Benefits and risks of adjuvant treatment with zoledronic acid in stage II/III breast cancer. 10 years follow-up of the AZURE randomized clinical trial (BIG 01/04).

Adjuvant bisphosphonates improve disease outcomes in postmenopausal early breast cancer (EBC) but the long-term effects are poorly described. The AZURE trial (ISRCTN79831382) was designed to determine whether adjuvant zoledronic acid (ZOL) improves disease outcomes in EBC. Previous analyses showed no effect on overall outcomes but identified benefits in postmenopausal women. Here we present the long-term risks and benefits of adjuvant ZOL with 10-years follow-up. PATIENTS AND METHODS: 3360 patients with stage II/III breast cancer were included in an academic, international, phase III, randomized, open label trial. Patients were followed up on a regular schedule until 10 years. Patients were randomized on a 1:1 basis to standard adjuvant systemic therapy +/- intravenous ZOL 4 mg every 3-4 weeks x6, and then at reduced frequency to complete 5 years treatment. The primary outcome was disease free survival (DFS). Secondary outcomes included invasive DFS (IDFS), overall survival (OS), sites of recurrence, skeletal morbidity and treatment outcomes according to primary tumor amplification of the transcription factor, MAF. Pre-planned subgroup analyses focused on interactions between menopausal status and treatment effects. RESULTS: With a median follow up of 117 months [IQR 70.4-120.4), DFS and IDFS were similar in both arms (HRDFS  = 0.94, 95%CI = 0.84-1.06, p = 0.340; HRIDFS  = 0.91, 95%CI = 0.82-1.02, p = 0.116). However, outcomes remain improved with ZOL in postmenopausal women (HRDFS  = 0.82, 95%CI = 0.67-1.00; HRIDFS  = 0.78, 95%CI = 0.64-0.94). In the 79% of tested women with a MAF FISH negative tumor, ZOL improved IDFS (HRIDFS  = 0.75, 95%CI = 0.58-0.97) and OS HROS  = 0.69, 95%CI = 0.50-0.94), irrespective of menopause. ZOL did not improve disease outcomes in MAF FISH + tumors. Bone metastases as a first DFS recurrence (BDFS) were reduced with ZOL (HRB-DFS  = 0.76, 95%CI = 0.63-0.92, p = 0.005). ZOL reduced skeletal morbidity with fewer fractures and skeletal events after disease recurrence. 30 cases of osteonecrosis of the jaw in the ZOL arm (1.8%) have occurred. CONCLUSIONS: Disease benefits with adjuvant ZOL in postmenopausal early breast cancer persist at 10 years of follow-up. The biomarker MAF identified a patient subgroup that derived benefit from ZOL irrespective of menopausal status.

The long road to elimination: malaria mortality in a South African population cohort over 21 years.

BACKGROUND: Malaria elimination is on global agendas following successful transmission reductions. Nevertheless moving from low to zero transmission is challenging. South Africa has an elimination target of 2018, which may or may not be realised in its hypoendemic areas. METHODS: The Agincourt Health and Demographic Surveillance System has monitored population health in north-eastern South Africa since 1992. Malaria deaths were analysed against individual factors, socioeconomic status, labour migration and weather over a 21-year period, eliciting trends over time and associations with covariates. RESULTS: Of 13 251 registered deaths over 1.58 million person-years, 1.2% were attributed to malaria. Malaria mortality rates increased from 1992 to 2013, while mean daily maximum temperature rose by 1.5 °C. Travel to endemic Mozambique became easier, and malaria mortality increased in higher socioeconomic groups. Overall, malaria mortality was significantly associated with age, socioeconomic status, labour migration and employment, yearly rainfall and higher rainfall/temperature shortly before death. CONCLUSIONS: Malaria persists as a small but important cause of death in this semi-rural South African population. Detailed longitudinal population data were crucial for these analyses. The findings highlight practical political, socioeconomic and environmental difficulties that may also be encountered elsewhere in moving from low-transmission scenarios to malaria elimination.

A randomised phase II trial and feasibility study of palliative chemotherapy in frail or elderly patients with advanced gastroesophageal cancer (321GO).

