Access to essential anticancer medicines for children and adolescents in Europe.

BACKGROUND: Essential anticancer medicines are an indispensable component of multidisciplinary treatment of paediatric malignancies. A European Society for Medical Oncology (ESMO) study reported inequalities in the availability of anticancer medicines for adult solid tumours and provided a model for the present survey. The aim of this survey was to assess the accessibility of essential medicines used in paediatric cancer patients aged 0 to 18 years across Europe from 2016 to 2018. METHODS: A list of medicines was drawn with input from the European Society for Paediatric Oncology (SIOP Europe) Clinical Research Council referring to the World Health Organization Model List of Essential Medicines for Children (WHO EMLc) 2017. A survey was sent to nominated national clinician and pharmacist rapporteurs and parent associations in up to 37 countries; answers were obtained from 34 countries. RESULTS: The full survey list contained 68 medicines, including 24 on the WHO EMLc 2017. Health professionals reported that 35% of all medicines were prescribed off-label in at least one country and that 44% were always available in >90% of countries. Only 63% of the EMLc 2017 medicines were reported as always available. The main determinant of unavailability was shortages, reported for 72% of medicines in at least one country. Out-of-pocket costs were reported in eight countries. Twenty-seven percent of orally administered medicines were never available in child-friendly formulations. Parents detailed individual efforts and challenges of facilitating ingestion of oral medicines as prescribed. Inequalities in access to pain control during procedures were reported by parents across Europe. CONCLUSIONS: Children and adolescents with cancer in Europe experience lack of access to essential medicines. Urgent actions are needed to address shortages, financial accessibility, availability of safe age-appropriate oral formulations, and pain management across Europe.

A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia.

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.

Gene expression profiling identifies different sub-types of retinoblastoma.

BACKGROUND: Mutation of the RB1 gene is necessary but not sufficient for the development of retinoblastoma. The nature of events occurring subsequent to RB1 mutation is unclear, as is the retinal cell-of-origin of this tumour. METHODS: Gene expression profiling of 21 retinoblastomas was carried out to identify genetic events that contribute to tumorigenesis and to obtain information about tumour histogenesis. RESULTS: Expression analysis showed a clear separation of retinoblastomas into two groups. Group 1 retinoblastomas express genes associated with a range of different retinal cell types, suggesting derivation from a retinal progenitor cell type. Recurrent chromosomal alterations typical of retinoblastoma, for example, chromosome 1q and 6p gain and 16q loss were also a feature of this group, and clinically they were characterised by an invasive pattern of tumour growth. In contrast, group 2 retinoblastomas were found to retain many characteristics of cone photoreceptor cells and appear to exploit the high metabolic capacity of this cell type in order to promote tumour proliferation. CONCLUSION: Retinoblastoma is a heterogeneous tumour with variable biology and clinical characteristics.

A comparison of McGrath and Macintosh laryngoscopes in novice users: a manikin study.

Direct laryngoscopy using the Macintosh laryngoscope is a difficult skill to acquire. Videolaryngoscopy is a widely accepted airway management technique that may be easier for novices to learn. We compared the McGrath videolaryngoscope and Macintosh laryngoscope by studying the performance of 25 medical students with no previous experience of performing tracheal intubation using an easy intubation scenario in a manikin. The order of device use was randomised for each student. After brief instruction each participant performed eight tracheal intubations with one device and then eight tracheal intubations with the other laryngoscope. Novices achieved a higher overall rate of successful tracheal intubation, avoided oesophageal intubation and produced less dental trauma when using the McGrath. The view at laryngoscopy was significantly better with the McGrath. Intubation times were similar for both laryngoscopes and became shorter with practice. There was no difference in participants' rating of overall ease of use for each laryngoscope.

The not-so-lazy-T: a modification of medial ectropion repair.

Medial involutional ectropion without excessive lateral canthal tendon laxity is often corrected using the lazy-T procedure. This procedure however carries a potential risk of canalicular damage, and locating the lower lid retractors can be difficult. We have developed a modification. Replacing the tarso-conjunctival diamond with a subconjuctival pocket posterior and inferior to the punctum, into which the lower lid retractors are advanced from the base of the wedge excision, which effectively ensures plication of the lower lid retractors while maintaining a straightforward procedure. The follow-up data on five procedures showed surgical and symptomatic success in all patients, without complications. These results confirm the efficacy of this modification of the lazy-T procedure in the correction of medial lower lid ectropion.

Hospital care by hospital-based and clinic-based faculty: a prospective, controlled trial.

