Safety of antiemetic prophylaxis with HTX-019 as a 30-min infusion in patients with cancer: a retrospective study.

The NK-1 receptor antagonist HTX-019 (CINVANTI [aprepitant injectable emulsion]) was approved for preventing chemotherapy-induced nausea and vomiting based on bioequivalence studies in healthy volunteers. The objective of this study was to evaluate HTX-019 safety in cancer patients. This retrospective analysis evaluated the safety of HTX-019 130 mg 30-min intravenous infusion, as part of a three-drug antiemetic regimen.

Does site-of-care for oncology infusion therapy influence treatment patterns, cost, and quality in the United States?

Background: The increase in hospital acquisition of community oncology clinics in the US has led to a shift in the site-of-care (SOC) for infusion therapy from the physician office (PO) to the hospital outpatient (HO) setting.

Objective: To investigate differences by SOC in treatment patterns, quality, and cost among patients with cancer undergoing first-line infusion therapy.

Research Design And Methods: This retrospective analysis identified adult patients from Humana medical claims who initiated infusion therapy from 2008-2012 for five common cancer types in which infusion therapy is likely, including early stage breast cancer; metastatic breast, lung, and colorectal cancers; and non-Hodgkin's lymphoma or chronic lymphocytic leukemia.

A Phase I Study of the Hsp90 Inhibitor AUY922 plus Capecitabine for the Treatment of Patients with Advanced Solid Tumors.

Background: This phase I study determined the maximum tolerated dose (MTD) of AUY922 with capecitabine in advanced solid tumors.

Methods: Capecitabine 1000 mg/m(2) PO BID was administered with escalating doses of AUY922 IV; the MTD of AUY922 was combined with capecitabine 1250 mg/m(2) (DL6).

Results: 23 patients were treated at 5 dose levels (22 mg/m(2)-70 mg/m(2)).

-Stratified Computerized Adaptive Testing in the Presence of Calibration Error.

-Stratified computerized adaptive testing with -blocking (AST), as an alternative to the widely used maximum Fisher information (MFI) item selection method, can effectively balance item pool usage while providing accurate latent trait estimates in computerized adaptive testing (CAT). However, previous comparisons of these methods have treated item parameter estimates as if they are the true population parameter values. Consequently, capitalization on chance may occur.

Steroid receptor RNA activator (SRA) modification by the human pseudouridine synthase 1 (hPus1p): RNA binding, activity, and atomic model.

The most abundant of the modified nucleosides, and once considered as the "fifth" nucleotide in RNA, is pseudouridine, which results from the action of pseudouridine synthases. Recently, the mammalian pseudouridine synthase 1 (hPus1p) has been reported to modulate class I and class II nuclear receptor responses through its ability to modify the Steroid receptor RNA Activator (SRA). These findings highlight a new level of regulation in nuclear receptor (NR)-mediated transcriptional responses.

A small RNA derived from RNA coactivator SRA blocks steroid receptor signaling via inhibition of Pus1p-mediated pseudouridylation of SRA: evidence of a novel RNA binding domain in the N-terminus of steroid receptors.

Estrogen receptors (ERs) and androgen receptors (ARs) are important targets for cancer therapy; however, the efficacy of receptor antagonists is limited, and alternative strategies are needed. Steroid receptor RNA Activator (SRA) is a long, noncoding RNA coactivator (although some protein-encoding 5' splice variants have also been reported) that requires pseudouridylation by Pus1p to stimulate steroid receptor signaling. A uridine at position 206 (U206), which is located in small hairpin structure STR5 in the conserved SRA core sequence, is a critical target for pseudouridylation.

Pseudouridine synthase 1: a site-specific synthase without strict sequence recognition requirements.

Pseudouridine synthase 1 (Pus1p) is an unusual site-specific modification enzyme in that it can modify a number of positions in tRNAs and can recognize several other types of RNA. No consensus recognition sequence or structure has been identified for Pus1p. Human Pus1p was used to determine which structural or sequence elements of human tRNA(Ser) are necessary for pseudouridine (Ψ) formation at position 28 in the anticodon stem-loop (ASL).

