tbuckley/cabot-search huggingface dataset:
Phase I trial of MLN2704 in patients with castrate-metastatic prostate cancer (CMPC)
Authors: M. D. Galsky, M. Eisenberger, S. Moore-Cooper, W. K. Kelly, S. Slovin, A. Morales, T. Curley, A. Delacruz, I. J. Webb, H. I. Scher
Journal: Journal of Clinical Oncology (2004)

4592 Background: MLN2704 is an immunoconjugate designed to deliver the maytansinoid anti-microtubule agent DM1 directly to prostate cancer cells through the prostate-specific membrane antigen (PSMA) targeted monoclonal antibody MLN591. Preclinical models have indicated significant activity in human prostate cancer xenografts. We report the results of the first phase I trial of MLN2704 in patients with CMPC. Methods: The study was designed to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and immunogenicity of a single ascending dose of MLN2704 administered intravenously over 2.5 hours. Based on emerging safety and PK data, repeat dosing at 4-week intervals was subsequently permitted. Patients with progressive CMPC and adequate organ function were eligible for enrollment. Results: 23 patients have received MLN2704 at doses ranging from 18 to 343 mg/m2 in this ongoing trial. 17 patients have received ≥ 3 doses. PK of antibody related analytes (J591-DM1, Total J591 and free J591) has been typical of monoclonal antibodies. Plasma levels of free DM1 have been detectable. No autoantibodies against MLN2704, MLN591 or DM1 have been detected. MLN2704 has been well-tolerated in the majority of patients. Transient elevations in hepatic transaminases, infusion-related fever/chills, nausea, and fatigue have been observed. Only one DLT, an uncomplicated febrile neutropenia, has been reported at the highest dose level (343 mg/m2). This patient also demonstrated a sustained > 50% PSA decline and remains on study at a reduced dose. One patient treated at the 264 mg/m2 dose level has experienced a PR by RECIST, improvement in intradermal metastatic lesions, and a durable 70% decline in PSA. This patient has received 7 doses and remains on study at 24 weeks. Conclusions: Anti-tumor activity has been observed at well tolerated doses of MLN2704. MTD is 343 mg/m2 or higher. Support: T32 CA-09207 Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Pharmaceuticals Bristol-Myers; Cell Therapeutics; Millennium Pharmaceuticals Cell Therapeutics; Millennium Pharmaceuticals AstraZeneca Speakers Bureau Millennium Pharmaceuticals ProQuest Investments ProQuest Investments
Radioimmunoassay of Alpha-Fetoprotein in Primary and Secondary Cancer of the Liver&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: E Ruoslahti, M Seppälä, P Vuopio, E Saksela, P Peltokallio
Journal: JNCI Journal of the National Cancer Institute (1972)

The serum alpha-fetoprotein (AFP) concentration was determined by radioimmunoassay in 14 primary liver cancers and 17 secondary liver cancers. With this method, unlike any previous one, AFP could be quantitated in a II the samples. The AFP levels in 10 of the 14 patients (71%) were one thousand times or more (3.5–840 µg/ml) above the normal serum level. Two sera had intermediate values (100 and 200 ng/ml) and 2 had normal AFP concentrations (9 and 16 ng/ml). A normal AFP level thus does not exclude the possibility of primary liver cancer. No correlation was found between the AFP level and the degree of malignancy of the tumor. Of the 17 patients with secondary liver cancer, 3 had an AFP concentration above the normal range. In these, the elevation was moderate, ranging from 60–400 ng/ml.
Differential requirement for de novo lipogenesis in cholangiocarcinoma and hepatocellular carcinoma of mice and humans
Authors: Lei Li, Li Che, Kevin M. Tharp, Hyo‐Min Park, Maria G. Pilo, Dan Cao, Antonio Cigliano, Gavinella Latte, Zhong Xu, Silvia Ribback, Frank Dombrowski, Matthias Evert, Gregory J. Gores, Andreas Stahl, Diego F. Calvisi, Xin Chen
Journal: Hepatology (2016)

