Scientific Developments in Imaging and Dosimetry for Molecular Radiotherapy.

Molecular radiotherapy is a rapidly developing field with new vector and isotope combinations continually added to market. As with any radiotherapy treatment, it is vital that the absorbed dose and toxicity profile are adequately characterised. Methodologies for absorbed dose calculations for radiopharmaceuticals were generally developed to characterise stochastic effects and not suited to calculations on a patient-specific basis. There has been substantial scientific and technological development within the field of molecular radiotherapy dosimetry to answer this challenge. The development of imaging systems and advanced processing techniques enable the acquisition of accurate measurements of radioactivity within the body. Activity assessment combined with dosimetric models and radiation transport algorithms make individualised absorbed dose calculations not only feasible, but commonplace in a variety of commercially available software packages. The development of dosimetric parameters beyond the absorbed dose has also allowed the possibility to characterise the effect of irradiation by including biological parameters that account for radiation absorbed dose rates, gradients and spatial and temporal energy distribution heterogeneities. Molecular radiotherapy is in an exciting time of its development and the application of dosimetry in this field can only have a positive influence on its continued progression.

Development of patient-specific molecular imaging phantoms using a 3D printer.

PURPOSE: The aim of the study was to investigate rapid prototyping technology for the production of patient-specific, cost-effective liquid fillable phantoms directly from patient CT data. METHODS: Liver, spleen, and kidney volumes were segmented from patient CT data. Each organ was converted to a shell and filling holes and leg supports were added using computer aided design software and prepared for printing. Additional fixtures were added to the liver to allow lesion inserts to be fixed within the structure. Phantoms were printed from an ultraviolet curable photopolymer using polyjet technology on an Objet EDEN 500V 3D printer. RESULTS: The final print material is a clear solid acrylic plastic which is watertight, rigid, and sufficiently durable to withstand multiple assembly and scanning protocols. Initial scans of the phantoms have been performed with Tc-99m SPECT and F-18 PET/CT. CONCLUSIONS: The organ geometry showed good correspondence with anatomical references. The methodology developed can be generally applied to other anatomical or geometrical phantoms for molecular imaging.

Monte Carlo verification of polymer gel dosimetry applied to radionuclide therapy: a phantom study.

This study evaluates the dosimetric performance of the polymer gel dosimeter 'Methacrylic and Ascorbic acid in Gelatin, initiated by Copper' and its suitability for quality assurance and analysis of I-131-targeted radionuclide therapy dosimetry. Four batches of gel were manufactured in-house and sets of calibration vials and phantoms were created containing different concentrations of I-131-doped gel. Multiple dose measurements were made up to 700 h post preparation and compared to equivalent Monte Carlo simulations. In addition to uniformly filled phantoms the cross-dose distribution from a hot insert to a surrounding phantom was measured. In this example comparisons were made with both Monte Carlo and a clinical scintigraphic dosimetry method. Dose-response curves generated from the calibration data followed a sigmoid function. The gels appeared to be stable over many weeks of internal irradiation with a delay in gel response observed at 29 h post preparation. This was attributed to chemical inhibitors and slow reaction rates of long-chain radical species. For this reason, phantom measurements were only made after 190 h of irradiation. For uniformly filled phantoms of I-131 the accuracy of dose measurements agreed to within 10% when compared to Monte Carlo simulations. A radial cross-dose distribution measured using the gel dosimeter compared well to that calculated with Monte Carlo. Small inhomogeneities were observed in the dosimeter attributed to non-uniform mixing of monomer during preparation. However, they were not detrimental to this study where the quantitative accuracy and spatial resolution of polymer gel dosimetry were far superior to that calculated using scintigraphy. The difference between Monte Carlo and gel measurements was of the order of a few cGy, whilst with the scintigraphic method differences of up to 8 Gy were observed. A manipulation technique is also presented which allows 3D scintigraphic dosimetry measurements to be compared to polymer gel dosimetry measurements without generating misleading errors due to the limited spatial resolution.

