Safe handling of cytotoxics: guideline recommendations.

BACKGROUND: This evidence-based practice guideline was developed to update and address new issues in the handling of cytotoxics, including the use of oral cytotoxics; the selection and use of personal protective equipment; and treatment in diverse settings, including the home setting. METHODS: The guideline was developed primarily from an adaptation and endorsement of an existing guideline and from three systematic reviews. Before publication, the guideline underwent a series of peer and external reviews to gather feedback. All comments were addressed, and the guideline was amended when required. The guideline applies to health care workers who could come into contact with cytotoxic drugs at any point in the medication circuit. The intended users are hospital administrators, educators, and managers; occupational health and safety services; and pharmacy and health care workers. RESULTS: The recommendations represent a reasonable and practical set of procedures that the intended users of this guideline should implement to minimize opportunities for accidental exposure. They are not limited to just the point of care; they cover the entire chain of cytotoxics handling from the time such agents enter the institution until they leave in the patient or as waste. CONCLUSIONS: Reducing the likelihood of accidental exposure to cytotoxic agents within the medication circuit is the main objective of this evidenced-based guideline. The recommendations differ slightly from earlier guidelines because of the availability of new evidence.

A phase II study of SB939, a novel pan-histone deacetylase inhibitor, in patients with translocation-associated recurrent/metastatic sarcomas-NCIC-CTG IND 200†.

BACKGROUND: A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate with chromatin-modifying complexes containing histone deacetylases (HDAC), and lead to epigenetic transcriptional dysregulation. HDAC inhibitors were shown to be effective in vitro, reversing gene repression by these complexes, restoring PTEN expression and apoptosis via the PI3K/Akt/mTOR pathway. PATIENTS AND METHODS: SB939 is an oral inhibitor of classes 1 and 2 HDAC. Eligible patients with recurrent or metastatic translocation-associated sarcoma (TAS) by local pathology were treated with 60 mg/day every other day for 3 of 4 weeks. Central pathology review was conducted with fusion oncogenes characterized, and HDAC2 expression correlated with efficacy in pre-specified methods. RESULTS: Twenty-two patients were treated with a median of 2 cycles. Fourteen patients were assessable for response with confirmed specific chromosomal translocations; 8 had a best response of stable disease (SD) (median duration 5.4 months) with no confirmed objective responses. The 3-month progression-free survival (PFS) rate was 49%. Among those with HDAC2 score ≥5, 7/10 had SD, versus 0/3 with HDAC2 score <5. SB939 was considered as well tolerated with <10% patients experienced ≥grade 3 toxicity. CONCLUSION: This study was stopped prematurely due to prolonged unavailability of SB939. No objective responses were seen. Although the observed SD in HDAC2 high patients was interesting, due to the small sample size, no definitive conclusion can be drawn about the efficacy of SB939 in this patient population. CLINICAL TRIAL: NCT01112384.

Cattle herd inspections and fly trapping for the detection of the Old World screw-worm fly (Chrysomya bezziana).

OBJECTIVES: To compare the sensitivity of inspections of cattle herds and adult fly trapping for detection of the Old World screw-worm fly (OWS). PROCEDURES: The incidence of myiases on animals and the number of OWS trapped with LuciTrap®/Bezzilure were measured concurrently on cattle farms on Sumba Island (Indonesia) and in peninsular Malaysia (two separate periods for the latter). The numbers of animal inspections and traps required to achieve OWS detection at the prevalent fly densities were calculated. RESULTS: On Sumba Island, with low-density OWS populations, the sensitivity of herd inspections and of trapping for OWS detection was 0.30 and 0.85, respectively. For 95% confidence of detecting OWS, either 45 inspections of 74 animals or trapping with 5 sets of 4 LuciTraps for 14 days are required. In Malaysia, at higher OWS density, herd inspections of 600 animals (twice weekly, period 1) or 1600 animals (weekly, period 2) always detected myiases (sensitivity = 1), while trapping had sensitivities of 0.89 and 0.64 during periods 1 and 2, respectively. For OWS detection with 95% confidence, fewer than 600 and 1600 animals or 2 and 6 LuciTraps are required in periods 1 and 2, respectively. CONCLUSIONS: Inspections of cattle herds and trapping with LuciTrap and Bezzilure can detect OWS populations. As a preliminary guide for OWS detection in Australia, the numbers of animals and traps derived from the Sumba Island trial should be used because the prevailing conditions better match those of northern Australia.

