Data Sharing, Clinical Trials, and Biomarkers in Precision Oncology: Challenges, Opportunities, and Programs at the Department of Veterans Affairs.

Cancer genomic research reveals that a similar cancer clinical phenotype (e.g., non-small cell lung cancer) can arise from various mutations in tumor DNA. Thus, organ of origin is not a definitive classification. Further, targeted therapy for cancer patients (precision oncology) capitalizes on knowledge of individual patient mutational status to deliver treatment directed against the protein products of these mutations with the goal of reducing toxicity and enhancing efficacy relative to traditional nontargeted chemotherapy.

Anaphylactoid reactions to vitamin K.

Anaphylactoid reactions in patients receiving intravenously administered vitamin K have been reported in the literature. To summarize the known data on anaphylactoid reactions from administration of vitamin K, we reviewed all published and unpublished reports of this adverse reaction. Published reports were obtained through medline (1966--1999) and EMBASE (1971--1999) searches of the English language literature and review of references from identified case reports. Unpublished reports were obtained using the Spontaneous Reporting System Adverse Reaction database of the United States Food and Drug Administration (FDA) between August 1968 and September 1997. All adverse drug reactions to vitamin K were categorized by route of drug administration, dose and standard adverse reaction code. In the FDA reports, we defined anaphylactoid reactions as any adverse drug reaction coded as either anaphylaxis, allergic reaction, apnea, dyspnea, death, heart arrest, hypotension, shock or vasodilatation. Additionally, all fatal and life-threatening FDA reported reactions were reviewed to determine if they could represent an anaphylactoid reaction missed by the above definition. The literature review uncovered a total of 23 cases (3 fatal) of anaphylactoid reactions from intravenous vitamin K. The FDA database contained a total of 2236 adverse drug reactions reported in 1019 patients receiving vitamin K by all routes of administration. Of the 192 patients with reactions reported for intravenous vitamin K, 132 patients (69 %) had a reaction defined as anaphylactoid, with 24 fatalities (18 %) attributed to the vitamin K reaction. There were 21 patients with anaphylactoid reactions and 4 fatalities reported with doses of intravenous vitamin K of less than 5 mgs. For the 217 patients with reactions reported due to vitamin K via a non-intravenous route of administration, 38 patients had reactions meeting the definition of anaphylactoid (18 %), with 1 fatality (3 %) attributed to the drug. The absolute risk of an anaphylactoid reaction to intravenous vitamin K cannot be determined by this study, but the relatively small number of documented cases despite widespread use of this drug suggest that the reaction is rare. Anaphylactic reactions and case fatality reports were found even when intravenous vitamin K was given at low doses by slow dilute infusion. The pathogenesis of this reaction is unknown and may be multifactorial with etiologies including vasodilation induced by the solubilizing vehicle or immune-mediated processes. We conclude that use of intravenous vitamin K should be limited to patients with serious hemorrhage due to a coagulopathy that is secondary to a relative or absolute deficiency of vitamin K.

Hiccups with high dose dexamethasone administration: a case report.

BACKGROUND: A 59-year-old male developed intractable hiccups during monthly therapy with high dose dexamethasone for multiple myeloma. Hiccups would begin hours after his first dose and continue over the 4 days of therapy. He sought assistance after his attempt at home remedies failed and the hiccups became exhausting. METHODS: The strong temporal relation between dexamethasone administration and the occurrence of hiccups indicated that dexamethasone was the cause of the patient's hiccups. Because he was responding to dexamethasone, the decision was made to continue therapy and to relieve his hiccups with metoclopramide. RESULTS: Low dose oral metoclopramide allowed the patient to continue therapy without a recurrence of the hiccups. CONCLUSIONS: Dexamethasone administration can result in intractable hiccups that persist for the duration of therapy. Low dose oral metoclopramide may prevent hiccups in patients in whom the discontinuation of dexamethasone therapy is not appropriate.

Acute renal failure after administration of intravenous immunoglobulin: review of the literature and case report.

Within in last 7 years the literature has published several reports of acute renal failure after the administration of intravenous immunoglobulin. Review of these cases finds that all occurrences in the United States except one involved a sucrose-containing immunoglobulin preparation, leading to the suspicion that sucrose may be the cause of the renal failure. Further investigation found that approximately 50 years ago, when sucrose was used as an osmotic diuretic, investigators reported acute renal failure in humans after intravenous infusions of 50 g or more. A patient at our institution developed acute renal failure similar to that described in published case reports after being administered a sucrose-containing immunoglobulin.

Efficacy and safety of combined anticoagulant and antiplatelet therapy versus anticoagulant monotherapy after mechanical heart-valve replacement: a metaanalysis.

