Advances in External Beam Radiation Therapy and Brachytherapy for Cervical Cancer.

The standard of care for the definitive treatment of locoregionally advanced cervical cancer is external beam radiation therapy (EBRT) with concurrent chemotherapy followed by a brachytherapy boost. Historically, EBRT was delivered via a two-dimensional technique based primarily on bony landmarks. This gave way to three-dimensional conformal radiation therapy, which allows for dose calculation and adjustment based on individual tumour and patient anatomy. Further technological advances have established intensity-modulated radiation therapy (IMRT) as a standard treatment modality, given the ability to maintain tumoricidal doses to target volumes while reducing unwanted radiation dose to nearby critical structures, thereby reducing toxicity. Routine image guidance allows for increased confidence in patient alignment prior to treatment, and the ability to visualise the daily position of the targets and organs at risk has been instrumental in allowing safe reductions in treated volumes. Additional EBRT technologies, including proton therapy and stereotactic body radiation therapy, may further improve the therapeutic index. In the realm of brachytherapy, a shift from point-based dose planning to image-guided brachytherapy has been associated with improved local control and reduced toxicity, with additional refinement ongoing. Here we will discuss these advances, the supporting data and future directions.

Motor function in children with congenital Zika syndrome.

AIM: To evaluate gross motor function and associated factors in children with congenital Zika syndrome (CZS). METHOD: Fifty-nine children (30 males, 29 females) with CZS at a mean (SD) age of 14.7 (3.9), months (range 5-29mo) were evaluated using the Gross Motor Function Measure (GMFM) and classified according to the Gross Motor Function Classification System (GMFCS). Neurological damage was evaluated by neuroimaging. The mothers' sociodemographic characteristics and general data on the children were obtained from interviews with the mothers and from the children's medical records. Correlational and multiple regression analyses were performed to identify factors associated with these children's motor function. RESULTS: In 81% of the children, motor function impairment was severe, classified as GMFCS level V. The overall GMFM score ranged from 5 to 210 (median 18; interquartile range 11), with only four children receiving scores in the D and E dimensions. The factors found to affect motor function were the presence of severe malformations of cortical development and small head circumference at birth. INTERPRETATION: Although motor impairment may be mild in some children, it is generally severe. Severe malformations of cortical development and small head circumference at birth were factors associated with poorer motor function, reflecting the greater severity of brain damage. WHAT THIS PAPER ADDS: Motor impairment is severe in most children with congenital Zika syndrome (CZS). Motor skills are adequate or close to adequate for age in 7% of children with CZS. Severe malformations of cortical development are associated with poor motor control. Small head circumference at birth is also associated with poor motor control.

FUNCIÓN MOTORA EN NIÑOS CON SÍNDROME DE ZIKA CONGÉNITO: OBJETIVO: Evaluar la función motora gruesa y los factores asociados en niños con síndrome de Zika congénito (CZS). MÉTODO: Cincuenta y nueve niños (30 varones, 29 mujeres) con CZS a una edad media (DE) de 14,7 (3,9), meses (rango 5-29 meses) se evaluaron utilizando la Medida de la función motora gruesa (GMFM) y se clasificaron de acuerdo con el Sistema de Clasificación de la Función Motora Gruesa (GMFCS). El impacto estructural neurológico se evaluó mediante neuroimagen. Las características sociodemográficas de las madres y los datos generales de los niños se obtuvieron en entrevistas con las madres y de los registros médicos de los niños. Se realizaron análisis de regresión correlacional y múltiple para identificar los factores asociados con la función motora de estos niños. RESULTADOS: En el 81% de los niños, el deterioro de la función motora fue grave, clasificado como nivel V de GMFCS. El puntaje general de GMFM varió de 5 a 210 (mediana 18; rango intercuartil 11), y solo cuatro niños recibieron puntajes en las dimensiones D y E. Los factores que afectaron la función motora fueron la presencia de malformaciones graves del desarrollo cortical y la circunferencia de la cabeza (microcefalia) al nacer. INTERPRETACIÓN: Aunque el deterioro motor puede ser leve en algunos niños, generalmente el impacto de CZS es grave. Las malformaciones graves del desarrollo cortical y la microcefalia al nacer fueron factores asociados con una función motora más limitada, lo que refleja la mayor gravedad del daño cerebral.