Field assessment of synthetic attractants and traps for the Old World screw-worm fly, Chrysomya bezziana.

The performance of newly developed trapping systems for the Old World screw-worm fly, Chrysomya bezziana has been determined in field trials on cattle farms in Malaysia. The efficacy of non-sticky traps and new attractants to trap C. bezziana and non-target flies was compared with the standard sticky trap and Swormlure. The optimal trap was a modified LuciTrap(®) with a new attractant mixture, Bezzilure-2. The LuciTrap/Bezzilure-2 caught on average 3.1 times more C. bezziana than the sticky trap with Swormlure (P<0.05) and provided selectivity for C. bezziana against Chrysomya megacephala and Chrysomya rufifacies with factors of 5.9 and 6.4, respectively. The LuciTrap also discriminates with factors of 90 and 3.6 against Hemipyrellia sp. and sarcophagid flesh flies respectively, compared to the sticky trap. The LuciTrap/Bezzilure-2 system is recommended for screwworm fly surveillance as it is more attractive and selective towards C. bezziana and provides flies of better quality for identification than the sticky trap.

Cortical and trabecular bone at the radius and tibia in postmenopausal breast cancer patients: a Peripheral Quantitative Computed Tomography (pQCT) study.

Bone morbidity associated with antineoplastic treatment is a significant health concern for postmenopausal breast cancer patients. Trials have demonstrated that adjuvant therapy with an Aromatase Inhibitor is associated with an increase in musculoskeletal disorders and bone fractures. The objective of this study was to utilize Peripheral Quantitative Computed Tomography (pQCT) to assess in vivo trabecular and cortical volumetric bone at peripheral skeletal sites in healthy postmenopausal women and breast cancer patients prescribed Anastrozole. Fifty-eight women were recruited for this study: 27 breast cancer patients and 31 healthy control participants. pQCT measurements were taken at distal and diaphyseal sites of the radius and tibia using a Stratec XCT-2000 pQCT scanner. Bone measurement values for total density and total content at the 4% radius; total and cortical content as well as cortical density at the 20% radius; total density at the 4% tibia; and cortical density at the 38% tibia were found to be significantly lower in breast cancer patients. Moreover, the duration of time on Anastrozole showed a significant negative correlation with the following measurements: total content at the 4% radius (r=-0.36, p<0.01); total content (r=-0.33, p<0.05), cortical content (r=-0.34, p<0.05) and cortical density (r=-0.44, p<0.01) at the 20% radius; as well as cortical density (r=-0.39, p<0.01) and cortical content (r=-0.27, p<0.05) at the 38% tibia. Overall, the breast cancer patients demonstrated significantly lower values for volumetric bone density and content at the radius and tibia compared with healthy postmenopausal women. Furthermore, this novel study found adverse effects from Anastrozole treatment primarily in cortical bone.

A phase II study of perifosine (D-21226) in patients with previously untreated metastatic or locally advanced soft tissue sarcoma: A National Cancer Institute of Canada Clinical Trials Group trial.

UNLABELLED: BACKGROUND/PATIENTS AND METHODS: 16 adult patients with untreated measurable locally advanced or metastatic inoperable soft tissue sarcoma were treated with oral perifosine, a synthetic alkylphospholipid, believed to inhibit MAP kinase (MAP-K), protein kinase C (PKC), Akt and other regulatory proteins. Perifosine was administered orally in cycles for 21 days out of 28. Loading doses were given day 1 each cycle (900 mg cycle 1, 300 mg cycle 2+) and 150 mg daily was given days 2-21 of each cycle. Cycles were repeated until disease progression, unacceptable toxicity or patient refusal. RESULTS: Seventeen patients were enrolled; 16 and 15 were evaluable for toxicity and response, respectively. A total of 30 cycles of perifosine were administered. Most toxic effects were grade 1 or 2 and commonly included nausea, vomiting, diarrhea, and fatigue (> or =40%). Hematologic toxicity was generally mild. There were no significant biochemical abnormalities due to the drug reported. There were 4 serious adverse events (SAE)-none of which was related to perifosine. No objective responses were seen; 4 patients had stable disease for 1.3 to 8.2 months and the remainder of the patients had progressive disease. CONCLUSIONS: Perifosine when given according to this dosing schedule does not show evidence of activity in a mixed population of adult soft tissue sarcoma patients.