The application of polymer gel dosimeters to dosimetry for targeted radionuclide therapy.

There is a lack of standardized methodology to perform dose calculations for targeted radionuclide therapy and at present no method exists to objectively evaluate the various approaches employed. The aim of the work described here was to investigate the practicality and accuracy of calibrating polymer gel dosimeters such that dose measurements resulting from complex activity distributions can be verified. Twelve vials of the polymer gel dosimeter, 'MAGIC', were uniformly mixed with varying concentrations of P-32 such that absorbed doses ranged from 0 to 30 Gy after a period of 360 h before being imaged on a magnetic resonance scanner. In addition, nine vials were prepared and irradiated using an external 6 MV x-ray beam. Magnetic resonance transverse relaxation time, T2, maps were obtained using a multi-echo spin echo sequence and converted to R2 maps (where T2 = 1/R2). Absorbed doses for P-32 irradiated gel were calculated according to the medical internal radiation dose schema using EGSnrc Monte Carlo simulations. Here the energy deposited in cylinders representing the irradiated vials was scored. A relationship between dose and R(2) was determined. Effects from oxygen contamination were present in the internally irradiated vials. An increase in O2 sensitivity over those gels irradiated externally was thought to be a result of the longer irradiation period. However, below the region of contamination dose response appeared homogenous. Due do a drop-off of dose at the periphery of the internally irradiated vials, magnetic resonance ringing artefacts were observed. The ringing did not greatly affect the accuracy of calibration, which was comparable for both methods. The largest errors in calculated dose originated from the initial activity measurements, and were approximately 10%. Measured R2 values ranged from 5-35 s(-1) with an average standard deviation of 1%. A clear relationship between R2 and dose was observed, with up to 40% increased sensitivity for internally irradiated gels. Curve fits to the calibration data followed a single exponential function. The correlation coefficients for internally and externally irradiated gels were 0.991 and 0.985, respectively. With the ability to accurately calibrate internally dosed polymer gels, this technology shows promise as a means to evaluate dosimetry methods, particularly in cases of non-uniform uptake of a radionuclide.

Streptococcus grouping latex kits: evaluation of five commercially available examples.

This study compares a recently introduced latex agglutination test for the serogrouping of beta-haemolytic streptococci against four internationally used commercial kits. The new kit is Prolex-Blue (Pro-Lab Diagnostics) and the comparators are Streptex (Murex), PathoDx (DPC), Streptococcus Grouping kit (Oxoid) and Prolex-White (Pro-Lab Diagnostics). A total of 302 consecutive clinical isolates are tested against all five kits, following the individual manufacturer's protocol, for both accuracy and speed. In addition, the data produced permits determination of the strengths or weaknesses of the kits against individual serotypes. Prolex-Blue proved to be both accurate and rapid, with a sensitivity of 99% and a specificity of 100%. Furthermore, average time to agglutination was substantially less than achieved by three of the other four kits evaluated.

Validation and application of verbal autopsies in a rural area of South Africa.

OBJECTIVE: To validate the causes of death determined with a single verbal autopsy instrument covering all age groups in the Agincourt subdistrict of rural South Africa. METHODS: Verbal autopsies (VAs) were conducted on all deaths recorded during annual demographic and health surveillance over a 3-year period (1992-95) in a population of about 63 000 people. Trained fieldworkers elicited signs and symptoms of the terminal illness from a close caregiver, using a comprehensive questionnaire written in the local language. Questionnaires were assessed blind by three clinicians who assigned a probable cause of death using a stepwise consensus process. Validation involved comparison of VA diagnoses with hospital reference diagnoses obtained for those who died in a district hospital; and calculation of sensitivity, specificity and positive predictive value (PPV) for children under 5 years, and adults 15 years and older. RESULTS: A total of 127 hospital diagnoses satisfied the criteria for inclusion as reference diagnoses. For communicable diseases, sensitivity of VA diagnoses among children was 69%, specificity 96%, and PPV 90%; among adults the values were 89, 93 and 76%. Lower values were found for non-communicable diseases: 75, 91 and 86% among children; and 64, 50 and 80% among adults. Most misclassification occurred within the category itself. For deaths due to accidents or violence, sensitivity was 100%, specificity 97%, and PPV 80% among children; and 75, 98 and 60% among adults. Since causes of death were largely age-specific, few differences in sensitivity, specificity and PPV were found for adults and children. The frequency distribution of causes of death based on VAs closely approximated that of the hospital records used for validation. CONCLUSION: VA findings need to be validated before they can be applied to district health planning. In Agincourt, a single verbal autopsy instrument provided a reasonable estimate of the frequency of causes of death among adults and children. Findings can be reliably used to inform local health planning and evaluation.