BACKGROUND: Elderly patients are commonly under-represented in cancer clinical trials. The 321GO was undertaken in preparation for a definitive phase three trial assessing different chemotherapy regimens in a frail and/or elderly population with advanced gastroesophageal (GO) cancer. METHODS: Patients with advanced GO cancer considered unfit for conventional dose chemotherapy were randomly assigned in a 1 : 1 : 1 ratio to: epirubicin, oxaliplatin and capecitabine (EOX); oxaliplatin and capecitabine (OX); and capecitabine alone (X) (all 80% of full dose and unblinded). The primary end point was patient recruitment over an 18-month period. A registration study recorded treatment choice for all patients with advanced GO cancer at trial centres. RESULTS: A total of 313 patients were considered for palliative chemotherapy for GO cancer over the 18-month period: 115 received full dose treatment, 89 less than standard treatment or entered 321GO and 111 no treatment. Within 321GO, 55 patients were randomly assigned (19 to OX and X; 17 to EOX). Progression-free survival (PFS) for all patients was 4.4 months and by arm 5.4, 5.6 and 3.0 months for EOX, OX and X, respectively. The number of patients with a good overall treatment utility (OTU), a novel patient-centred endpoint, at 12 weeks was 3 (18%), 6 (32%) and 1 (6%) for EOX, OX and X, respectively. At 6 weeks, 22 patients (41%) had experienced a non-haematologic toxicity ⩾grade 3, most commonly lethargy or diarrhoea. The OTU was prognostic for overall survival in patients alive at week 12 (logrank test P=0.0001). CONCLUSIONS: It is feasible to recruit elderly and/or frail patients with advanced GO cancer to a randomised clinical trial. The OX is the preferred regimen for further study. Overall treatment utility shows promise as a comparator between treatment regimens for feasibility and randomised trials in the elderly and/or frail GO cancer population.

Piezoelectric generators for biomedical and dental applications: effects of cyclic loading.

This paper presents the results of a study of the effect of cyclic loading parameters on the performance of piezo crystals. The output power of the crystals was observed to increase with parameters such as the cyclic frequency and the dynamic load range. However, the output power also decreased with increasing mean load. The efficiency of the crystal was calculated based on the mechanical energy applied to the piezo crystal. The ratio of the electrical output to mechanical energy input was taken as the efficiency of the crystal. This ratio was seen to increase with the cycling frequency, and also with the dynamic load range. However, increasing mean load caused the efficiency to drop significantly. The implications of the results are discussed for possible applications implanted bioMEMS and microelectronics systems.

Undiagnosed pulmonary tuberculosis deaths in rural South Africa.

This research explores death from pulmonary tuberculosis (PTB) using a verbal autopsy (VA) tool within the established Agincourt Health and Demographic Surveillance System site in South Africa's rural northeast. Previous work on active case finding in the area highlighted a modest burden of undiagnosed PTB in the community. This VA research confirms the existence of undiagnosed PTB deaths, with 13 (46%) of 28 PTB deaths among the permanent adult population (n = 38,251) going undetected by the health service. There was a median duration of coughing in the community of 16 weeks among these undiagnosed PTB deaths. As most undiagnosed cases present to the health service at some point during their illness, intervention strategies to support early diagnosis at this level can only be re-emphasised by this work.

Molecular epidemiological analysis of community circulating respiratory syncytial virus in rural South Africa: Comparison of viruses and genotypes responsible for different disease manifestations.

Human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infection in children in both the industrialized and developing world. Most molecular epidemiological studies have, until now, focused on isolates from hospitalized infants in industrialized countries. Limited data have been available with regard to community circulating RSV, especially from Africa. The present study compares RSV isolates from infants attending rural community clinics in the Northern province of South Africa, with isolates from hospitalized infants in Soweto, near Johannesburg, South Africa, during the same period. A multiplex nested polymerase chain reaction was developed for analyzing the clinical specimens, a technique that permits subtyping and nucleotide sequence analysis of the second variable region of the G-protein gene. Community- and hospital-based isolates from young children in South Africa, as well as isolates from Mozambique were compared phylogenetically. One subgroup B community isolate was identified that had a G-protein truncated by approximately 35 amino acids, however, the other community isolates were not significantly different from hospital isolates. Evidence was found that the same RSV genotypes and viruses could cause mild upper respiratory tract infections or lower respiratory tract infections or severe RSV in young infants.

Revision of species of Minerisporites, Azolla and associated plant microfossils from deposits of the Upper Palaeocene and Palaeocene/Eocene transition in the Netherlands, Belgium and the USA.