A phase II trial of vinflunine as monotherapy or in combination with trastuzumab as first-line treatment of metastatic breast cancer.

We investigated the microtubulin inhibitor vinflunine—with trastuzumab in human epidermal growth factor receptor-2 (HER2)-positive patients—as first-line metastatic breast cancer therapy. HER2-negative patients received vinflunine on day 1; HER2-positive patients received vinflunine/trastuzumab every 21 days. Forty-eight patients in each treatment group were planned; the sponsor terminated the study early.

Phase II study of biweekly pemetrexed and gemcitabine in patients with previously untreated advanced non-small cell lung cancer.

Introduction: Pemetrexed and gemcitabine are safe and active non-small cell lung cancer (NSCLC) therapies when administered every 3 weeks. Biweekly scheduling was studied in this phase II trial.

Methods: The primary objective was to assess the overall response rate in chemotherapy-naive patients with unresectable stage III/IV NSCLC.

Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab.

PURPOSE Tracheoesophageal fistulae are rare complications of thoracic cancers and their treatments. Novel antiangiogenic agents in cancer treatment such as bevacizumab potentially impact wound healing and may contribute to tracheoesophageal fistula development. PATIENTS AND METHODS We conducted two independent phase II clinical trials in small-cell lung cancer and non-small-cell lung cancer using bevacizumab in combination with chemotherapy and radiation.

Partial activity is seen with many substitutions of highly conserved active site residues in human Pseudouridine synthase 1.

Pseudouridine synthase 1 (Pus1p) is an enzyme that converts uridine to Pseudouridine (Psi) in tRNA and other RNAs in eukaryotes. The active site of Pus1p is composed of stretches of amino acids that are highly conserved and it is hypothesized that mutation of select residues would impair the enzyme's ability to catalyze the formation of Psi. However, most mutagenesis studies have been confined to substitution of the catalytic aspartate, which invariably results in an inactive enzyme in all Psi synthases tested.

Pus3p- and Pus1p-dependent pseudouridylation of steroid receptor RNA activator controls a functional switch that regulates nuclear receptor signaling.

It was previously shown that mouse Pus1p (mPus1p), a pseudouridine synthase (PUS) known to modify certain transfer RNAs (tRNAs), can also bind with nuclear receptors (NRs) and function as a coactivator through pseudouridylation and likely activation of an RNA coactivator called steroid receptor RNA activator (SRA). Use of cell extract devoid of human Pus1p activity derived from patients with mitochondrial myopathy and sideroblastic anemia, however, still showed SRA-modifying activity suggesting that other PUS(s) can also target this coactivator. Here, we show that related mPus3p, which has a different tRNA specificity than mPus1p, also serves as a NR coactivator.

A previously unidentified activity of yeast and mouse RNA:pseudouridine synthases 1 (Pus1p) on tRNAs.

Mouse pseudouridine synthase 1 (mPus1p) was the first vertebrate RNA:pseudouridine synthase that was cloned and characterized biochemically. The mPus1p was previously found to catalyze Psi formation at positions 27, 28, 34, and 36 in in vitro produced yeast and human tRNAs. On the other hand, the homologous Saccharomyces cerevisiae scPus1p protein was shown to modify seven uridine residues in tRNAs (26, 27, 28, 34, 36, 65, and 67) and U44 in U2 snRNA.

A retrospective cohort study to assess the impact of therapeutic substitution of darbepoetin alfa for epoetin alfa in anemic patients with myelodysplastic syndrome.

Darbepoetin alfa and epoetin alfa are used to treat anemia in the undertreated population of patients with myelodysplastic syndrome (MDS). We implemented guidelines to switch anemic patients with MDS from epoetin alfa 40,000 U weekly to darbepoetin alfa 200 microg every 2 weeks and then conducted a retrospective cohort study of the initial 263 treated patients. Patients (> or = 18 years old, MDS diagnosis) were either previously treated with epoetin alfa (received 16 weeks of prior epoetin alfa and either switched to darbepoetin alfa or remained on epoetin alfa) or treatment-naive (no previous erythropoietin therapy and received only 1 agent for 16 weeks).