Causes of death in a rural area of South Africa: an international perspective.

The study compares the cause of death profile in a rural area of South Africa (Agincourt), with that in a rural area of West Africa (Niakhar), and in a developed country with the same life expectancy (France, 1951) in order to determine causes with high and low mortality and priorities for future health interventions. In the two African sites, causes of death were assessed by verbal autopsies, whereas they were derived from regular cause of death registration in France. Age-standardized death rates were used to compare cause-specific mortality in the three studies. Life expectancy in Agincourt was estimated at 66 years, similar to that of France in 1951, and much higher than that of Niakhar. Causes of death with outstandingly high mortality in Agincourt were violent deaths (homicide and suicide), accidents (road traffic accidents and household accidents), certain infectious diseases (HIV/AIDS, tuberculosis, diarrhea and dysentery), certain chronic diseases (cancer of genital organs, liver cirrhosis, gastrointestinal hemorrhage, maternal mortality, epilepsy, acute rheumatic fever, and pneumoconiosis) and malnutrition of young children (kwashiorkor). Causes of death with lower mortality than expected were primarily respiratory diseases (pneumonia, bronchitis, influenza, lung cancer), other cancers, vaccine preventable diseases (measles, whooping cough, tetanus), and marasmus. Verbal autopsies could be used in a rural area of a developing country without formal cause of death registration to identify the most salient health problems of the population, and could be compared with a formal cause of death registration system of a developed country.

The Agincourt demographic and health study--site description, baseline findings and implications.

OBJECTIVES: To present baseline results from first-phase demographic and health surveillance in the Agincourt field site, Bushbuckridge. To contrast findings with international data, and comment on their relevance to health development. DESIGN: Multi-round, prospective community-based study. Baseline census, 1992. SETTING: A subdistrict in South Africa's rural north-east, adjacent to the border with Mozambique. SUBJECTS: Entire population of the Agincourt subdistrict. OUTCOME MEASURES: Baseline variables for each resident included age, sex, months spent at home during 1991, mother alive/dead, highest educational standard achieved, and refugee status. A full demographic profile was constructed. RESULTS: In 1992 the subdistrict contained 57,609 persons, 26.4% of whom were Mozambican, with a population density of 148 persons per km2. Forty-four per cent were under 15 years of age, and the dependency ratio was 93%. Fertility was declining, along with a moderate decline in adult female mortality. The approximate total fertility rate was 4.0; teenage parenting was common and almost 40% of 19-year-olds had at least one child. Over 60% of men and 14% of women in the 30-49-year age group were migrants, resulting in a high proportion of single-parent households. Despite improvements, most children experienced delays in reaching primary school, and less than half made the transition to secondary school. Educational levels among Mozambican children were lower than those of local children. CONCLUSIONS: Agincourt contains a complex mix of communities comprising migrant workers, Mozambicans and a more stable permanent population. The area shares features with sub-Saharan Africa, although the mortality and fertility transitions have progressed further. Reliable, local information is essential for managing decentralised health systems.

Who dies from what? Determining cause of death in South Africa's rural north-east.