We performed a metaanalysis of five randomized controlled trials to compare the efficacy and safety of combined oral anticoagulant and antiplatelet therapy versus oral anticoagulants alone after prosthetic heart-valve replacement. The combined regimen reduced embolism and overall mortality by approximately 67% (pooled odds ratio [OR] 0.33; 95% confidence interval [CI] 0.16 to 0.69; p = 0.0032) and 40% (OR 0.60; 95% CI 0.32 to 1.12; p = 0.11), respectively, but increased the risk of hemorrhage by approximately 65% (OR 1.65; 95% CI 1.15 to 2.39; p = 0.0069) and of major gastrointestinal hemorrhage by approximately 250% (OR 3.47; 95% CI 1.43 to 8.40; p = 0.0058). It is estimated that for every 1.6 patients who had their stroke prevented by combination therapy, there was an excess of one major gastrointestinal bleed. This metaanalysis suggests that the benefits derived from the enhanced antithrombotic potential of combined therapy outweigh the toxic effects resulting from the enhanced anticoagulant potential of this regimen.

Comparison of a standard and a sensitive thromboplastin in monitoring low intensity oral anticoagulant therapy.

The greater precision in prothrombin time monitoring obtained using thromboplastins with low international sensitivity index (ISI) values are believed to result in improved patient care. The authors conducted a blinded prospective study of 84 random patients on low-intensity warfarin therapy who were monitored with either a sensitive (ISI, 1.3) or standard (ISI, 1.9) thromboplastin. For the patients monitored with standard and sensitive thromboplastins, respectively, no difference was found in the degree of anticoagulation (standard thromboplastin mean INR, 2.4 vs. 2.5, P = .37; sensitive thromboplastin mean INR, 2.6 vs. 2.6, P = .74; mean daily warfarin dose, 5.1 vs. 4.7 mg, P = .28) or efficacy (warfarin dosage adjustments, 117 vs. 116; clinic visits, 362 vs. 378; percentage of therapeutic INR determinations, 47% vs. 48%). In addition, no difference was found in bleeding prevalence or severity (.22 vs. .27 events per person-year observation). The authors concluded that monitoring anticoagulant therapy in the INR range of 2-3 with a standard thromboplastin may be comparable to monitoring with a more sensitive thromboplastin with respect to efficacy, safety, and degree of anticoagulation achieved.

A clinical study monitoring low-intensity anticoagulant therapy with a standard-sensitivity thromboplastin.

The ability of the prothrombin time to measure the anticoagulant effect of warfarin sodium varies depending on the particular tissue thromboplastin used in performing the test. Based on studies using sensitive thromboplastins, lower therapeutic ranges of anticoagulation are recommended. The adequacy of monitoring therapy in this lower range with the relatively insensitive thromboplastins commonly used in North America is unestablished. This 16-month prospective study used a standard North American thromboplastin to monitor 157 anticoagulated patients treated in a low therapeutic range. Of the 1734 prothrombin times generated, 876 (56%) were therapeutic, with 400 (23%) below and 458 (26%) above the therapeutic range. These results are comparable with those published in trials in which more sensitive thromboplastins were used in a similar therapeutic range. We conclude that standard North American thromboplastins are adequately suited to monitor therapy in this lower range.

The bleeding time response to aspirin. Identifying the hyperresponder.

The authors measured the template bleeding time in 11 normal people before and 2, 4, 12, 24, and 48 hours after the subjects ingested a single dose of 74 mg of aspirin (ASA). The entire experiment was repeated twice at two-week intervals, with the dose of ASA increased to 325 mg and finally 3,900 mg. The mean increase was maximal at 4 and 12 hours, regardless of the dose administered, with a return to baseline by 48 hours. The authors then performed bleeding times in a prospective randomized double-blinded fashion on an additional 39 subjects at baseline and seven hours after they ingested either placebo or ASA 325 mg. The mean baseline bleeding time was 5.2 minutes (SD +/- 1.4), with a mean prolongation after ASA of 2.1 minutes (SD +/- 1.9). The authors identified 5 of 37 (14%) subjects as hyper-responders (HRs) using the criterion of a bleeding time prolongation of greater than 5.9 minutes (greater than 2 SD beyond the mean prolongation). Neither baseline bleeding time, threshold sensitivity of collagen-induced platelet aggregation, nor other tests of hemostatic function discriminated HRs from normals. The authors conclude that in subjects with normal baseline bleeding times, a prolongation of greater than 5.9 minutes when measured seven hours after the administration of a single dose of 325 mg of ASA can discriminate HRs from normals.