily groups, respectively. Increases in the proportion of PASI 75 responses were seen across all dose levels by week 4. Improvement in itch and quality of life were observed at all doses relative to placebo with the greatest improvement seen in the 400-mg dose group. Overall, the incidence of adverse events (AEs) was similar across treatment groups, and no relationship between frequency of AE and GSK2586184 dose was identified. Differential gene expression was observed in involved and uninvolved skin at baseline and in involved skin after 2 weeks of treatment with GSK2586184.Our study demonstrates that 12 weeks of treatment with GSK2586184 resulted in clinical improvement and was generally well tolerated in patients with moderate-to-severe plaque-type psoriasis.
Long-Term Outcomes of Patients With Recent-Onset Rheumatoid Arthritis After 10 Years of Tight Controlled Treatment
Authors: Iris M. Markusse, Gülsah Akdemir, Linda Dirven, Yvonne P.M. Goekoop-Ruiterman, Johannes H.L.M. van Groenendael, K. Huub Han, T.H. Esmeralda Molenaar, Saskia Le Cessie, Willem F. Lems, Peter A.H.M. van der Lubbe, Pit J.S.M. Kerstens, André J. Peeters, H. Karel Ronday, Peter B.J. de Sonnaville, Irene Speyer, Theo Stijnen, Saskia ten Wolde, Tom W.J. Huizinga, Cornelia F. Allaart
Journal: Annals of Internal Medicine (2016)

Background: Treat-to-target therapy is effective for patients with rheumatoid arthritis (RA), but long-term results of continued targeted treatment are lacking. Objective: To evaluate long-term outcomes in patients with early RA after 10 years of targeted treatment in 4 treatment strategies. Design: Randomized trial. (Nederlands Trial Register: NTR262 and NTR265) Setting: The Netherlands. Patients: 508 patients with early active RA. Intervention: Sequential monotherapy (strategy 1), step-up combination therapy (strategy 2), or initial combination therapy with prednisone (strategy 3) or with infliximab (strategy 4), all followed by targeted treatment aiming at low disease activity. Measurements: Functional ability (Health Assessment Questionnaire [HAQ] score) and radiographic progression (Sharp–van der Heijde score) were primary end points. Survival in the study population was compared with the general population using the standardized mortality ratio. Results: 195 of 508 of patients (38%) dropped out of the study (28% in strategy 4 vs. 40% to 45% in strategies 1 to 3, respectively). At year 10, mean HAQ score (SD) was 0.57 (0.56); 53% and 14% of patients were in remission and drug-free remission, respectively, without differences among the strategies. Over 10 years, mean HAQ scores were 0.69, 0.72, 0.64, and 0.58 in strategies 1 to 4, respectively (differences not clinically relevant). Radiographic damage was limited for all strategies, with mean Sharp–van der Heijde estimates during follow-up of 11, 8, 8, and 6 in strategies 1 to 4, respectively (P = 0.15). Standardized mortality ratio was 1.16 (95% CI, 0.92 to 1.46) based on 72 observed and 62 expected deaths, with similar survival among the 4 strategies (P = 0.81). Limitation: Dropout rate varied by strategy. Conclusion: In patients with early RA, initial (temporary) combination therapy results in faster clinical improvement and targeted treatment determines long-term outcomes. Drug-free remission, with prevention of functional deterioration and clinically relevant radiographic damage, and normalized survival are realistic outcomes. Primary Funding Source: Dutch College of Health Insurance Companies, Schering-Plough, and Janssen.
An Epidemiologic Study of Infectious Mononucleosis in a New England College
Authors: Alfred S. Evans, Elizabeth D. Robinton
Journal: New England Journal of Medicine (1950)

THE frequency of epidemics of infectious mononucleosis in a community or in institutions is difficult to determine since this disease is not usually reported to public-health agencies. Yet if one takes the published literature as a sounding board for the behavior of this condition during the last twenty-five years in the United States, one is struck by the fact that despite an increasingly voluminous number of reports devoted to its clinical and laboratory aspects the number of publications dealing with actual epidemics of infectious mononucleosis is singularly few. For example, in the first three decades of this century and after . . .
Daily administration of interferon alpha 2b and utility of combination therapy with ribavirin as initial treatment for chronic hepatitis C.
Authors: A. Ricchiuti, P. Ciccorossi, F. Costa, M. Bellini, Da . Massa Carrara P, P. Arpe, F. Maggi, M.L. Vatteroni, M. Bendinelli, G. Maltinti, S Marchi
Journal: Hepatology (1999)
Thyroid Dysfunction in Pregnancy
Authors: George W. Greenman, Mary O. Gabrielson, June Howard-Flanders, Morris A. Wessel
Journal: New England Journal of Medicine (1962)