A randomized phase II study of two schedules of bryostatin-1 (NSC339555) in patients with advanced malignant melanoma: A National Cancer Institute of Canada Clinical Trials Group study.

PURPOSE: This study addressed the efficacy and toxicity of the novel compound Bryostatin-1 (NSC 339555), a novel agent with antineoplastic, hematopoietic and immunomodulatory activity in a variety of in vitro and in vivo systems. PATIENTS AND METHODS: This phase II study randomly assigned chemotherapy-naïve patients with untreated metastatic melanoma and measurable disease to two schedules of treatment: Arm A, 25 microg/m2 bryostatin-1 given as a 24 hour continuous infusion weekly or Arm B, 120 microg/m2 bryostatin-1 given as a 72 hour continuous infusion every 2 weeks. Although objective response was assessed using standard NCIC CTG criteria, antitumour activity was assessed using a multivariate endpoint incorporating both response (CR and PR) and early progression (PD at < or = 8 weeks). Seventeen patients were randomized to each arm. RESULTS: Arm A was better tolerated with 86.7% of 15 evaluable patients receiving > or = 90% of planned dose intensity versus 76.5% of 17 evaluable patients in Arm B. On Arm B, three patients experienced serious adverse events and three patients had to be removed from protocol therapy due to toxicity. The most common side effect was myalgia (33% grade 1-2 on Arm A versus 65% on Arm B with 5 patients experiencing grade 3 and one patient grade 4). Lethargy was more common on Arm A but more severe on Arm B. Other side effects such as nausea, diarrhea and headache were generally mild to moderate in nature and occurred with a similar frequency on both arms. Hematologic and biochemical toxicity were minimal. This trial was closed early because the protocol-stopping rule was met based on lack of required responses and on the number of early progressions on both arms. No partial or complete responses were seen; 3 patients randomized to Arm A had stable disease (duration 9-24 weeks) as did 4 patients (duration 10-38 weeks) randomized to Arm B. CONCLUSION: Arm A was better tolerated than Arm B. We conclude that bryostatin-1 has little efficacy in the treatment of metastatic melanoma with either of the schedules studied.

Genetically modified dendritic cells in cancer therapy: implications for transfusion medicine.

Dendritic cells (DCs) are a heterogeneous population of antigen-presenting cells (APCs) identified in various tissues, including the skin (Langerhans cells), lymph nodes (interdigitating and follicular DCs), spleen, and thymus. Properties of DCs include the ability to (1) capture, process, and present foreign antigens; (2) migrate to lymphoid-rich tissue; and (3) stimulate innate and adaptive antigen-specific immune responses. Until recently, the ability to study DCs has been limited by their absence in most culture systems. It is now known that specific cytokines can be used to expand DCs to numbers sufficient for their in vitro evaluation and for their use in human immunotherapy trials. Human DCs can be derived from hematopoietic progenitors (CD34+-derived DCs) or from adherent peripheral blood monocytes (monocyte-derived DCs). Cultured DCs can be recognized by a typical veiled morphologic appearance and expression of surface markers that include major histocompatibility complex class II, CD86/B7.2, CD80/B7.1, CD83, and CD1a. DCs are susceptible to a variety of gene transfer protocols, which can be used to enhance biological function in vivo. Transduction of DCs with genes for defined tumor antigens results in sustained protein expression and presentation of multiple tumor peptides to host T cells. Alternatively, DCs may be transduced with genes for chemokines or immunostimulatory cytokines. Although the combination of ex vivo DC expansion and gene transfer is relatively new, preliminary studies suggest that injection of genetically modified autologous DCs may be capable of generating anti-tumor immune responses in patients with cancer. Preclinical animal studies showing potent antigen-specific tumor immunity after DC-based vaccination support this hypothesis and provide rationale to further evaluate this approach in patients. Preliminary human studies are now required to evaluate optimal DC dose, schedule of vaccination, route of delivery, and maturational state of cultured cells. Initiation of these phase I/II cell therapy-based studies will occur in collaboration with hospital-based transfusion facilities. Issues relating to cell harvesting, storage, culture methodology, and administration require the collaborative efforts of basic scientists, immunologists, clinical investigators, and transfusion medicine staff to ensure strict quality control of injected cellular products. This review is intended to provide a brief overview of clinical DC-based gene transfer.

