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Concept: Antineoplastic

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BACKGROUND:: Oral antineoplastic drugs, not generally covered by Medicare Part B, have assumed an increasingly important role in cancer treatment. OBJECTIVE:: We examined use and spending on infused/injected (Part B covered) and non-Part B antineoplastic agents in a Medicare beneficiary population with cancer, and the effect of supplemental insurance. RESEARCH DESIGN:: This retrospective, observational study used pooled 1997-2007 data from the Medicare Current Beneficiary Survey, linked to Medicare claims. Logistic regression models identified factors associated with antineoplastic use. Generalized linear models were used to estimate spending among antineoplastic users. Population studied: A total of 1836 Medicare beneficiaries with newly diagnosed cancer were selected based on the presence of claims-based diagnoses after a 12-month washout period. RESULTS:: Five hundred fifty-nine (31.0%) Medicare beneficiaries received antineoplastic therapy; 395 (21.3%) used Part B, 253 (14.6%) used non-Part B antineoplastics. Spending per user was $7841 (any), $10,364 (Part B), and $1535 for non-Part B antineoplastics. Supplemental insurance was associated with antineoplastic use. Primary cancer site and age were key predictors of spending among users. Spending on non-Part B antineoplastics increased during 2006-2007 relative to 2004-2005 but time trends were not significant in multivariate analysis. CONCLUSIONS:: Antineoplastic therapy use by Medicare beneficiaries is sensitive to the presence but not type of supplemental insurance. Non-Part B therapy was used by a relatively large proportion of beneficiaries with cancer receiving therapy, although spending was less than for Part B therapy. Monitoring the role of supplemental insurance, and particularly the role of Medicare Part D is a critical area for ongoing research.

Concepts: Medicare Prescription Drug, Improvement, and Modernization Act, Medicare, Medicare Part D, Antineoplastic, Regression analysis

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Determining drug to antibody ratios (DAR) for antibody-drug conjugates (ADCs) in early research and development can be hampered by difficulties in accurate weighing of the effector payload and subsequent determination of its extinction coefficient. Two maytansinoids, DM1 and DM4, potent antimitotic agents used in clinical ADCs, were derivatized with the compact fluorophore BODIPY F using two different linker designs. We identified DM1-mal-BODIPY as a conjugate with little through-space interaction between the maytansinoid and BODIPY chromophores. The 1:1 stoichiometry between the maytansinoid and BODIPY makes the molar concentration of both components equal and the extinction coefficient of the maytansinoid in proportion with the known BODIPY chromophore according to Beer’s Law. By only derivatizing 50 μg of unpurified DM1 and analyzing about 25 μg of DM1-mal-BODIPY by UV-VIS, we determined εDM1 252 nm and εDM1 280 nm as 26,355 +/- 360 cm-1M-1 and 5230 +/- 160 cm-1M-1, respectively. These values are nearly identical to those accepted for DM1 based on weighing >100 mg of pure sample. Surprisingly, some of the maytansinoid-BODIPY conjugates that were synthesized were partially or completely fluorescence-quenched. The green fluorescence of quenched DM4-acetamide-BODIPY could be fully restored in the presence of an antibody designed to tightly bind maytansine. We exploited this observation to develop a simple “mix and read” fluorogenic immunoassay for detection of ng quantities of maytansinoids.

Concepts: Binomial coefficient, Molar absorptivity, Antineoplastic, Chromophore, Determinacy, Coefficient, Concentration, Mole

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Despite the classification as known or suspected human carcinogens, by the International Agency for Research on Cancer, the antineoplastic drugs are extensively used in cancer treatment due to their specificity and efficacy. As human carcinogens, these drugs represent a serious threat to the healthcare workers involved in their preparation and administration. This work aims to contribute to better characterize the occupational exposure of healthcare professionals to antineoplastic drugs, by assessing workplace surfaces contamination of pharmacy and administration units of two Portuguese hospitals. Surface contamination was assessed by the determination of cyclophosphamide, 5-fluorouracil, and paclitaxel. These three drugs were used as surrogate markers for surfaces contamination by cytotoxic drugs. Wipe samples were taken and analyzed by HPLC-DAD. From the total of 327 analyzed samples, in 121 (37 %) was possible to detect and quantify at least one drug. Additionally, 28 samples (8.6 %) indicate contamination by more than one antineoplastic drug, mainly in the administration unit, in both hospitals. Considering the findings in both hospitals, specific measures should be taken, particularly those related with the promotion of good practices and safety procedures and also routine monitoring of surfaces contamination in order to guarantee the appliance of safety measures.

Concepts: Chemotherapeutic agents, Antineoplastic drugs, Antineoplastic, Occupational safety and health

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The objective of this randomized, prospective and controlled study was to investigate the ability of a closed-system transfer device (CSTD; BD-Phaseal) to reduce the occupational exposure of two isolators to 10 cytotoxic drugs and compare to standard compounding devices.