FUNÇÃO MOTORA EM CRIANÇAS COM SÍNDROME CONGÊNITA DE ZIKA: OBJETIVO: Avaliar a função motora grossa e fatores associados em crianças com síndrome congênita de Zika (SCZ). MÉTODO: Cinquenta e nove crianas (30 do sexo masculino, 29 do sexo feminino) com SCZ com uma média (DP) de idade de 14,7 (3,9) meses (variação 5-29m) foram avaliadas usando a Medida da Função Motora Grossa (GMFM) e classificadas de acordo com o Sistema de Classificação da Função Motora Grossa (GMFCS). O dano neurológico foi avaliado por neuroimagem. As características sócio-demográficas da mãe e dados gerais sobre as crianças foram obtidos em entrevistas com as mães e a partir dos prontuários medicos. Análises de correlação e de regressão múltipla foram realizadas para identificar fatores associados com a função motora destas crianças. RESULTADOS: Em 81% das crianças, o comprometimento da função motora era severo, classificao como nível GMFCS V. O escore geral da GMFM various de 5 a 210 (mediana 18; intervalo interquartil 11), com apenas quatro crianças recebendo pontuações nas dimensões D e E. Os fatores que afetaram a função motora grossa foram a presença de malformações severas no desenvolvimento cortical, e o pequeno perímetro cefálico ao nascimento. INTERPRETAÇÃO: Embora a deficiência motora possa ser leve em algumas crianças, em geral ela é severa. Malformações severas no desenvolvimento cortical e o pequeno perímetro cefálico foram fatores associados com pior função motora, refletindo a maior severidade do dano cerebral.

Successful community-based laboratory services program for long-term care facilities, Part 2.

Hagerstown Medical Laboratory, Inc., located in Hagerstown, Maryland, has an outreach program that currently provides laboratory services to 52 long-term care facilities. Part 1 of this series, published in the May/June 2001 issue of Clinical Leadership & Management Review, discussed general organization, staffing, and safety issues for their Nursing Home Program. Part 2 relates their experience with contracts, fees, and reimbursement.

Utilization and cost of health care services for children with attention-deficit/hyperactivity disorder.

BACKGROUND: Despite an increasing prevalence of diagnosed attention-deficit/hyperactivity disorder (ADHD) among children, the impact of ADHD on utilization and costs of health care services is largely unknown. OBJECTIVE: To examine differences in health care utilization and costs between children with and without ADHD. DESIGN: Retrospective matched cohort study conducted from January 1 to December 31, 1997. Setting. Health maintenance organization in western Washington State. PARTICIPANTS: Children aged 3 through 17 years who were continuously enrolled in the health maintenance organization and used services during 1997 were eligible. Children were identified with ADHD if they had a diagnosis of ADHD or a prescription for a stimulant medication using automated patient files. Children without ADHD were randomly selected as controls and matched 4:1 to children with ADHD on age and sex. OUTCOME MEASURE: Utilization and costs of specific categories of health care services. Results. A total of 2992 children (5.2%) were identified with ADHD. Children with ADHD incurred significantly greater per capita total costs ($1465 vs $690) than children without ADHD. Children with ADHD had 9.9 times more outpatient mental health visits (1.35/year vs 0.14/year), 3.4 times more pharmacy fills (11.25/year vs 3.30/year), and 1.6 times more primary care visits (3.84/year vs 2.36/year) than children without ADHD. The adjusted incremental costs were estimated to be $375 (95% confidence interval: $336-$416) for children with ADHD alone and $812 (95% confidence interval: $671-$973) for children with ADHD plus coexisting mental health disorders. CONCLUSIONS: Children with ADHD use significantly more health care resources and incur significantly higher costs than children without ADHD. Coexisting mental health disorders substantially increase the cost of treating ADHD. Resource allocation decisions should consider the contributions of primary care, outpatient mental health, and pharmacy costs to the overall costs of care for children with ADHD.