BACKGROUND: The hospital length of stay decreases and clinical outcomes are maintained when teaching hospitals involve hospital-based attending physicians in comparison with traditional attending physicians. The attending physician's time commitment, including the number of hours per day and months per year, required to achieve this result is unknown. This study compared the clinical outcomes and cost of care for patients treated by hospital-based and clinic-based attending physicians devoting dramatically different amounts of time to supervising residents on the medical wards of a suburban county hospital. METHODS: Patients were alternately admitted to 2 groups of ward teams. Faculty who attended 10 months of the year supervised one group. The comparison group's attending physicians were on service for 2 months or less and maintained clinic responsibilities while on service. The cost of patient care was compared by means of the length of stay, total hospital costs, and costs for ancillary services. Hospital mortality and readmission rates compared clinical outcomes. RESULTS: There were 4456 patients hospitalized on the medical wards of a teaching service. No differences were detected in the length of stay (4.37 +/- 0.1 days for hospital-based and 4.39 +/- 0.1 days for clinic-based attending physicians). Hospital cost was observed to be similar (average cost, $5989 and $5977 per patient, respectively). The clinical outcomes were equivalent, with adjusted mortality rates for hospital-based attending physicians of 3.2% vs 3.9% for clinic-based attending physicians (P =.28). CONCLUSION: An increase of faculty time and involvement for supervision of resident-managed hospital care did not improve clinical outcomes or decrease costs during the 1-year study period.

The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53.

Topoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response (DDR) genes, such as ATM and TP53. Here, we characterise the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DDR at nano-molar concentrations and this is mediated primarily through ATR- and DNA-PK- but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest, was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model. Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DDR genes.

Streptococcus bovis catheter infection and the short bowel syndrome.

Streptococcus bovis bacteremia has been associated with several gastrointestinal disorders, most notably carcinoma of the colon. This report describes a 57-year-old woman with short bowel syndrome in whom S. bovis bacteremia and an infection of an indwelling parenteral nutrition catheter developed. A barium enema revealed diverticula and a foreshortened small intestine. This case implicates the short bowel syndrome in the pathogenesis of S. bovis bacteremia and supports empiric antibiotic coverage for both skin flora and enteric pathogens in patients with Hickman catheter sepsis and known gastrointestinal pathologic conditions.

Superwarfarin poisoning in children: a prospective study.

This prospective study was undertaken to determine the incidence, severity, time of onset, and duration of coagulopathy in children following accidental ingestion of long-acting anticoagulant rodenticides, often called "superwarfarins." Of 110 children, who ingested superwarfarins and in whom one or more prothrombin time values were obtained, 8 had a prothrombin time ratio (patient to control) of greater than or equal to 1.2, indicative of anticoagulation. Prothrombin time values obtained 48 hours after ingestion were more likely to be prolonged (6/34, 17.6%) than values obtained 24 hours after ingestion (2/104, 1.9%) (P less than .005). The occurrence of an abnormal prothrombin time could not be predicted based on the history of amount ingested or on the presence of the characteristic green-blue product dye in or around the child's mouth. Acute toxicity was evidenced by transient abdominal pain, vomiting, and heme positive stools in 2 patients. The duration of prothrombin time prolongation could not be determined because of the few values obtained after 48 hours. To detect all possible abnormal prothrombin time values, 24- and 48-hour determinations are recommended after a child has ingested a superwarfarin.

Prospective evaluation of anticoagulant reversal with oral vitamin K1 while continuing warfarin therapy unchanged.

STUDY OBJECTIVES: To study the efficacy and safety of partially correcting therapeutic anticoagulation by administering oral vitamin K1. DESIGN: Prospective interventional trial. SETTING: Outpatient anticoagulation clinic. PATIENTS: Patients who required reversal of their normal or excessive therapy with oral anticoagulant drugs were recruited. INTERVENTIONS: All patients received a single oral dose of vitamin K1. The dose was calculated using a regression formula and was intended to decrease the international normalized ratio (INR) to a predetermined value. Patient follow-up continued for 8 weeks. We compared the actual change of the INR to the predicted change. RESULTS: Sixty-five reversals of anticoagulant therapy were initiated in the study group. Sixty-four of the 65 reversals were successful. The mean (+/-SEM) initial INR was 2.6+/-0.1 for the preprocedure patients and 8.4+/-0.5 for the excessively anticoagulated patients. The predicted change in the INR correlated with the actual change (r = 0.92, p < 0.0001). There were no thromboembolic events and only one hemorrhagic complication. The mean (+/-SEM) dose of oral vitamin K1 was 5.0+/-0.3 mg for the preprocedure patients and 10.0+/-1.0 mg for the excessively anticoagulated patients. CONCLUSIONS: The administration of a single oral dose of vitamin K1 is a safe and effective method for partially reversing anticoagulant therapy without disrupting the daily maintenance dose of warfarin. A reliable regression formula was developed to predict the dose of vitamin K1 needed to achieve the desired INR.