Species of the megaspore genus Minerisporites Potonié, megaspore apparatuses of species of the water fern Azolla Lamarck, and some associated organic-walled microfossils recovered from deposits of the Upper Palaeocene and Palaeocene/Eocene transition in the southern part of the Netherlands and neighbouring Belgium are redescribed on the basis of an examination of specimens under scanning and transmission electron microscopes. Originally studied about 40 years ago by S.J. Dijkstra, the re-examination has enabled emended diagnoses to be produced for six taxa: Minerisporites glossoferus (Dijkstra) Tschudy, M. mirabilis (Miner) Potonié, M. mirabilissimus (Dijkstra) Potonié, Azolla schopfii Dijkstra, A. teschiana Florschütz, and A. velus (Dijkstra) Jain and Hall. In addition, a revised description is provided for massulae of Salvinia Séguier that were originally thought to be megaspores and, hence, named by Dijkstra as Triletes? exiguus. The gross morphology and construction of the exospore of the species of Minerisporites are similar, but nevertheless sufficiently distinct for them to be maintained as separate taxa. Monolete microspores are preserved in hollows in the reticulate surface of some of the specimens of M. mirabilissimus. This is consistent with the presumed isoetalean affinity of Minerisporites. An apparent stratigraphic morphocline from M. glossoferus to M. mirabilis, suggested previously, is confirmed following our reassessment of their characteristics. The species of Azolla are all multi-floated, but they differ from each other in several ways, in particular with respect to the ultrastructure of the megaspore wall. They are also distinct from all other species that have been considered in sufficient detail for satisfactory comparisons to be made. The massulae of A. teschiana are described for the first time. The floats in A. velus are attached to the proximal part of the megaspore only by suprafilosal hairs. There are no maniculae. It is argued that these structures do not exist in either this or any other species of Azolla. Whole fertile fossil remains that demonstrate the nature and habitat of the living plants are known for all three genera. Hence, their reproductive structures can be used with confidence in palaeoenvironmental interpretation. The overall assemblage, which also includes a few specimens of the marsilealean megaspore Molaspora lobata (Dijkstra) Hall, undoubtedly reflects the presence of lowland aquatic and semi-aquatic vegetation.

Assessing the potential for the stomatal characters of extant and fossil Ginkgo leaves to signal atmospheric CO2 change.

The stomatal density and index of fossil Ginkgo leaves (Early Jurassic to Early Cretaceous) have been investigated to test whether these plant fossils provide evidence for CO(2)-rich atmosphere in the Mesozoic. We first assessed five sources of natural variation in the stomatal density and index of extant Gingko biloba leaves: (1) timing of leaf maturation, (2) young vs. fully developed leaves, (3) short shoots vs. long shoots, (4) position in the canopy, and (5) male vs. female trees. Our analysis indicated that some significant differences in leaf stomatal density and index were evident arising from these considerations. However, this variability was considerably less than the difference in leaf stomatal density and index between modern and fossil samples, with the stomatal index of four species of Mesozoic Ginkgo (G. coriacea, G. huttoni, G. yimaensis, and G. obrutschewii) 60-40% lower than the modern values recorded in this study for extant G. biloba. Calculated as stomatal ratios (the stomatal index of the fossil leaves relative to the modern value), the values generally tracked the CO(2) variations predicted by a long-term carbon cycle model confirming the utility of this plant group to provide a reasonable measure of ancient atmospheric CO(2) change.

Active case finding: understanding the burden of tuberculosis in rural South Africa.

SETTING: The Agincourt demographic and health surveillance site in South Africa's rural Northern Province. OBJECTIVES: To accurately assess the true burden of tuberculosis in a rural sub-district with a known high prevalence of human immunodeficiency virus. DESIGN: Data on hospital registrations of tuberculosis were combined with data from an ongoing demographic health and surveillance system to accurately describe the burden of tuberculosis in a well-defined community. Undiagnosed active cases of sputum-positive disease in the community were detected among chronic coughers identified by heads of household during a single-pass census interview. RESULTS: The incidence of hospitalised tuberculosis among the permanently resident population (n = 56 566) was 212/100,000 person-years during 1999. The average point prevalence of detected tuberculosis (all forms) among patients aged over 10 years was 133/100,000, and 81/100,000 for sputum-positive pulmonary disease. This compares with a point prevalence of 16/100,000 cases of sputum-positive disease detected through active case finding. CONCLUSION: For every nine cases of sputum positive pulmonary tuberculosis being treated at any one time, there are two cases of undiagnosed disease in the community. This study demonstrates a modest burden of undiagnosed tuberculosis among residents in a rural sub-district in South Africa.

Evaluating computerized health information systems: hardware, software and human ware: experiences from the Northern Province, South Africa.