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most prevalent types of primary liver cancer. These malignancies have limited treatment options, resulting in poor patient outcomes. Metabolism reprogramming, including increased de novo lipogenesis, is one of the hallmarks of cancer. Fatty acid synthase (FASN) catalyzes the de novo synthesis of long‐chain fatty acids from acetyl‐coenzyme A and malonyl‐coenzyme A. Increased FASN expression has been reported in multiple tumor types, and inhibition of FASN expression has been shown to have tumor‐suppressing activity. Intriguingly, we found that while FASN is up‐regulated in human HCC samples, its expression is frequently low in human ICC specimens. Similar results were observed in mouse ICC models induced by different oncogenes. Ablating FASN in the mouse liver did not affect activated AKT and Notch (AKT/Notch intracellular domain 1) induced ICC formation in vivo. Furthermore, while both HCC and ICC lesions develop in mice following hydrodynamic injection of AKT and neuroblastoma Ras viral oncogene homolog oncogenes (AKT/Ras), deletion of FASN in AKT/Ras mice triggered the development almost exclusively of ICCs. In the absence of FASN, ICC cells might receive lipids for membrane synthesis through exogenous fatty acid uptake. In accordance with the latter hypothesis, ICC cells displayed high expression of fatty acid uptake‐related proteins and robust long‐chain fatty acid uptake. Conclusion: Our data demonstrate that FASN dependence is not a universal feature of liver tumors: while HCC development is highly dependent of FASN and its mediated lipogenesis, ICC tumorigenesis can be insensitive to FASN deprivation; our study supports novel therapeutic approaches to treat this pernicious tumor type with the inhibition of exogenous fatty acid uptake . (H epatology 2016;63:1900‐1913)
Outbreak of anthrax in adults and adolescents: a review of nine cases in a regional teaching hospital in East Hungary
Authors: Z. Orlos, E. Rakoczi, O. Misak, B. Lenart, G. Ocsai, I. Kovacs, S. Gorzsas, L. Kardos, Z. Lampe, Z. Szilvassy, I. Varkonyi
Journal: Clinical Microbiology and Infection (2016)
<i>EGFR</i> mutations in men and cigarette smokers with lung adenocarcinoma.
Authors: M. Pietanza, S. P. D'Angelo, M. L. Johnson, P. K. Paik, G. J. Riely, V. A. Miller, M. F. Zakowski, V. W. Rusch, M. Ladanyi, M. G. Kris
Journal: Journal of Clinical Oncology (2010)

10538 Background: EGFR mutations underlie the sensitivity of lung cancers to erlotinib and gefitinib and are more commonly found in never smokers and women. Previously, we reported the presence of EGFR mutations in 51% of patients with lung adenocarcinoma who were never smokers (Pham, et al. JCO 2006), with a similar incidence of mutations in men (23%) and women (27%). Here we have examined the frequency of EGFR mutations in former smokers, current smokers, and men. Methods: With IRB approval, we reviewed the medical records of all patients with lung adenocarcinoma and EGFR mutation testing results. We determined the frequency of EGFR mutations and characterized their association with clinical variables, including cigarette smoking status (former, current, never) and gender. Results: EGFR mutation status was determined in 2080 lung adenocarcinomas. Although the frequency of EGFR mutations was significantly higher in never smokers, EGFR mutations in former and current smokers represented 39% of all mutations detected (168/432, 95% CI, 34-44%). EGFR mutations were found in 13% of tumors from former smokers (149/1188, 95% CI, 11-15%), 5% of tumors from current smokers (19/352, 95% CI, 3-8%), and 49% of tumors from never smokers (264/540, 95% CI, 45-53%). EGFR mutations were found in 17% (141/826, 95% CI, 15-20%) of tumors from men and 23% of tumors from women (291/1254, 95% CI, 21-26%), with mutations in men representing 33% (141/432, 95% CI, 28-37%) of all those detected. Conclusions: EGFR mutations occur frequently in patients with a history of cigarette smoking and in men. Testing for activating EGFR mutations (especially exon 19 deletions and exon 21 L858R substitution) should be considered for all patients with adenocarcinoma of the lung at diagnosis, regardless of other clinical characteristics. This strategy can extend the use of tyrosine kinase inhibitors to all individuals with a high likelihood of benefit. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Boehringer Ingelheim, Genentech, Roche
Influence of glutathione S-transferase A1 genotype on intravenous busulfan pharmacokinetics
Authors: C. M. Walko, N. Patel, J. Revollo, J. Whitley, J. Serody, D. Gabriel, T. Comeau, H. McLeod, T. C. Shea
Journal: Journal of Clinical Oncology (2008)