Information on cause of death is essential for rational public health planning, yet mortality data in South Africa is limited. In the Agincourt subdistrict, verbal autopsies (VA) have been used to determine cause of death. A VA is conducted on all deaths recorded during annual demographic and health surveillance. Trained lay fieldworkers interview a close caregiver to elicit signs and symptoms of the terminal illness. Each questionnaire is reviewed by three medical practitioners blind to each other's assessment, who assign a 'probable cause of death' where possible. Of 1001 deaths of adults and children identified between 1992 and 1995, 932 VAs were completed. The profile of deaths reflects a mixed picture: the 'unfinished agenda' of communicable disease and malnutrition (diarrhoea and kwashiorkor predominantly) are responsible for over half of deaths in under-fives, accidents are prominent in the 5-14 age-group, while the 'emerging agenda' of violence and chronic degenerative disease (particularly circulatory disease) is pronounced among the middle-aged and elderly. This profile shows the social and demographic transition to be well underway within a rural, underdeveloped population. Validation of VA findings demonstrate that the cause of death profile derived from VA can be used with confidence for planning purposes. Findings of note include the high death rates from kwashiorkor and violence, emerging AIDS and pulmonary tuberculosis, and circulatory deaths in the middle-aged and young elderly. A deeper understanding of the causal factors underlying these critical health problems is needed to strengthen policy and better target interventions.

Reversal in mortality trends: evidence from the Agincourt field site, South Africa, 1992-1995.

OBJECTIVE: To examine changes in mortality in rural South Africa over the period 1992-1995 by age, sex and cause of death. DESIGN: As with much of sub-Saharan Africa, South Africa lacks effective vital registration and information on mortality is lacking. The Agincourt demographic and health surveillance system was established to inform health policy and practice with regard to rural subdistrict populations. METHODS: Prospective community-based study involving annual update of a household census with enquiry into all birth, death and migration events. All reported deaths (n = 1001) are the subject of a verbal autopsy. RESULTS: An increasing trend in overall mortality relative to general population growth in the study area is apparent. There is evidence for a reversal in the previously declining trend in mortality among women 20-44 years. A comparison of 1992-1993 with 1994-1995 shows that most of the increase in mortality is concentrated in the younger adult (20-49 year) age group. AIDS and related diseases, particularly tuberculosis, appear primarily responsible. Injuries and violence (especially homicide) and circulatory disease are important, under-recognized causes of death, although their levels have remained constant over the period. CONCLUSIONS: Mortality from AIDS and related diseases appears responsible for the probable reversal in mortality emerging in South Africa's rural northeast. Findings carry implications for the emerging system of decentralized health care.

Establishing priorities for advocacy in South African Health.

PIP: To develop an appropriate health policy agenda, the National Progressive Primary Health Care Network (NPPHC) and the South African Health and Social Services Organization (SAHSSO) conducted situational analyses in 4 areas: an informal peri-urban area within the Durban functional region in Natal, a rural area in the Mhala-Mapulaneng district in the North Eastern Transvaal, the informal settlement of Botshabelo in the Orange Free State, and a dense township dwelling in Soweto. The analyses were based on interviews with health workers and community leaders, a national survey, and a questionnaire for health service administrators. All 4 areas were characterized by poverty, unemployment, low educational levels, lack of a clean water supply or refuse removal system, housing shortages or overcrowding, and political violence. Preventable diseases, such as water-borne diarrhea and malnutrition, cause substantial morbidity, yet health services tend to be inaccessible, distributed inequitably, of poor quality, and with unclear administrative structures. Community members interviewed indicated that clinic fees were too high, especially given the low quality of care, and there was a general mistrust of the competency of doctors and nurses. There was a lack of consensus on the meaning of community participation; some viewed it as a vehicle for empowerment, while others felt the strategy would be exploited as a means to deny government assistance. Overall, respondents were supportive of a greater role for community health workers and more involvement on the part of nongovernmental organizations. A priority, at present, is attention to the many socioeconomic factors that are compromising the health of black South Africans and overshadowing the rationalization of health services.^ieng

Protein energy malnutrition and its recognition in outpatient departments in Venda hospitals.