Pseudouridine modification in Caenorhabditis elegans spliceosomal snRNAs: unique modifications are found in regions involved in snRNA-snRNA interactions.

Background: Pseudouridine (Psi) is an abundant modified nucleoside in RNA and a number of studies have shown that the presence of Psi affects RNA structure and function. The positions of Psi in spliceosomal small nuclear RNAs (snRNAs) have been determined for a number of species but not for the snRNAs from Caenorhabditis elegans (C. elegans), a popular experimental model system of development.

Mitochondrial myopathy and sideroblastic anemia (MLASA): missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation.

A missense mutation in the PUS1 gene affecting a highly conserved amino acid has been associated with mitochondrial myopathy and sideroblastic anemia (MLASA), a rare autosomal recessive oxidative phosphorylation disorder. The PUS1 gene encodes the enzyme pseudouridine synthase 1 (Pus1p) that is known to pseudouridylate tRNAs in other species. Total RNA was isolated from lymphoblastoid cell lines established from patients, parents, unaffected siblings, and unrelated controls, and the tRNAs were assayed for the presence of pseudouridine (Psi) at the expected positions.

Regulation of nuclear receptor activity by a pseudouridine synthase through posttranscriptional modification of steroid receptor RNA activator.

Nuclear receptors (NRs) induce transcription through association with coactivator complexes. We identified a pseudouridine synthase (PUS), mPus1p, as a coactivator for retinoic acid receptor (mRAR)gamma and other NR-dependent transactivation. mPus1p is a member of the truA subfamily of PUSs, a class of enzymes that isomerize uridine to pseudouridine in noncoding RNAs, such as tRNA, to ensure proper folding and function.

Effectiveness of darbepoetin alfa versus epoetin alfa in patients with chemotherapy-induced anemia treated in clinical practice.

Primary Purpose: The objective of this retrospective observational cohort study was to compare the effectiveness of darbepoetin alfa with that of epoetin alfa in patients with chemotherapy-induced anemia using data from noncontemporaneous chart audits conducted at a community-based oncology practice.

Materials And Methods: For the first chart audit, data were collected from consecutive patients with nonmyeloid malignancies with diagnoses of chemotherapy-induced anemia and hemoglobin levels < or = 10.5 g/dl who were receiving concurrent chemotherapy and had at least 5 weeks of visits from July-September 2000.

Epoetin alfa 60,000 U once weekly followed by 120,000 U every 3 weeks increases and maintains hemoglobin levels in anemic cancer patients undergoing chemotherapy.

Purpose: Epoetin alfa administered s.c. three times weekly or once weekly increases hemoglobin (Hb) levels, decreases transfusion requirements, and improves quality of life in anemic cancer patients receiving chemotherapy.

Caenorhabditis elegans pseudouridine synthase 1 activity in vivo: tRNA is a substrate, but not U2 small nuclear RNA.

The formation of pseudouridine (Psi) from uridine is post-transcriptional and catalysed by pseudouridine synthases, several of which have been characterized from eukaryotes. Pseudouridine synthase 1 (Pus1p) has been well characterized from yeast and mice. In yeast, Pus1p has been shown to have dual substrate specificity, modifying uridines in tRNAs and at position 44 in U2 small nuclear RNA (U2 snRNA).

A phase I trial of weekly paclitaxel plus prolonged oral eniluracil/5-fluorouracil in patients with refractory malignancies.

Purpose: This phase I study was conducted to determine the dose-limiting toxicity (DLT), maximum-tolerated doses, and recommended phase II doses of the combination of weekly intravenous paclitaxel and oral eniluracil/5-fluorouracil (5-FU).

Patients And Methods: Patients received paclitaxel i.v.