14635 Background: The alkylating agent busulfan (Bu) is commonly used in allogeneic stem cell transplantation conditioning regimens in combination with immunosuppressive drugs such as cyclophosphamide and fludarabine. Toxicity and efficacy have been correlated with Bu levels and underscore the importance of further understanding the reasons behind Bu pharmacokinetic (PK) variability. Metabolism of Bu involves conjugation to glutathione primarily via the A1 isoform of glutathione S-transferase (GSTA1). Polymorphisms in GSTA1 have been correlated with the clearance of oral Bu in a small study of 12 Japanese patients. In this study we investigated the relationship between intravenous Bu clearance and GSTA1 in a primarily Caucasian population. Methods: All patients were enrolled in one of two prospective PK-based studies at the University of North Carolina. All patients received Bu 0.8 mg/kg intravenously over 2 hours 12–15 days prior to stem cell transplantation as part of these PK studies. Blood samples for PK analysis were collected before the dose and at regular intervals up to 10 hours following the dose. In addition, a blood sample was also collected for DNA extraction at baseline. Bu levels were measured by HPLC analysis and DNA was extracted using QIAmp DNA Blood Mini Kit. Patients were genotyped for GSTA1 promoter SNP C-69T using pyrosequencing. A paired t-test was used to compare the clearances in each group. Results: Genotype data was available for 37 patients. The GSTA1 C/C genotype was present in 8 patients, C/T in 25 patients, and T/T in 4 patients. The geometric mean Bu clearance (mL/min) was 17200 (range 8547 to 33883) for patients with the C/C genotype, and 13629 (range 8733 to 22983) for patients with at least one T allele. A trend towards a lower clearance was seen with the patients with at least one T allele compared with the C/C patients (p = 0.064). Survival and toxicity at 100 days following transplant has not been reached for all patients and thus has yet not been analyzed. Conclusions: Patients with the GSTA1 genotype containing at least one T allele have a lower Bu clearance compared with the C/C genotype. This difference approached, but did not reach statistical significance perhaps as a result of the small number of C/C genotype patients available for study. No significant financial relationships to disclose.
&lt;italic&gt;N&lt;/italic&gt;-Nitrosophenacetin: Its Synthesis, Characterization, Mutagenicity, and Teratogenicity&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J K Lin, J Y Yen, H W Chang, S Y Lin-Shiau
Journal: JNCI Journal of the National Cancer Institute (1984)

Reaction of phenacetin (CAS: 62-44-2; p-acetophenetidide) with nitrous fumes (N2O3) in glacial acetic acid at 0-5 degrees C yields N-nitrosophenacetin (NP), 2-nitrophenacetin, N-nitroso-2-nitrophenacetin (NNP), and other compounds. Both NP and NNP are fairly stable at low temperature (-30 degrees C) but extremely labile at ambient temperature. NP (median lethal dose to Sprague-Dawley rat: 21 mg/kg body wt) is 80 times more toxic than its parent compound phenacetin and is directly mutagenic to bacterial cells including Salmonella typhimurium and Sarcina lutea. The mutagenicity of NP is comparable to that of N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS: 70-25-7; 1-methyl-3-nitro-1-nitrosoguanidine] and requires no microsomal metabolic activation. The teratogenic potential of NP was studied in White Leghorn chick embryos given a single dose of 5-15 micrograms/egg on day 6 of incubation. A low incidence of exencephaly and eyelid defect and a high incidence of feather and claw malformations were found in the treated group; no such malformed embryos were found in the control group. The teratogenicity of NP was found to be weaker than that of MNNG, but stronger than that of N-methyl-N-nitrosourea (CAS: 684-93-5), dimethylnitrosamine (CAS: 62-75-9; N-nitrosodimethylamine), and diethylnitrosamine (CAS: 15-18-5; N-nitrosodiethylamine).
Restoring Africa’s health systems after Ebola
Authors: Jane Feinmann
Journal: BMJ (2015)