Male sexual dysfunction in mice bearing targeted mutant alleles of the PEA3 ets gene.

PEA3, a member of the Ets family of transcriptional regulatory proteins, is expressed in a unique spatial and temporal pattern during mouse embryogenesis; its overexpression is positively correlated with HER2-mediated breast tumorigenesis in both humans and mice. To determine whether PEA3 plays a part in development and oncogenesis and to uncover its normal physiological role, we generated mice lacking functional PEA3 by gene targeting in embryonic stem cells. PEA3(-/-) mice arose from heterozygous crosses with the expected Mendelian frequency, revealing that PEA3 is dispensable for embryogenesis. PEA3 mutant mice displayed no overt phenotype and lived a normal life span. However, PEA3-deficient males failed to reproduce. PEA3 is expressed in several male sexual organs, but gross and histological analyses of the organs from PEA3(-/-) mice revealed no abnormalities. Spermatogenesis and spermiogenesis also appeared normal in mice homozygous for the PEA3 mutation, and their sperm were capable of fertilizing eggs in vitro. PEA3(-/-) males engaged in normal mating behavior, but they did not set copulatory plugs and sperm could not be detected in the uteri of females that had mated with PEA3(-/-) males. Erections could be evoked by abdominal pressure in PEA3-deficient male mice, and the results of in vitro experiments revealed that the corpus cavernosum isolated from PEA3 mutant males relaxed in response to acetylcholine. Therefore, the infertility of PEA3 mutant males involves either mechanisms proximal to the cavernosal smooth muscle or an ejaculatory dysfunction. However, PEA3 mutant mice are phenotypically distinguishable from other knockout mice with such deficits and thus provide a unique model for further investigation of male sexual dysfunction.

Immunolocalization of matrix metalloproteinases and their inhibitors in clinical specimens of bone metastasis from breast carcinoma.

Matrix metalloproteinases (MMPs) are essential in several stages of the metastatic process, and in normal bone development and remodeling. We explored whether the interaction between tumor cells and bone leads to changes in MMP and tissue inhibitor of MMP (TIMP) expression thus affecting osteolysis in metastatic bone disease. Using immunohistochemistry we have investigated the MMP/TIMP expression in tumor cells, fibroblasts, osteoblasts and osteoclasts. Thirty one specimens of bone metastasis from breast carcinoma were stained for MMP-1, -2, -9, MT1-MMP and TIMP-1, and -2 and compared with staining in normal breast tissue, primary breast carcinoma and normal bone. Specimens came from patients in three clinical scenarios: from open biopsies without or with pathological fracture, or bone marrow biopsies containing tumor from patients with pancytopenia but without clinical evidence of osteolysis. By bone histomorphometry the latter group showed a heavy tumor load not different from the open biopsy groups but displayed little active bone resorption and low numbers of osteoclasts. Cell type-specific MMP/TIMP expression was observed and the staining patterns were comparable between the three groups of patients. Though no major differences in the MMP/TIMP staining of tumor cells and fibroblasts were observed between bone metastasis and primary tumor, we showed that tumor cells do express MMPs capable of degrading bone matrix collagen. The number and activity of osteoclasts and osteoblasts was increased dramatically in bone metastases, their MMP/TIMP profiles, however, were not different from normal bone, suggesting that the mechanism of bone degradation by osteoclasts is not different from normal bone remodelling.

The activity of the Ets transcription factor PEA3 is regulated by two distinct MAPK cascades.