Successful community-based laboratory services program for long-term care facilities, Part 1.

Hagerstown Medical Laboratory, Inc. (HML) is a regional reference laboratory in Hagerstown, Maryland, that provides laboratory services to more than 50 long-term care facilities (LTCFs, or nursing homes) in Western Maryland and West Virginia. HML also operates the rapid response laboratory at Washington County Hospital and performs house calls for homebound or bedridden patients through its Nursing Home Program (NHP). This article relates HML's successful experience with an outreach program that provides laboratory services to LTCFs.

Impact of the change in polio vaccination schedule on immunization coverage rates: a study in two large health maintenance organizations.

OBJECTIVE: In January 1997, one of the most significant changes to United States vaccine policy occurred when polio immunization guidelines changed to recommend a schedule containing inactivated polio vaccine (IPV). There were concerns that parent or physician reluctance to accept IPV into the routine childhood immunization schedule would lead to lowered coverage. We determined whether adoption of an IPV schedule had a negative impact on immunization coverage. DESIGN: A cohort study of 2 large health maintenance organizations (HMOs), Group Health Cooperative and Kaiser Permanente Northern California, was conducted. For analysis at 12 months of age, children who were born between October 1, 1996, and December 31, 1997, and were commercially insured and covered by Medicaid were continuously enrolled; for analysis at 24 months of age, children who were born between October 1, 1996, and June 30, 1997, and were commercially insured and covered by Medicaid were continuously enrolled. The 3 measures of immunization status at 12 and 24 months of age were up-to-date status, cumulative time spent up-to-date, and the number of missed opportunity visits. RESULTS: At both HMOs, children who received IPV were as likely to be up to date at 12 months as were children who received oral poliovirus vaccine (OPV), whereas at Group Health, children who received IPV were slightly more likely to be up to date at 24 months (relative risk: 1.12; 95% confidence interval [CI]: 1.05, 1.19). These findings were consistent for children who were covered by Medicaid. At Kaiser Permanente, children who received IPV spent ~3 fewer days up to date in the first year of life, but this difference did not persist at 2 years of age. At Group Health, children who received IPV were no different from those who received OPV in terms of days spent up to date by 1 or 2 years of age. At Group Health, children who received IPV were less likely to have a missed opportunity by 12 months old (odds ratio [OR] 0.46; 95% CI: 0.31, 0.70), but this finding did not persist at 24 months of age. At Kaiser Permanente, children who received IPV were more likely to have a missed opportunity by 12 months (OR 2.06; 95% CI: 1.84, 2.30), and 24 months of age (OR 1.50; 95% CI: 1.36, 1.67). CONCLUSIONS: The changeover from an all-OPV schedule to one containing IPV had little if any negative impact on vaccine coverage. Use of IPV was associated with a small increase in the likelihood of being up to date at 2 years of age at one of the HMOs and conversely was associated with a small increase in the likelihood of having a missed-opportunity visit in the other HMO.polio, poliomyelitis, vaccination, immunization coverage.

Variation in clinician recommendations for multiple injections during adoption of inactivated polio vaccine.