Despite enormous investment world-wide in computerized health information systems their overall benefits and costs have rarely been fully assessed. A major new initiative in South Africa provides the opportunity to evaluate the introduction of information technology from a global perspective and assess its impact on public health. The Northern Province is implementing a comprehensive integrated hospital information system (HIS) in all of its 42 hospitals. These include two mental health institutions, eight regional hospitals (two acting as a tertiary complex with teaching responsibilities) and 32 district hospitals. The overall goal of the HIS is to improve the efficiency and effectiveness of health (and welfare) services through the creation and use of information, for clinical, administrative and monitoring purposes. This multi-site implementation is being undertaken as a single project at a cost of R130 million (which represents 2.5 per cent of the health and welfare budget on an annual basis). The implementation process commenced on 1 September 1998 with the introduction of the system into Mankweng Hospital as the pilot site and is to be completed in the year 2001. An evaluation programme has been designed to maximize the likelihood of success of the implementation phase (formative evaluation) as well as providing an overall assessment of its benefits and costs (summative evaluation). The evaluation was designed as a form of health technology assessment; the system will have to prove its worth (in terms of cost-effectiveness) relative to other interventions. This is more extensive than the traditional form of technical assessment of hardware and software functionality, and moves into assessing the day-to-day utility of the system, the clinical and managerial environment in which it is situated (humanware), and ultimately its effects on the quality of patient care and public health. In keeping with new South African legislation the evaluation process sought to involve as many stakeholders as possible at the same time as creating a methodologically rigorous study that lived within realistic resource limits. The design chosen for the summative assessment was a randomized controlled trial (RCT) in which 24 district hospitals will receive the HIS either early or late. This is the first attempt to carry out an RCT evaluation of a multi-site implementation of an HIS in the world. Within this design the evaluation will utilize a range of qualitative and quantitative techniques over varying time scales, each addressing specific aims of the evaluation programme. In addition, it will attempt to provide an overview of the general impact on people and organizations of introducing high-technology solutions into a relatively unprepared environment. The study should help to stimulate an evaluation culture in the health and welfare services in the Northern Province as well as building the capacity to undertake such evaluations in the future.

Delivery of non-surgical oncology care.

The changes and options for future change in the provision of non-surgical oncology care within the UK are discussed in the context of the recommendations of the Calman report, the drive towards site specialization and the changing nature of the specialties of clinical and medical oncology. Options for the creation of an improved and more flexible service are discussed.

Duplication of 8p23.1: a cytogenetic anomaly with no established clinical significance.

We present seven families with a cytogenetic duplication of the short arm of chromosome 8 at band 8p23.1. The duplication has been transmitted from parents to offspring in four of the seven families. In three families, the source of the extra material and its euchromatic origin were established using FISH with a YAC which was mapped to 8p23.1 and a whole chromosome paint for chromosome 8. FISH signals from this YAC were significantly larger on the duplicated chromosome compared with the normal chromosome in all six family members tested. Comparative genomic hybridisation (CGH) on a representative subject was consistent with these results. The families were ascertained for a variety of mostly incidental reasons including prenatal diagnosis for advanced maternal age. The transmission of this duplication by multiple phenotypically normal family members with no history of reproductive loss suggests the existence of a novel class of 8p23.1 duplications, which can be regarded as euchromatic variants or duplications with no phenotypic effect.

Ultrastructural interpretation of the Late Cretaceous megaspore Glomerisporites pupus and its associated microspores.

The ultrastructure of the Late Cretaceous (Santonian-?early Campanian) megaspore Glomerisporites pupus and its associated microspores has been examined in an attempt to resolve a number of problems concerning the interpretation of their morphology. The new observations presented are based on an analysis of entire, fragmentary, and thin-sectioned specimens under scanning and transmission electron microscopes. These add to, and partly correct, previous observations on this taxon. They include the following: (1) The exine of the megaspore consists of thin, homogeneous, outer undulating and inner electron dense layers, with a thicker zone of spongy structure in-between. (2) The perispore (or perine) of the megaspore comprises four layers, in order towards the exterior: loose filamentous, dense filamentous, vacuolate, and columnar. (3) This is completely enclosed by a thick mat of hairs, which appears to be attached to the underlying perisporal layers by means of connections with a few of the "spines" that originate from the dense filamentous zone, and with some elements of the columnar perine. (4) The tripartite neck (acrolamella) of the spore, which is hidden beneath the mat of hairs, is predominantly an extension of the dense filamentous and vacuolate layers, but also involves the columnar layer, especially in the lower part. (5) Some of the numerous small floats that are embedded in the mat have hairs originating from them. (6) Both long tangled and circinate hairs surround the perispore of the microspores. (7) The exine of the microspore was at least partly attached to the perispore when the organ was viable. (8) It comprises four zones that vary in structure and electron density. These facts and comparisons made with other megaspores and their associated microspores confirm evolutionary links between G. pupus and several taxa included within the Salviniaceae (Azolla, Parazolla, Salvinia) and possible ancestors of this group (the parent plants of Ariadnaesporites and Capulisporites).