PEA3, a member of the Ets family of transcriptional regulatory proteins, binds to the PEA3 promoter element and stimulates transcription through this site. The activity of the PEA3 element is regulated by mitogens, activated receptor tyrosine kinases, and oncogenic members of the Ras signal transduction pathway. However, it is not clear whether PEA3 mediates transcriptional regulation by these agents because a number of different Ets proteins can functionally interact with the PEA3 element. To specifically learn whether the activity of PEA3 is regulated, we investigated the ability of constitutively-activated Ras (Ha-RasV12) and signaling proteins downstream of Ras to alter PEA3-dependent reporter gene expression in COS cells. Ha-RasV12 and activated proteins in both the extra-cellular regulated kinase (ERK) and the stress-activated protein kinase (SAPK) or Jun N-terminal kinase (JNK) cascades independently stimulated PEA3-mediated gene expression. Ha-RasV12 stimulation of PEA3 activity was reduced by dominant-negative mutants in each of these protein kinase cascades, suggesting that Ras activates PEA3 through both pathways. Furthermore, the ability of unique activators of each kinase cascade to stimulate PEA3-dependent gene expression was selectively reduced by dominant-negative mutants within the homologous but not the heterologous pathway. Hence two distinct mitogen-activated protein kinase (MAPK) cascades regulate PEA3 activity. PEA3 was phosphorylated in vivo at serine residues consistent with the possibility that it may be a direct target of MAPKs.

Control of horn fly (Diptera: Muscidae) in Florida with an Australian trap.

A newly developed Haematobia spp. trap is described, and results are presented from field trials to reduce populations of adult horn fly, Haematobia irritans L., on 5 dairy farms in western Florida and Alabama during the summer of 1992. We compared fly infestations on milkers subjected to trapping, versus either dry cattle on the same farm or milkers on a nearby farm, without the trap but where traditional horn fly control practices were used. Results gave 96.9% (95% CI, 93.8-98.4) reduction compared with dry cattle with a mean count of 228 per animal, and 90.2% (84.5-94.5%) compared with milkers on the control farms with a mean count of 113. Trapping removed the need to use insecticides to control this pest on milking dairy cattle and so offers a practical, environmentally acceptable, safe, and sustainable means of horn fly control on cattle which pass through the trap regularly.

Profile of blood donors in Port Moresby.

A record analysis study was conducted on blood donors in the greater Port Moresby area to determine the trend in the number of blood donations and the profile of donors between 1985 and 1994. There was no significant change in the donation trend between 1985-1989 and 1990-1994. While there were no changes in the age distribution between these two periods, there were significant increases in female donors (from 17% to 25%) and new donors (47% to 54%) during 1990-1994. The study data show that there has been a problem in the retention of donors in the greater Port Moresby area during the 1990-1994 period.

Papua New Guinea Red Cross Blood Transfusion Service: present status and future considerations.

About 28,000 units of blood are collected per annum. This is adequate for present needs. 11 donors have been found positive for human immunodeficiency virus (HIV) since testing started in 1987, 8 of these in the last year and a half. No case of transmission of HIV by transfusion in Papua New Guinea has been established. Although the prevalence varies in different areas, on average 15% of donors are positive for hepatitis B. The impact of these figures, future requirements for quantity of blood and the need for additional testing of donations for hepatitis C (HCV) and cytomegalovirus (CMV) will require clear evaluation of the choices and firm decisions.

PIP: The Papua New Guinea Red Cross Blood Transfusion Program, a nongovernmental organization based in Port Moresby General Hospital, has an agreement with the government to "recruit and maintain suitable donor panels and collect and store blood at appropriate centers." The government provides staff (except for the Director and Deputy Director), buildings, and equipment. About 28,000 units of blood are collected each year from unpaid donors at government and church hospitals and mobile sites. Almost 50% of donors are new donors. Generally, the demand for blood is met. Donations are tested for hepatitis B and HIV. Since screening commenced in 1987, 11 donors have been found to be HIV-infected. No case of HIV transmission by transfusion has been established. On average, 15% of donors are positive for hepatitis B. Future goals include consolidation of a stable group of donors who give blood repeatedly and reliably and evaluation of the need for screening of blood supplies for hepatitis C and cytomegalovirus infections. The total annual cost of the blood transfusion program is about K200,000.