OBJECTIVES: To describe variation in clinician recommendations for multiple injections during the adoption of inactivated poliovirus vaccine (IPV) in 2 large health maintenance organizations (HMOs), and to test the hypothesis that variation in recommendations would be associated with variation in immunization coverage rates. DESIGN: Cross-sectional study based on a survey of clinician practices 1 year after IPV was recommended and computerized immunization data from these clinicians' patients. STUDY SETTINGS: Two large West Coast HMOs: Kaiser Permanente in Northern California and Group Health Cooperative of Puget Sound. OUTCOME MEASURES: Immunization status of 8-month-olds and 24-month-olds cared for by the clinicians during the study. RESULTS: More clinicians at Group Health (82%), where a central guideline was issued, had adopted the IPV/oral poliovirus vaccine (OPV) sequential schedule than at Kaiser (65%), where no central guideline was issued. Clinicians at both HMOs said that if multiple injections fell due at a visit and they elected to defer some vaccines, they would be most likely to defer the hepatitis B vaccine (HBV) for infants (40%). At Kaiser, IPV users were more likely than OPV users to recommend the first HBV at birth (64% vs 28%) or if they did not, to defer the third HBV to 8 months or later (62% vs 39%). In multivariate analyses, patients whose clinicians used IPV were as likely to be fully immunized at 8 months old as those whose clinicians used all OPV. At Kaiser, where there was variability in the maximum number of injections clinicians recommended at infant visits, providers who routinely recommended 3 or 4 injections at a visit had similar immunization coverage rates as those who recommended 1 or 2. At both HMOs, clinicians who strongly recommended all possible injections at a visit had higher immunization coverage rates at 8 months than those who offered parents the choice of deferring some vaccines to a subsequent visit (at Kaiser, odds ratio [OR]: 1.2; 95% confidence interval [CI]: 1.0-1.5; at Group Health, OR: 1.8; 95% CI: 1.1-2.8). CONCLUSIONS: Neither IPV adoption nor the use of multiple injections at infant visits were associated with reductions in immunization coverage. However, at the HMO without centralized immunization guidelines, IPV adoption was associated with changes in the timing of the first and third HBV. Clinical policymakers should continue to monitor practice variation as future vaccines are added to the infant immunization schedule.

Association of lower continuity of care with greater risk of emergency department use and hospitalization in children.

CONTEXT: The benefits of continuity of pediatric care remain controversial. OBJECTIVE: To determine whether there is an association between having a continuous relationship with a primary care pediatric provider and decreased risk of emergency department (ED) visitation and hospitalization. DESIGN: Retrospective cohort study. Setting and Population. We used claims data from 46 097 pediatric patients enrolled at Group Health Cooperative, a large staff-model health maintenance organization, between January 1, 1993, and December 31, 1998, for our analysis. To be eligible, patients had to have been continuously enrolled for at least a 2-year period or since birth and to have made at least 4 visits to one of the Group Health Cooperative clinics. MAIN EXPOSURE VARIABLE: A continuity of care (COC) index that quantifies the degree to which a patient has experienced continuous care with a provider. MAIN OUTCOME MEASURES: ED utilization and hospitalization. RESULTS: Compared with children with the highest COC, children with medium continuity were more likely to have visited the ED (hazard ratio [HR]: 1.28 [1.20-1.36]) and more likely to be hospitalized (HR: 1.22 [1.09-1.38]). Children with the lowest COC were even more likely to have visited the ED (HR: 1.58 [1.49-1.66]) and to be hospitalized (HR: 1.54 [1.33-1.75]). These risks were even greater for children on Medicaid and those with asthma. CONCLUSIONS: Lower continuity of primary care is associated with higher risk of ED utilization and hospitalization. Efforts to improve and maintain continuity may be warranted.

The association between greater continuity of care and timely measles-mumps-rubella vaccination.

OBJECTIVES: This study assessed whether greater continuity of care is associated with timely administration of measles-mumps-rubella (MMR) vaccination. METHODS: We studied 11,233 patients continuously enrolled in Group Health Cooperative (GHC) from birth to 15 months. We used a preestablished index to quantify continuity of care based on the number of primary care providers in relation to the number of clinic visits. MMR vaccination status at 15 months was assessed with automated immunization data systems at GHC. RESULTS: In a logistic regression model, both medium continuity (odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.08, 1.33) and high continuity (OR = 1.36, 95% CI = 1.22, 1.52) were associated with increased likelihood of being immunized by 15 months compared with patients in the lowest tercile of continuity of care. CONCLUSION: Greater continuity of care is associated with more timely immunization.

Validity testing of commercial urine cocaine metabolite assays: I. Assay detection times, individual excretion patterns, and kinetics after cocaine administration to humans.