Sierra Leone may have been declared Ebola-free, but the outbreak brought an already weak health system to its knees, writes <b>Jane Feinmann</b>. The charity Doctors of the World is well versed in bringing care to the most vulnerable people in both developing and developed countries, which is why we’ve chosen it for <i>The BMJ</i>’s Christmas appeal this year. Please give generously
Chemotherapy administration associated errors before and after use of electronic order entry and decision support
Authors: D. L. Kirlin, M. G. DeVoe, L. V. Brennan, D. R. Drosick, J. H. Essell, D. K. Hawley, R. M. Bowman, D. Heaton, M. N. Neuss, J. J. Guo
Journal: Journal of Clinical Oncology (2007)

19528 Chemotherapy Administration Associated Errors Before and After Use of Electronic Order Entry and Decision Support Background: Chemotherapy administration is an important part of oncology practice and as treatment plans have evolved, their complexity has increased. Our practice has developed a software program that incorporates decision support and safety checks. Here we report the errors we have noted before and after utilization of this system. Methods: Drug administration errors are tracked through a mandatory “incident report” process that requires staff to report whenever an error is recognized. All reports from 2003 (the year before utilization of the chemotherapy software) and 2006 were reviewed. We compared the number and type of errors from the two time periods. Results: • Statistically significant *increase or † decrease at alpha level 0.05. • 1 rate is expressed per 100,000 treatments • 2 “Other” errors are those which could not be classified otherwise and had no impact on the patient Conclusions: The frequency of recognized errors associated with chemotherapy administration is very low (0.03%) and while still unacceptable, much lower than the 5% reported for medication administration in general. (Kaushal, Arch Int Med 163:1409 2003) A computerized software support system did not make a statistically significant change in the total frequency of administration errors but did significantly decrease wrong drug errors even as the complexity of treatment protocols increased. A class of error “Planned Drug Missed” was recognized because of a formal declaration of treatment plan. There may be significant reporting bias consequent to increased recognition and subsequent reporting of errors when a computerized system and formal declaration of treatment plan is in place. However, no matter the system, the human/computer interface remains a potential source of error. [Table: see text] No significant financial relationships to disclose.
Pharmacokinetics (PK) of PF-02341066, a dual ALK/MET inhibitor after multiple oral doses to advanced cancer patients.
Authors: W. Tan, K. D. Wilner, Y. Bang, E. L. Kwak, R. G. Maki, D. R. Camidge, B. J. Solomon, S. I. Ou, R. Salgia, J. W. Clark
Journal: Journal of Clinical Oncology (2010)