Concepts: Antineoplastic, Device, Occupational safety and health

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Computerized physician order entry (CPOE) systems reduce medical errors (MEs). Nevertheless, a CPOE system may also lead to new types of errors, especially when it is first implemented. The objectives of this study were to determine the impact of a CPOE on the number of MEs and to identify the types of MEs in prescriptions issued by the Haematology Department 5 years after the implementation of the CPOE system.

Concepts: Physician, Antineoplastic, Implementation, Occupational safety and health, Hematology, Medicine, Specialty, Computer physician order entry

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Contamination of workplace surfaces by antineoplastic drugs presents an exposure risk for healthcare workers. Traditional instrumental methods to detect contamination such as liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) are sensitive and accurate but expensive. Since immunochemical methods may be cheaper and faster than instrumental methods, we wanted to explore their use for routine drug residue detection for preventing worker exposure.

Concepts: Drugs, Multiplex, Antineoplastic, Laborer, Drug, Surface, Illness

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Functional heterogeneity within tumors presents a significant therapeutic challenge. Here we show that quiescent, therapy-resistant Sox2(+) cells propagate sonic hedgehog subgroup medulloblastoma by a mechanism that mirrors a neurogenic program. Rare Sox2(+) cells produce rapidly cycling doublecortin(+) progenitors that, together with their postmitotic progeny expressing NeuN, comprise tumor bulk. Sox2(+) cells are enriched following anti-mitotic chemotherapy and Smoothened inhibition, creating a reservoir for tumor regrowth. Lineage traces from Sox2(+) cells increase following treatment, suggesting that this population is responsible for relapse. Targeting Sox2(+) cells with the antineoplastic mithramycin abrogated tumor growth. Addressing functional heterogeneity and eliminating Sox2(+) cells presents a promising therapeutic paradigm for treatment of sonic hedgehog subgroup medulloblastoma.

Concepts: G0 phase, Sonic the Hedgehog, Antineoplastic, Tumor, Sonic hedgehog, Cancer, Brain tumor, Oncology

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Exposure to antineoplastic drugs confers health risks to workers, yet little is known about the exposure after a drug spill, nor has the relationship between exposure and organizational factors such as staffing and work environment been studied.

Concepts: Antineoplastic, Occupational safety and health

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We previously reported that antineoplastic drug contamination is found on various work surfaces situated throughout the hospital medication system (process flow of drug within a facility from initial delivery to waste disposal). The presence of drug residual on surfaces suggests that healthcare workers involved in some capacity with the system may be exposed through dermal contact. The purpose of this paper was to determine the dermal contamination levels of healthcare employees working throughout a hospital and to identify factors that may influence dermal contamination. We selected participants from six hospitals and wiped the front and back of workers' hands. Wipe samples were analyzed for cyclophosphamide (CP), a commonly used antineoplastic drug, using high-performance liquid chromatography-tandem mass spectrometry. Participants were asked about their frequency of handling antineoplastic drugs, known contact with CP on their work shift, gender, job title, and safe drug handling training. In addition, participants were surveyed regarding their glove usage and hand washing practices prior to wipe sample collection. We collected a total of 225 wipe samples. Only 20% (N = 44) were above the limit of detection (LOD) of 0.36ng per wipe. The average concentration was 0.36ng per wipe, the geometric mean < LOD, the geometric standard deviation 1.98, and the range < LOD to 22.8ng per wipe. Hospital employees were classified into eight different job categories and all categories had some dermal contamination levels in excess of the LOD. The job category with the highest proportion of samples greater than the LOD were those workers in the drug administration unit who were not responsible for drug administration (volunteer, oncologist, ward aide, dietician). Of note, the highest recorded concentration was from a worker who had no known contact with CP on their work shift. Our results suggest that a broader range of healthcare workers than previously believed, including those that do not directly handle or administer the drugs (e.g. unit clerks, ward aides, dieticians, and shipper/receivers), are at risk of exposure to antineoplastic drugs. A review of control measures to minimize antineoplastic drug exposure that encompasses a wide array of healthcare workers involved with the hospital medication system is recommended.

Concepts: Mean, Antineoplastic, Medicine, Liquid chromatography-mass spectrometry, Standard deviation

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The expression of acid ceramidase (AC) - a cysteine amidase that hydrolyses the proapoptotic lipid ceramide - is abnormally high in several human tumors, which is suggestive of a role in chemoresistance. Available AC inhibitors lack, however, the potency and drug-likeness necessary to test this idea. Here we show that the antineoplastic drug carmofur, which is used in the clinic to treat colorectal cancers, is a potent AC inhibitor and that this property is essential to its anti-proliferative effects. Modifications in the chemical scaffold of carmofur yield new AC inhibitors that act synergistically with standard antitumoral drugs to prevent cancer cell proliferation. These findings identify AC as an unexpected target for carmofur, and suggest that this molecule can be used as starting point for the design of novel chemosensitizing agents.

Concepts: Antineoplastic, Benign tumor, Brain tumor, Tumor, Colorectal cancer, Neoplasm, Oncology, Cancer