A validity study of eight commercial urine assays for detection of cocaine metabolite was performed on clinical specimens collected from human subjects who received single 20-mg intravenous doses of cocaine hydrochloride. The specimens were collected under controlled conditions and analyzed in random order under blind conditions. Benzoylecgonine concentration in each specimen also was determined by gas chromatography/mass spectrometry (GC/MS). Mean times of detection of the last positive specimen (greater than or equal to 300 ng/mL of benzoylecgonine equivalents) after cocaine administration varied among seven of the commercial tests from 16.9 to 52.9 h in the following ascending order: Toxi-Lab less than TDx = EMIT dau = EMIT st less than Abuscreen less than Coat-A-Count = Double Antibody. In contrast, a commercial spot test (KDI Quik Test) which was evaluated for detection of cocaine metabolite produced both false positives and false negatives for benzoylecgonine and was not considered to be a valid test for detection of cocaine metabolite. Half-lives of excretion of benzoylecgonine among four subjects varied from 5.9 to 7.9 h, and overall recovery of benzoylecgonine varied from 15.0 to 34.3% of the administered dose of cocaine.

Gas chromatography/electron impact mass fragmentometric determination of urinary 6-acetylmorphine, a metabolite of heroin.

A procedure for detection and quantification of urinary 6-acetylmorphine (6-AM), a metabolite of heroin, is described. After initial solvent extraction from urine, the 6-AM was purified either by acid-base liquid-liquid extraction or by solid-phase extraction techniques. The 6-AM was then derivatized to its propionyl ester, which was characterized by gas chromatography/mass spectrometry in the electron impact mode. Confirmation of 6-AM was accomplished by comparing retention times and relative abundances of selected ions with that of a standard. Quantification was based on 6-[2H3]acetyl-N-[2H3]methylnormophine (6-[2H6]AM) as internal standard. Excellent linearity was obtained in the concentration range 1-100 ng/mL. The overall yield after solvent extraction and acid-base purification ranged from 79 to 82%; for solvent extraction and solid-phase purification, it was 92 to 95%. The limit of detection was 810 pg/mL. Within-run and between-run CVs for 6-AM at concentrations in the range 1-100 ng/mL were generally less than 5% and less than 10%, respectively.

Marijuana-laced brownies: behavioral effects, physiologic effects, and urinalysis in humans following ingestion.

Five drug-free male subjects ingested marijuana-laced brownies in a double-blind crossover study designed to test for behavioral effects, physiologic effects, and urinary cannabinoid metabolites produced as a result of consumption of marijuana plant material cooked in foodstuff. On three separate occasions, each subject consumed two brownies which contained 1.6 g of marijuana plant material. Placebo marijuana plant material (0% THC) was mixed with marijuana plant material (2.8% THC) so that each subject ingested equivalent marijuana plant material of 0, 1, and 2 marijuana cigarettes (2.8% THC). Subjects scored significantly higher on behavioral measures after consumption of brownies containing THC than with placebo; however, the effects were slow to appear and variable. Peak effects occurred 2.5 to 3.5 h after dosing. Modest changes in pulse and blood pressure also were noted. Urinalyses by EMIT d.a.u. assay and Abuscreen RIA for cannabinoids and GC/MS assay for THCCOOH indicated that substantial amounts of marijuana-related metabolites were excreted over a period of 3 to 14 days. No positives were produced as a result of ingestion of placebo brownies.

GC/MS analysis of phencyclidine acid metabolite in human urine.

Available methods for determining PCP use are based on the presence of the parent drug in urine. PCP, however, is very potent and is extensively metabolized; it is therefore present in urine in only small quantities. This work was undertaken to determine whether an amino acid metabolite of PCP, 5-(N-(1'-phenylcyclohexyl)amino)pentanoic acid, can be used to determine PCP use. A solid phase adsorption technique was developed to extract the amino acid metabolite from urine. Recovery averaged 93%, and subsequent GC/MS analysis was free from interference. Analysis of 67 urine samples demonstrated that the amino acid metabolite exists in human urine in significant quantities.

Outward transcutaneous chemical migration: implications for diagnostics and dosimetry.