THE ability of a woman with a thyroid disorder to become pregnant, to carry a pregnancy to term and to produce an infant with adequate endowment for good development is diminished unless the disease is well controlled.1 2 3 4 5 6 7 8 9 10 The delivery of an apparently normal live-born infant at term does not necessarily indicate that the product of the pregnancy is satisfactory. No matter how careful the appraisal, it is not possible at birth to recognize all congenital malformations, to evaluate mental retardation critically or to determine the infant's developmental capabilities.11 12 13 14 15 16 The outcome of any pregnancy can be better assessed if the baby . . .
A Trial of Desmopressin (1-Desamino-8-D-Arginine Vasopressin) to Reduce Blood Loss in Uncomplicated Cardiac Surgery
Authors: Thomas Hackmann, Randall D. Gascoyne, Sheldon C. Naiman, Gershon H. Growe, Linda D. Burchill, W.R. Eric Jamieson, Samuel B. Sheps, Martin T. Schechter, Gary E. Townsend
Journal: New England Journal of Medicine (1989)

Previous studies have suggested that desmopressin may reduce the bleeding diathesis that often complicates open-heart surgery. To pursue this question further, we performed a double-blind, randomized, placebo-controlled trial to determine whether the previously reported beneficial effect of desmopressin on hemostasis during complex cardiac surgery was applicable to all elective cardiac surgical procedures involving cardiopulmonary bypass. In 150 consecutive patients, most of whom underwent primary coronary-artery bypass grafting, we compared the effects of intravenous desmopressin (0.3 μg per kilogram of body weight) with those of saline placebo on postoperative blood loss and the need to replace blood products. The median amount of blood lost within the first 24 hours after operation was similar in the desmopressin and placebo groups (865 vs. 738 ml; P = 0.26). The postoperative use of blood replacement products did not differ significantly between the groups (1025 ml [95 percent confidence interval, 300 to 4140 ml] in the desmopressin group and 860 ml [247 to 5346 ml] in the placebo group). Desmopressin is believed to exert its hemostatic effect by releasing von Willebrand factor. The level of ristocetin cofactor, a functional index of the level of von Willebrand factor, was increased approximately twofold from base line in both treatment groups 90 minutes and 24 hours after the administration of medication. Similarly, the levels of von Willebrand factor multimers increased uniformly in both groups. These findings may be consistent with a normal stress response of von Willebrand factor to major surgery and could explain our failure to detect a therapeutic effect of desmopressin. We conclude that the majority of patients who undergo elective cardiac surgery receive no hemostatic benefit from the use of desmopressin. (N Engl J Med 1989;321:1437–43.)
The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation
Authors: Amy Langdon, Nathan Crook, Gautam Dantas
Journal: Genome Medicine (2016)

The widespread use of antibiotics in the past 80 years has saved millions of human lives, facilitated technological progress and killed incalculable numbers of microbes, both pathogenic and commensal. Human-associated microbes perform an array of important functions, and we are now just beginning to understand the ways in which antibiotics have reshaped their ecology and the functional consequences of these changes. Mounting evidence shows that antibiotics influence the function of the immune system, our ability to resist infection, and our capacity for processing food. Therefore, it is now more important than ever to revisit how we use antibiotics. This review summarizes current research on the short-term and long-term consequences of antibiotic use on the human microbiome, from early life to adulthood, and its effect on diseases such as malnutrition, obesity, diabetes, and Clostridium difficile infection. Motivated by the consequences of inappropriate antibiotic use, we explore recent progress in the development of antivirulence approaches for resisting infection while minimizing resistance to therapy. We close the article by discussing probiotics and fecal microbiota transplants, which promise to restore the microbiota after damage of the microbiome. Together, the results of studies in this field emphasize the importance of developing a mechanistic understanding of gut ecology to enable the development of new therapeutic strategies and to rationally limit the use of antibiotic compounds.
Cystathioninuria in Two Healthy Siblings
Authors: Thomas L. Perry, David F. Hardwick, Shirley Hansen, Donna L. Love, Sydney Israels
Journal: New England Journal of Medicine (1968)