2596 Background: PF-02341066 (PF) is a selective, ATP-competitive, small molecule orally bioavailable inhibitor of the ALK and MET/HGF receptor tyrosine kinases being developed for the treatment of cancer. Methods: Preliminary PK data were collected for the first 80 cancer patients enrolled in the ongoing study A8081001, an open-label, multi- center phase I dose-escalation, safety, pharmacokinetic, and exploratory study (J Clin Oncol 27:15s, 2009). PF was administered orally to patients under fasting conditions in continuous 28-day cycles. Doses ranged from 50-200 mg QD and 200-300 mg BID. Serial blood samples were collected on lead-in Day 7, Cycle 1 Day 1, Cycle 1 Day 15, and/or Cycle 2 Day 1; and predose samples were collected on Days 1 and/or 15 of Cycles 2-5. Plasma concentrations of PF were determined using a validated analytical method. Results: Peak concentrations were reached at approximately 4 hours (hrs), followed by a multi-exponential decline with an average terminal half-life of 43 to 51 hrs across doses. PF AUC increased with median accumulation ratios ranging 1.7-3.4 after QD dosing and 4.0-5.9 after BID dosing, respectively. Repeated administration at 250 mg BID (maximum recommended dose for phase 2/3) for ≥15 days produced a median trough plasma concentration of 256 ng/mL (45 nM, free drug), exceeding the target efficacious levels for ALK and MET predicted from preclinical models. Subjects receiving doses ranging from 100-200 mg QD and 200 mg to 300 mg BID generally demonstrated linear PK, as evidenced by proportional increases in mean AUC. PF exposure was similar between Asian (N=13) and non-Asian (N=20) patients at 250 mg BID. Co-administration with a standard high-fat meal appeared not to change the geometric mean of AUC and Cmax of PF following single 250-mg PF doses. A 3.6-fold (90% CI: 2.7-4.9) increase in the single-dose oral midazolam AUC was observed following 28 days of PF dosing at 250 mg BID, suggesting that PF is a moderate CYP3A4 inhibitor. Conclusions: PF AUC generally increased proportionally with doses over the therapeutic dose range studied. PF AUC accumulated by 4.0-5.9-fold after multiple doses with a terminal half-life of 43-51 hrs. A high-fat meal did not appear to change PF PK. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Peter MacCullum Cancer Center, Pfizer
Abstract 17060: Implantable Cardioverter Defibrillator Events and Mortality in Unexplained Cardiac Arrest Subjects in the Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER)
Authors: Petsy P So, Jeffrey S Healey, Vijay S Chauhan, David H Birnie, Jean Champagne, Shubhayan Sanatani, Kamran Ahmad, Emily Ballantyne, Brenda Gerull, Raymond Yee, Allan C Skanes, Lorne J Gula, Peter Leong-Sit, George J Klein, Michael H Gollob, Christopher S Simpson, Mario Talajic, Martin Gardner, Andrew D Krahn
Journal: Circulation (2013)

Background: Implantable cardioverter defibrillators (ICDs) have been shown to reduce mortality in survivors of life-threatening arrhythmias. It is important to understand the rate of ICD events and...
Impact of Febuxostat on Renal Function in Gout Patients With Moderate‐to‐Severe Renal Impairment
Authors: Kenneth G. Saag, Andrew Whelton, Michael A. Becker, Patricia MacDonald, Barbara Hunt, Lhanoo Gunawardhana
Journal: Arthritis & Rheumatology (2016)

Renal impairment is a risk factor for gout and a barrier to optimal gout management. We undertook this exploratory study to obtain data that have been heretofore limited regarding the safety and efficacy of febuxostat in patients with moderate-to-severe renal impairment (estimated glomerular filtration rate [GFR] 15-50 ml/minute/1.73 m(2) ).Ninety-six gout patients with moderate-to-severe renal impairment were enrolled in a 12-month multicenter, randomized, double-blind, placebo-controlled study. Patients were randomly assigned at a 1:1:1 ratio to receive 30 mg febuxostat twice daily, 40/80 mg febuxostat once daily, or placebo. The primary efficacy end point was the change in serum creatinine (Cr) level from baseline to month 12. Secondary end points included the change in estimated GFR from baseline to month 12 and the proportion of patients with a serum uric acid (UA) level of <6.0 mg/dl at month 12.At month 12, there were no significant differences in the change in serum Cr level from baseline, or in the change in estimated GFR from baseline, in either febuxostat group compared to the placebo group. The proportion of patients with a serum UA level of <6.0 mg/dl at month 12 was significantly greater in both febuxostat groups compared to the placebo group (both P < 0.001). At least 1 treatment-emergent adverse event (TEAE) occurred in 78.1% of patients receiving 30 mg febuxostat twice daily, 87.5% of patients receiving 40/80 mg febuxostat once daily, and 78.1% of patients receiving placebo. TEAEs most frequently involved the categories of renal failure and impairment and renal function analyses.Febuxostat proved to be efficacious in serum UA reduction and was well tolerated in gout patients with moderate-to-severe renal impairment. Patients randomly assigned to receive febuxostat demonstrated significantly lower serum UA levels and no significant deterioration in renal function.
NIAID Funds Research on Nonantibiotic Treatments of Infection
Authors: Julie A. Jacob
Journal: JAMA (2016)

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