Chemical substances migrate outwards from within the body to the skin surface by diffusion from cutaneous capillaries across the epidermis. Heretofore, study of transepidermal chemical emissions have been restricted to substances which are in the vapor phase at skin surface temperature. We have investigated outward transcutaneous chemical migration of nongaseous chemicals by devising an occlusive transcutaneous chemical collection system, consisting of a tape-encased plug of gelled saline in which activated carbon is dispersed. Investigations of nine chemicals in 'fuzzy' rats, rhesus monkeys, and man provide data which are consistent with a general theory of outward transcutaneous chemical migration. This noninvasive continuous transcutaneous sampling technique provides a new method for investigating skin permeability in vivo and may provide a basis for convenient diagnosis and monitoring of chemical exposure.

Passive inhalation of marijuana smoke: urinalysis and room air levels of delta-9-tetrahydrocannabinol.

In two separate studies, 5 drug-free male volunteers with a history of marijuana use were passively exposed to the sidestream smoke of 4 and 16 marijuana cigarettes (2.8% delta-9-tetrahydrocannabinol [THC]) for 1 h each day for 6 consecutive days. A third study was similarly performed with 2 marijuana-naive subjects passively exposed to the smoke of 16 marijuana cigarettes. Passive smoke exposure was conducted in a small, unventilated room. Room air levels of THC and CO were monitored frequently. All urine specimens were collected and analyzed by EMIT d.a.u. assay, Abuscreen radioimmunoassay and GC/MS. The studies show that significant amounts of THC were absorbed by all subjects at the higher level of passive smoke exposure (eg., smoke from 16 marijuana cigarettes), resulting in urinary excretion of significant amounts of cannabinoid metabolites. However, it seems improbable that subjects would unknowingly tolerate the noxious smoke conditions produced by this exposure. At the lower level of passive marijuana-smoke exposure, specimens tested positive only infrequently or were negative. Room air levels of THC during passive smoke exposure appeared to be the most critical factor in determining whether a subject produced cannabinoid-positive urine specimens.

Detection and quantitation of urinary 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid, a metabolite of tetrahydrocannabinol, by capillary gas chromatography and electron impact mass fragmentography.

A procedure for detection and quantitation of 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid, a major metabolite of delta-9-tetrahydrocannabinol in urine, has been described. Since the metabolite is present in both conjugated and unconjugated forms, hydrolysis of urine was carried out to increase the sensitivity of detection. The acidic metabolite was isolated by strongly basic anion exchange resin, and subsequently derivatized to methyl 1-dehydroxy-1-methoxy-11-nor-delta-9-tetrahydrocannabinol-9-carbox ylate (1a) by methyliodide in the presence of tetramethylammonium hydroxide. The derivatized product was separated in a capillary column gas chromatograph, and finally detected by a mass spectrometer under electron impact mode. Confirmation of the product was carried out by monitoring three ions that represent the major portions of the molecule and comparing their relative abundances to that of a standard. Quantitation was based on 5'-2H3-11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid as internal standard. Excellent linearity was obtained over the range of 2 to 1000 ng/mL. The overall yield of extraction using the anion exchange resin was 50 to 60%. This extraction process is rapid and suitable for a large number of sample analyses. The methylated product (1a) is stable for at least 72 hr at room temperature.

Simultaneous identification and quantitation of codeine and morphine in urine by capillary gas chromatography and mass spectroscopy.

An analytical procedure for simultaneous determination of codeine and morphine in urine is described. The detection of codeine and morphine is based on liquid-liquid extraction and derivatization to the acetylated compounds. The acetylated codeine and morphine are separated by capillary gas chromatography and identified mass spectrometrically by selected ion monitoring (SIM). Quantitative determination was carried out by SIM using nalorphine as internal standard. Excellent linearity was obtained over a concentration range of 25 to 800 ng/mL. The overall recovery for codeine and morphine in the extraction was found to be 58% and 40%, respectively. The on-column sensitivity for both compounds was 2 ng at a peak-to-noise ratio of 5:1. The derivatives, acetylcodeine, diacetylmorphine, and diacetylnalorphine were stable at room temperature for 72 hr.