The efficacy of diazinon impregnated ear tags against buffalo fly and resulting weight gains and diazinon residues in meat and milk.

Ear tags impregnated with 20% diazinon were evaluated for their efficacy against the buffalo fly (Haematobia irritans exigua) on beef cattle in southern Queensland. Buffalo fly numbers and weight changes were recorded and diazinon residues in tissues of beef cattle and milk from lactating dairy cattle were assayed at different time intervals after tagging. In 2-efficacy trials conducted over 19 and 20 weeks, the mean numbers of buffalo fly on cattle each fitted with ear tags were 1 to 9 and 0 to 16, respectively, in trials 1 and 2, compared with 44 to 345 and 26 to 306 per head on untreated herds, respectively, despite regular spraying of the untreated herd in trial 1 with cypermethrin to reduce fly burdens. Percentage buffalo fly control was 96.7 to 99.5% and 89.3 to 100% in the 2 trials. Cattle fitted with ear tags gained an average of 94 kg body weight after 5 months compared with 61 kg in the untreated herd, a net increase of 60% in treated animals compared with 28% in the untreated herd. Mean diazinon residue concentrations in the fat of perianal tissue biopsies were 0.02 to 0.03 mg/kg 1 to 8 weeks after tagging. Mean diazinon residue concentrations in the butterfat of milk from lactating dairy cattle were 0.01 to 0.04 mg/kg after tagging.

Impedance imaging using induced currents.

The principal features of an electrical impedance tomography system using induced currents are described. Images of the distribution of conductivity in a two-dimensional phantom are obtained using an algorithm based on a sensitivity matrix. Results are also presented which demonstrate the separation of conductivity and permittivity images from measurements of the complex peripheral voltage, the formation of unreferenced permittivity images, and the use of capacitively coupled electrodes in a measuring system without direct electrical contact.

Dispersal of the Old World screw-worm fly Chrysomya bezziana.

Dispersal of the Old World screw-worm fly, Chrysomya bezziana Villeneuve, was studied in Papua New Guinea by releasing radio-isotope labelled, laboratory-reared flies and collecting their labelled egg masses from sentinel cattle. A log-linear model was developed to describe recapture rate. Distance was found to dominate the model and was represented by a bilinear ('broken-stick') term as log-distance. Further terms in the model such as attractiveness of the site (estimated from the number of non-labelled egg masses), the season of the year and a time trend were statistically significant but of minor importance. From the model, the median distance females dispersed before depositing an egg mass was 10.8 km. The maximum distance from the release site that egg masses were recovered was 100 km. The dispersal ability of C. bezziana is discussed in terms of its impact on the prospects of eradicating this species using SIRM if an outbreak occurred in Australia.

The arotinoids: early clinical experience and discussion of future development.

There has been great interest in the use of drugs attempting to modify the properties of malignant cells without necessarily destroying them. The family of compounds known as the retinoids have shown particular promise in this area. Current interest is directed towards established retinoids such as ATRA and 13-CRA. Newer synthetic retinoids such as fenretinide, the arotinoid Ro 40-8757, and 9-cis retinoic acid have been entering clinical trials. Ro 40-8757 is a particularly interesting new arotinoid with properties quite distinct from the other retinoids. It has different binding proteins and appears to regulate different genes than the classical retinoids such as ATRA or 13-CRA. Furthermore, it appears active against a different spectrum of malignancies. It also appears to have a relatively favourable side-effect profile. In addition to its anti-proliferative effects, this arotinoid may play a role in protection of bone marrow function after use of cytotoxic drugs. Development of Ro 40-8757 was halted before the compound had entered phase II testing due to lack of resources. Future developmental programmes for retinoids should move rapidly to explore the potential of interesting combinations identified in preclinical models. Retinoids should be considered primarily as drugs which modulate and enhance the effects of other active anticancer agents. Their development should not be prevented because they are unlikely to be active as single agents against common solid tumours.