Inv(10)(p11.2q21.2), a variant chromosome.

We present 33 families in which a pericentric inversion of chromosome 10 is segregating. In addition, we summarise the data on 32 families in which an apparently identical inv(10) has been reported in the literature. Ascertainment was through prenatal diagnosis or with a normal phenotype in 21/33 families. In the other 12 families, probands were ascertained through a wide variety of referral reasons but in all but one case (a stillbirth), studies of the family showed that the reason for referral was unrelated to the chromosome abnormality. There has been, to our knowledge, no recorded instance of a recombinant chromosome 10 arising from this inversion and no excess of infertility or spontaneous abortion among carriers of either sex. We propose that inv(10)(p11.2q21.2) can be regarded as a variant analogous to the pericentric inversion of chromosome 2(p11q13). We conclude that prenatal chromosome analysis is not justified for inv(10) carriers. In addition, family investigation of carrier status is not warranted in view of the unnecessary concern this may cause parents and other family members.

Two enhancer domains control early aspects of the complex expression pattern of Msx1.

To understand how the complex embryonic expression pattern of the Msx1 gene is produced a transgenic analysis of 13 kb of DNA around the Msx1 locus was carried out. Most of the extensive expression pattern of the Msx1 gene was reproduced in transgenics using the LacZ gene fused to 5 kb of Msx1 5' flanking DNA. Two enhancer domains were identified which produced this pattern. The distal element produced expression in the first arch and the nasal epithelium and was restricted to 240 bp. However, the proximal element which produced expression in superficial nasal epithelium, dorsal and ventral myotome, limb mesenchyme, eye, ear, roof plate, second arch, genital ridge and epiphysis, was contained in only 78 bp.

Unbalanced translocation in a mother and her son in one of two 5;10 translocation families.

We present two families with different distal long arm 5;10 translocations. In one family the propositus and his mother inherited the same derived chromosome 10 from the maternal grandfather who has a balanced t(5;10)(q35.3;q26.13). The phenotype of both the affected patients is milder and only partially overlaps with that of previous cases of distal 10q deletion. Other previously reported cases of transmitted imbalance are also remarkable for mild phenotype, occurrence of deletions rather than duplications and a strong bias toward maternal as opposed to paternal transmission. In the second family, the propositus inherited a derived chromosome 10 from his mother who carries a balanced (t(5;10)(q35.1;q26.3) translocation; his clinical manifestations are consistent with an emerging phenotype for distal 5q duplications.

Observation of individual chemical reactions in solution.

Discrete chemical reaction events occurring in solution have been observed by single photon detection of a bimolecular, chemiluminescent reaction. The reactants were generated from 9,10-diphenylanthracene in acetonitrile with potential pulses applied to an ultramicroelectrode. Electrogenerated radical ions of opposite sign react to yield the excited singlet state of the parent compound. The chemical reactions were restricted to a 20-femtoliter volume adjacent to the electrode by the use of rapid potential pulses. Individual chemical reaction events were stochastic and followed the Poisson distribution, and the interarrival time between successive reaction events was exponentially distributed.

Stability studies on admixtures of 5-fluorouracil with carboplatin and 5-fluorouracil with heparin for administration in continuous infusion regimens.

The therapeutic index of several anticancer agents may be improved by replacing rapid infusion/bolus injection schedules with prolonged continuous infusion regimens. Admixtures of 5-fluorouracil (5FU) with carboplatin and 5FU with heparin were subjected to stability studies to establish the feasibility of administering these infusions on an in-patient and out-patient basis, respectively. In the first study the stability of carboplatin was determined in an admixture of carboplatin and 5FU for neoadjuvant treatment of in-patients with oesophageal carcinoma by 5-day infusion. A previous study had reported significant carboplatin degradation in 5FU/carboplatin admixtures. Our results were consistent with this study and demonstrated that under ward conditions (25 degrees C) carboplatin also degraded (16% in 24 h) in dilute admixtures with 5FU. However, the addition of a citric acid buffer, which reduced infusion pH from 8.65 to 6.5, increased the stability of carboplatin (4.8% degradation in 24 h), without compromising 5FU solubility or stability. In a second study, the stability of an infusion containing 5FU and heparin was determined. Prolonged continuous infusion is routinely used for adjuvant treatment of colorectal carcinoma but episodes of thromboses and occlusion of the central venous catheter have been associated with this treatment.(ABSTRACT TRUNCATED AT 250 WORDS)