Between April and June 1988 the number of children under 5 years old attending outpatient departments of Venda hospitals who had protein energy malnutrition (PEM) was determined, the proportions at 3 Venda hospitals were compared, and what percentage of these children was detected by attendant health workers was determined. Approximately 6% had severe PEM; this finding was consistent for all 3 hospitals. The rates for mild PEM were 22% for Tshilidzini and Donald Fraser Hospitals and 33% for Siloam Hospital. This statistically significant difference has not been explained. Health workers failed to recognise about 25% of children with severe PEM and 50% of children with mild PEM. It is suggested that certain interventions and activities are essential if PEM is to be adequately managed: these are efficient monitoring; pre-employment and in-service education for health workers; a breast-feeding and weaning survey; and an investigation of the variation of malnutrition among Venda hospitals.

Child health in farm workers' communities.

Black women who had borne one or more children in the 5 years preceding the study and who were resident on white-owned farms were sampled in a multistage cluster procedure from the population of two magisterial districts of the southern Transvaal, Ventersdorp and Balfour. The purpose of this study was to determine mothers' knowledge and behaviour regarding the health of their children, to correlate this with personal and social characteristics of the mothers, and to document aspects of their physical environment. Only 50% of mothers had completed 4 or more years of formal education. One in three had experienced the death of at least 1 of her children. Water and sanitation facilities were inadequate for most. Little was known about oral rehydration solution preparation or about growth monitoring. Most children were breast-fed. Between 50% and 63% of the children had vaccinations appropriate for their ages, depending on whether evidence from clinic cards or from mothers' memories was taken as valid. The single most important determinant of the appropriate knowledge and behaviour of mothers was education. Basic living and social conditions of farm workers require improvement and the health services must be re-orientated to deliver comprehensive primary care.

Kawasaki disease manifesting with acute cholangitis. A case report.

A 3-year-old boy, who developed the signs and symptoms characteristic of Kawasaki disease, is described. The child also had an 8 cm tender hepatomegaly. Hydrops of the gallbladder could not be shown. Liver biopsy showed marked infiltration of inflammatory cells, including neutrophil and eosinophil leucocytes in the portal tracts involving the periphery of the portal arteries and veins, and acute inflammation of the bile ducts with neutrophil and eosinophil infiltration of the walls. Overt cholangitis has been described only once before in Kawasaki disease, when a viral agent was suggested as being important in the pathogenesis. Although the clinical and laboratory findings in cases of Kawasaki disease clearly suggest an acute infection--as they did in this case--no aetiological agent has yet been incriminated. The possibility of a drug-induced auto-allergic or hypersensitivity state is considered. Evidence for such a state includes a history of drug administration, pathological findings similar to peri-arteritis nodosa--a condition often associated with a hypersensitivity state--the presence of eosinophils in the lesions and a response to treatment with aspirin, a drug known to ameliorate hypersensitivity states.

Immunological disorders--the evolution of an hypothesis.

In honouring the memory of Dr Alwyn Zoutendyk, a respected member of the staff of the South African Institute for Medical Research, attention is called to the studies of the immunological disorders. While investigating serum hepatitis affecting soldiers of the US army following the administration of yellow fever vaccine, an antigen similar to that later called the Australia antigen, now hepatitis B surface antigen, was found in the acute phase serum and the corresponding antibody was found in convalescence. This finding and subsequent studies suggested there was a group of disease, which we called the hyperreactive auto-allergic disorders, of which examples were to be found in every system. The obverse of these we called the hyporeactive immunologically deficient disorders resulting from defects of the cell or serum components of the immunological reactions, of which many examples have also been found.

Botshabelo's vaccination survey.

This community-based survey evaluates vaccination coverage of small children and socio-economic status of their households in a randomly selected sample of a black South African township. It reveals a poverty-stricken community, where only 19% of the children surveyed were fully vaccinated. It is suggested that expansion of health infrastructures together with a co-ordinated strategy of immunisation would result in a spectacular increase in vaccination coverage.