Tests in two siblings with cystathioninuria indicated that the disorder is congenital and not secondary. Yet both children enjoy good physical and mental health. Their parents excrete substantial amounts of cystathionine in urine only after methionine loading, and thus appear to be heterozygous for the cystathioninuria gene. It is possible that the mental defect and other serious disorders that have been described in six of the seven previously reported cases of cystathioninuria were coincidental, and in no way the result of the genetically determinded deficiency of the cystathionine-cleaving enzyme. Cystathioninuria may prove to be a benign disorder requiring no treatment.
Renal function evolution in cancer patients. Results of the IRMA-2 study
Authors: S. Oudard, N. Janus, J. Gligorov, P. Beuzeboc, I. Ray, J. Morere, J. Spano, X. Pourrat, G. Deray, V. Launay- Vacher
Journal: Journal of Clinical Oncology (2009)

e20574 Background: In 2007, the IRMA-1 study reported the high prevalence of renal insufficiency (RI) in cancer patients. Because of this high frequency, the IRMA-2 study started to investigate the evolution of renal function in cancer patients. Methods: Data were collected for cancer patients presenting at one of the 19 IRMA-2 centers in March 2005. Data included: sex, age, weight, serum creatinine (SCR), haemoglobinemia, type of tumour, metastasis (bone and/or visceral) anticancer drugs. Dialysis, myeloma and lymphoma patients were not included. Glomerular filtration rate was estimated with the abbreviated RD (aRD) formula at the inclusion. Patients were retrospectively followed during 2 years after the inclusion, every 6 months, from March 2005 (T0) to March 2007 (T24). Results: 4945 cancer patients (breast 1816, colorectal 747, lung 463, ovarian 294, prostate 251) were included in 19 cancer centre in France. Median age 60.0, mean weight 66.2, 62.8% were women. Mean GFR decreased from 90.8 ml/min/1.73m 2 to 83.7 over the two years (table). Meanwhile, the prevalence of RI increased, reaching 62.9% and 17.5% for a GFR&lt;90 and &lt;60, respectively at T24 (table). Among the 4945 patients, 193 (7.6% of the 2525 patients who were alive at the end of the study) had a SCR determination at each time point. Among the 641 patients with a SCR at T0 and at T24, 41.6% of those with a GFR&gt;=90 at T0 had a GFR&lt;90 at T24. Furthermore, 17.7% of patients with mild renal insufficiency (60 to 90) at T0 had a GFR&lt;60 at T24. Conclusions: IRMA-2 shows that renal function decreases rapidly in cancer patients with a loss in GFR of more than 3.5 mL/min/1.73m 2 per year. This suggests that cancer patients are more exposed to a deterioration of renal function and that it should be closely monitored with at least a regular estimation of renal function, for instance every 6 months. So far, such a follow-up is not performed in clinical practice. Furthermore, drug therapy should be reevaluated, dosages adjusted when necessary, and some potentially nephrotoxic drugs changed for less or non-nephrotoxic drugs if possible. No significant financial relationships to disclose.
MBT-0206 enhances the anti-tumor treatment in a highly metastatic human pancreatic cancer mouse model
Authors: Armine Papyan, Alexander Werner, Ivan Ischenko, Maksim Yezhelyev, Michael Teifel, Uwe Michaelis, Christiane J. Bruns
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

4104 

Treatment of pancreatic cancer is still an unsolved problem because of the limited efficacy of systemic chemotherapy. MBT-0206 is a new anti-cancer agent which targets the neovascular endothelial cells of the tumor vasculature1,2. It is composed of paclitaxel bound to a cationic lipid complex, which has been shown to preferentially accumulate in endothelial cells of pancreatic tumor vessels in transgenic RIP-Tag2 mice3. In the current study we investigated the anti-cancer potential of a combination therapy of MBT-0206 with the standard chemotherapeutic drug gemcitabine against highly metastatic human pancreatic cancer (L3.6pl) growing orthotopically in nude mice. In order to evaluate the biodistribution of MBT-0206, fluorescently labeled cationic lipid complexes (LipoRed™) were injected systemically. For therapeutic studies, animals bearing a L3.6pl tumor were treated for 19 days either by i.v. injected MBT-0206 (5 mg paclitaxel/kg) three times a week, by i.p. injected gemcitabine (100 mg/kg) two times a week or by a combination of both treatments. The biodistribution of fluorescently labeled cationic lipid complexes (LipoRed™) revealed a highly selective accumulation in the tumor vessels compared to surrounding normal pancreas. Administration of the paclitaxel encapsulating MBT-0206 resulted in a strong growth inhibition of primary pancreatic tumors with a tumor size of 46% of the control size at the end of the treatment, which was similar to the efficacy of gemcitabine (47%). Combination therapy led to a strong enhancement of the anti-tumor activity, resulting in a tumor size of only 21% of untreated control tumors. In addition, MBT-0206 alone markedly inhibited the formation of liver metastases and reduced both liver and lymph node metastases when combined with gemcitabine. Interestingly, a dose reduction of gemcitabine by 50% (50 mg/kg) resulted in a comparable therapeutic efficacy and better tolerability of the combination therapy. In summary, these data demonstrate a strong anti-tumor activity of the anti-neovascular targeting agent MBT-0206. Furthermore, the efficacy of MBT-0206 is enhanced when used in combination with gemcitabine. Our results suggest that MBT-0206 as an anti-neovascular agent is a promising candidate for the treatment of pancreatic cancer. 1Kunstfeld R. et al., J Invest Dermatol 120: 476-482, 2003 2Schmitt-Sody M. et al., Clin Cancer Res 9: 2335-2341, 2003 3Thurston et al., J Clin Invest 101:1401-13, 1998
Replacement Dosage of L-Thyroxine in Hypothyroidism
Authors: Jerrold M. Stock, Martin I. Surks, Jack H. Oppenheimer
Journal: New England Journal of Medicine (1974)