Marked bone marrow eosinophilia at the time of relapse of acute myeloblastic leukaemia in association with the appearance of translocation t(12;20)(q24;q11).

We report a case of acute myeloblastic leukaemia (AML), FAB type M2, with karyotype t(8;21)(q22;q22), who at the time of relapse showed marked eosinophilia of the bone marrow. Karyotype analysis showed the appearance of an additional clone t(8;21)(q22;q22),t(12;20)(q24;q11). To the best of our knowledge, marked eosinophilia has not been reported in association with this particular chromosomal translocation.

Traumatic hyphaema: a retrospective study of 314 cases.

A retrospective study was made of 314 consecutive cases of traumatic hyphaema in a mixed urban and rural Scottish population. Secondary haemorrhage occurred in 4.1% of cases and was not associated with a worsening of final visual acuity. There were no identifiable risk factors for secondary haemorrhage. Poor visual outcome was in most cases attributable to retinal pathology. The use of antifibrinolytic agents does not appear to be necessary in such a population, and the importance of detecting associated retinal detachment is emphasised.

The IOMC organisations: a source of chemical safety information.

The Inter-Organisation Programme for the Sound Management of Chemicals (IOMC) was established in 1995 as a mechanism to co-ordinate the efforts of Inter-governmental Organisations in promoting the sound management of chemicals. The seven participating organisations are the United Nations Environment Programme (UNEP), the International Labour Organisation (ILO), the United Nations Food and Agriculture Organisation (FAO), the World Health Organisation (WHO), the United Nations Industrial Development Organisation (UNIDO), the United Nations Institute for Training and Research (UNITAR), and the Organisation of Economic Cooperation and Development (OECD). Members consult on the planning, programming, implementation and monitoring of activities undertaken jointly or individually, and help ensure that programmes are mutually supportive, complementary and avoid duplication of efforts, thus meeting the overall needs of the users more efficiently and effectively. To deal with technical work, the IOMC established smaller thematic groups in the main programme areas of Agenda 21's Chapter 19. One such group promotes information exchange work. Within this IOMC framework, the seven organisations have developed approaches and products to help customers find chemical safety information, as well as improving modalities of access to these data. These mechanisms come in addition to and complement the extensive information products and databases developed and provided by the individual organisations. This article presents an overview of the role of each organisation, an introduction to its electronic information products and tools, and a discussion of the products of this joint effort.

A controlled comparison of traditional feeding tube verification methods to a bedside, electromagnetic technique.

BACKGROUND: Benefits of enteral feeding are diminished by aspiration pneumonia and mechanical complications of misplaced feeding tubes. To avoid complications, clinicians determine the location of the tip before feeding. This study compares diagnostic test characteristics of 4 techniques for tip localization. METHODS: A prospective, blinded trial was conducted on the wards and critical care units of four acute-care hospitals. Patients requiring at least 3 days of enteral feeding were studied. Four observers at each institution used a randomly assigned technique to determine a tube's tip location. Methods included auscultation, aspiration with inspection or pH determination of aspirated material, and a recently developed electromagnetic technique. Results were compared with radiographic determination. Success rates were compared using sensitivity, specificity, and likelihood ratios. RESULTS: The 4 methods agreed with the radiograph in (mean, 95% confidence interval): 84 (80 to 88)%, 50 (45 to 55)%, 56 (51 to 61)%, and 76 (72 to 81)% of observations, respectively. Only the electromagnetic method and aspiration identified all tubes located above the diaphragm (negative likelihood ratio 0 and sensitivity 100%). Aspiration was unsuccessful in making a determination in 53% of the observations, whereas the electromagnetic method was successful 90% of the time.

Bioavailability of warfarin in a patient with severe short bowel syndrome.

Acquired warfarin resistance has resulted from altered drug metabolism and excessive vitamin K. A third possible mechanism, decreased gastrointestinal absorption of the drug, was examined in a patient with short bowel syndrome and severe malabsorption who demonstrated transient warfarin resistance. Despite the resistance, bioavailability studies demonstrated normal drug absorption and a prolonged half-life. The parenteral administration of vitamin K proved to be the cause of the prolonged warfarin resistance.

Complications of long arm-catheters: a randomized trial of central vs peripheral tip location.