The replacement dose of L-thyroxine was determined in 44 patients with hypothyroidism, 35 with primary thyroidal insufficiency and nine with pituitary failure. In patients with primary hypothyroidism the adequacy of replacement was confirmed by thyrotropin radioimmunoassay values within the normal range. The average daily replacement dose of thyroxine was 169 jug per day (2.25 μg per kilogram), and 89 per cent of the patients were maintained with doses between 100 and 200 μg per day. This amount is significantly less than recommended in current textbooks. The replacement dose correlated with body weight. The average serum thyroxine concentration in treated patients, 8.1 μg per 100 ml, was only slightly higher than that in 55 controls, 7.1 μg. Over 96 per cent of patients receiving replacement had thyroxine concentrations in the generally accepted normal range. The average serum concentration of tri-iodothyronine in treated patients was 130 ng per 100 ml — slightly less than that in control subjects, 140 ng. These data support previous estimates that the bulk of circulating tri-iodothyronine in euthyroid subjects with unstimulated glands is derived from the peripheral conversion of thyroxine. (N Engl J Med 290:529–533, 1974)
Anaphylactic Reaction Following Injection of Heparin
Authors: Amoz I. Chernoff
Journal: New England Journal of Medicine (1950)

THE occurrence of reactions following the use of anticoagulants in the management of patients with myocardial infarction, pulmonary infarction and thrombophlebitis and after vascular surgery has served to emphasize the potential danger of these drugs. In general, the reactions either have been local (pain, abscess formation, hematoma, necrosis) or have resulted from overdosage, with bleeding into various parts of the body. Little has been written concerning allergic reactions to anticoagulants, particularly to heparin. Thus, Murray1 reported on the use of heparin in 440 patients without the occurrence of anaphylaxis. Crafoord and Jorpes2 analyzed the results of some 30,000 doses of . . .
ATPS-50REVISITING CARBOPLATIN AS A THERAPY FOR GLIOBLASTOMA (GBM)
Authors: Jenny Liao, Lori Maxwell, Michael Blough, Gregory Cairncross
Journal: Neuro-Oncology (2015)

INTRODUCTION: The DNA alkylating agent, temozolomide (TMZ), given during and after radiotherapy (RT) improves the survival of patients with glioblastoma (GBM). TMZ is unequivocally helpful for patients with GBMs in which the DNA repair protein, O6-methylguanine-DNA methyltransferase (MGMT), has been silenced by methylation of the MGMT gene promoter (i.e., 40%). For the remainder, whose GBMs express MGMT, and are therefore more resistant to TMZ, the addition of TMZ to RT adds little benefit. Moreover, many who benefit initially acquire resistance to TMZ through treatment-induced mutations. The need for other therapies for GBM motivated us to re-examine carboplatin, a DNA crosslinking agent whose development for use against GBM was curtailed by the emergence of TMZ. Carboplatin is well tolerated and crosses the blood brain barrier, making it an agent of interest. METHODS: Ten brain tumor initiating cell (BTIC) lines derived from newly diagnosed or previously treated GBMs were assessed for sensitivity to carboplatin (5 or 10 ug/mL for 8 days) or TMZ (10 ug/mL for 8 days); viability was measured using the AlamarBlue assay. RESULTS: All BTICs were sensitive to carboplatin; lines derived from untreated methylated GBMs were equally sensitive to carboplatin and TMZ. Sensitivity to TMZ was only observed in BTICs that were MGMT methylated and derived from untreated patients. BTICs with an unmethylated MGMT promoter that were derived from newly diagnosed patients were resistant to TMZ, as where those from previously treated patients. CONCLUSIONS: TMZ resistance, is a major obstacle to the successful treatment of GBM; hence, the need for alternatives to TMZ. This study demonstrates that carboplatin is active against BTICs, and may be useful in situations where resistance to TMZ is seen. Although in vivo work is required to bolster the relevance of this finding, our observations suggest that carboplatin may be warrant further study for GBM.