BACKGROUND: This two-part study initially evaluated complications associated with catheters inserted via upper extremity veins. The second prospective phase compared thrombotic risk of peripheral catheter tips vs a central vein terminus. METHODS: Patients from public institutions with infectious diseases were observed throughout their inpatient and outpatient use of IV catheters. Seventy-two and 39 patients enrolled in phase 1 and phase 2, respectively. Phase 1 consisted of prospective observations and analysis of complications and associated risk factors. Phase 2 randomized patients to a catheter tip location in the superior vena cava or the axillosubclavian-innominate vein and compared the incidence of thrombosis, phlebitis, and infection. RESULTS: In phase 1, there was an increased risk of thrombosis with peripheral tip localization (61% vs 16%, p < .05). Phase 2 confirmed increased thrombosis with tips in the axillosubclavian-innominate vein compared with the superior vena cava (60% vs 21%, p < .05) with an improved survival for central tip catheters (p < .02). Catheters associated with thrombosis were more likely to become infected (r = 0.48, p < .02). CONCLUSIONS: The experience supports use of the long arm catheter as an effective device for parenteral therapy. A novel method for placing these catheters makes most patients candidates for this approach. Placing a long arm-catheter's tip in the central venous circulation reduces the risk of thrombosis. A high incidence of tip misdirection indicates a need for radiographic confirmation before use.

Nutritional and metabolic response to acute spinal-cord injury.

The metabolic response to complete spinal cord injury was prospectively studied in 10 patients with Frankel class A spinal cord injury. Weekly excretory and balance studies profile the changes in nitrogen, calcium, and 3-methylhistidine excretion in relation to body weight and metabolic rate. The initial resting energy expenditures were 10% below what was predicted, and body weight decreased by 10%. Nitrogen excretion paralleled the changes in body weight. Calcium excretion increased for 3 weeks and reached a plateau 150% above baseline. Our results chronicle the magnitude of metabolic response to spinal shock. Comparison with reported values shows this response exceeds that seen in immobilized patients. Nitrogen excretion rose to levels seen in highly stressed patients and must be considered in the management of patients with acute spinal-cord injury.

The reliability of muscle function analysis using different methods of stimulation.

BACKGROUND: The purpose of our study was to determine the reliability of nonvolitional muscle function analysis (MFA) by determining the day-to-day and within-day reliability of conventional electrical stimulation and a newer, magneto-electrical stimulation method, using standard laboratory methodology. METHODS: Ten healthy, human immunodeficiency virus-negative adult men volunteered as subjects. MFA consisted of measuring the maximal relaxation rate, for magneto-electrical stimulation at 1 Hz and conventional electrical stimulation at 20 Hz, and force-frequency ratios using conventional electrical stimulation at 10 Hz:20 Hz and 10 Hz:50 Hz. Within-day and day-to-day reliability were determined by calculating the coefficient of variation (CV) for all subjects. RESULTS: Maximal relaxation rate using magneto-electrical stimulation had a significantly lower CV compared with the other nonvolitional MFA methods (p = .002). CONCLUSIONS: Maximal relaxation rate using magneto-electrical stimulation was more reliable and technically easier than the other muscle function parameters examined. However, the day-to-day CV of muscle function parameters is larger than traditional nutrition assessment techniques. Development within the field should strive to improve testing techniques so that the reliability of MFA will allow definition of a range of normal values against which an individual's value can be compared. Until this is available, the precision and reliability of MFA restrict its use to research and population studies.

Microtiter plate technique for the measurement of glutathione in fresh and cryopreserved lymphoblasts using the enzyme recycling method.

Glutathione is an intracellular, nonprotein thiol that appears to play an important role in protection of the cell against cytotoxic drugs (1) and has been implicated in the control of cell cycling (2,3) and apoptosis (4,5). It can exist in an oxidized (disulfide, [GSSG]) and a reduced (sulphydryl, [GSH]) form. In general, GSSG comprises less than 1% of the total intracellular glutathione. In circumstances of oxidative stress, GSH dimerizes to form glutathione disulfide (GSSG), making protons available to neutralize reactive oxygen species (Reaction 1). In vivo, reduction of GSSG is catalysed by glutathione reductase, efficiently regenerating high intracellular GSH levels (Reaction 2).

Orienting the elderly to new modes of health care delivery.

There is increasing interest in meeting the health care needs of senior citizens enrolling in an HMO system of prepaid health care. The orientation program "Senior Share in Your Care" (SSIYC) was developed to help seniors make the transition from the private physician's office to the HMO setting. This program allows for an integrated approach to care of the elderly. The senior citizen experiences personal attention to his health care needs within the first week of membership. This paper describes recommendations for serving the health care needs of the elderly as well as the program benefits.