Maternal pre-pregnancy body mass index and risk of preterm birth: a collaboration using large routine health datasets.

BACKGROUND: Preterm birth (PTB) is a leading cause of child morbidity and mortality. Evidence suggests an increased risk with both maternal underweight and obesity, with some studies suggesting underweight might be a greater factor in spontaneous PTB (SPTB) and that the relationship might vary by parity. Previous studies have largely explored established body mass index (BMI) categories. Our aim was to compare associations of maternal pre-pregnancy BMI with any PTB, SPTB and medically indicated PTB (MPTB) among nulliparous and parous women across populations with differing characteristics, and to identify the optimal BMI with lowest risk for these outcomes. METHODS: We used three UK datasets, two USA datasets and one each from South Australia, Norway and Denmark, together including just under 29 million pregnancies resulting in a live birth or stillbirth after 24 completed weeks gestation. Fractional polynomial multivariable logistic regression was used to examine the relationship of maternal BMI with any PTB, SPTB and MPTB, among nulliparous and parous women separately. The results were combined using a random effects meta-analysis. The estimated BMI at which risk was lowest was calculated via differentiation and a 95% confidence interval (CI) obtained using bootstrapping. RESULTS: We found non-linear associations between BMI and all three outcomes, across all datasets. The adjusted risk of any PTB and MPTB was elevated at both low and high BMIs, whereas the risk of SPTB was increased at lower levels of BMI but remained low or increased only slightly with higher BMI. In the meta-analysed data, the lowest risk of any PTB was at a BMI of 22.5 kg/m2 (95% CI 21.5, 23.5) among nulliparous women and 25.9 kg/m2 (95% CI 24.1, 31.7) among multiparous women, with values of 20.4 kg/m2 (20.0, 21.1) and 22.2 kg/m2 (21.1, 24.3), respectively, for MPTB; for SPTB, the risk remained roughly largely constant above a BMI of around 25-30 kg/m2 regardless of parity. CONCLUSIONS: Consistency of findings across different populations, despite differences between them in terms of the time period covered, the BMI distribution, missing data and control for key confounders, suggests that severe under- and overweight may play a role in PTB risk.

Elective labor induction vs expectant management of pregnant women at term and children's educational outcomes at 8 years of age.

OBJECTIVE: To estimate the effect of elective induction of labor at 39 weeks' gestation on children's educational outcomes as measured using the Australian National Assessment Program-Literacy and Numeracy (NAPLAN) tests in school year 3 (∼8 years of age), compared with expectant management. METHODS: We merged perinatal data on all infants born in South Australia from 1999 to 2008 with children's school assessment data from NAPLAN. The study population included all singleton infants born without a malformation at 39-42 weeks in vertex presentation. Children who had undertaken the NAPLAN test in school year 3 were included. We excluded births to women who had a contraindication to vaginal delivery and those with a condition possibly justifying elective delivery before 39 weeks. The outcome of interest was children's educational outcome as measured using NAPLAN, which includes five learning domains (reading, writing, spelling, grammar and numeracy). Each domain was categorized according to performance at or below vs above the national minimum standard (NMS). Average treatment effects (ATEs) of elective induction of labor at 39 weeks compared with expectant management on the proportion of children performing at/below the NMS for each domain were estimated using the augmented inverse-propensity-weighted estimator, accounting for potential confounders. RESULTS: Of 53 843 children born at 39-42 weeks in vertex presentation from 1999 to 2008 and who were expected to participate in the year-3 NAPLAN from 2008 to 2015, a total of 31 120 had at least one year-3 NAPLAN domain. Of these, 1353 children were delivered after elective induction of labor at 39 weeks while 29 767 children were born following expectant management. The ATEs (mean differences) of elective induction of labor at 39 weeks compared with expectant management on the proportion of children scoring at/below the NMS on each domain were 0.01 (95% CI, -0.02 to 0.03) for reading, 0.02 (95% CI, 0.00-0.04) for writing, 0.01 (95% CI, -0.01 to 0.04) for spelling, 0.02 (95% CI, -0.01 to 0.04) for grammar and 0.03 (95% CI, 0.00-0.05) for numeracy. CONCLUSION: Elective induction of labor at 39 weeks did not affect children's standardized literacy and numeracy testing outcomes at 8 years of age when compared with expectant management. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

A whole-of-population study of term and post-term gestational age at birth and children's development.

OBJECTIVE: To examine the risk of poor child development according to week of gestation at birth, among children born ≥ 37 weeks' gestation. DESIGN: Population-based study using linked data (n = 12,601). SETTING: South Australia. POPULATION: All births ≥ 37 weeks' gestation. METHODS: Relative risks of developmental vulnerability for each week of gestation were calculated with adjustment for confounders and addressing missing information. MAIN OUTCOME MEASURES: Child development was documented by teachers during a national census of children attending their first year of school in 2009, using the Australian Early Development Index (AEDI). Children scoring in the lowest 10% of the AEDI were categorised as developmentally vulnerable. RESULTS: The percentage of children vulnerable on one or more AEDI domains for the following gestational ages 37, 38, 39, 40, 41, 42-45 weeks was 24.8, 22.3, 20.6, 20.0, 20.4 and 24.2, respectively. Compared with children born at 40 weeks, the adjusted relative risks [(95% confidence interval (CI)] for vulnerability on ≥ 1 AEDI domain were; 37 weeks 1.13 (0.99-1.28), 38 weeks 1.05 (0.96-1.15), 39 weeks 1.02 (0.94-1.12), 41 weeks 1.00 (0.90-1.11) and 42-45 weeks 1.20 (0.84-1.72). CONCLUSIONS: Children born at 40-41 weeks' gestation may have the lowest risk of developmental vulnerability at school entry, reinforcing the importance of term birth in perinatal care. Early term or post-term gestational age at birth can help clinicians, teachers and parents recognise children with potential developmental vulnerabilities at school entry.

Are trajectories of self-regulation abilities from ages 2-3 to 6-7 associated with academic achievement in the early school years?

BACKGROUND: The aim of this study was to estimate the association between two key aspects of self-regulation, 'task attentiveness' and 'emotional regulation' assessed from ages 2-3 to 6-7 years, and academic achievement when children were aged 6-7 years. METHODS: Participants (n = 3410) were children in the Longitudinal Study of Australian Children. Parents rated children's task attentiveness and emotional regulation abilities when children were aged 2-3, 4-5 and 6-7. Academic achievement was assessed using the Academic Rating Scale completed by teachers. Linear regression models were used to estimate the association between developmental trajectories (i.e. rate of change per year) of task attentiveness and emotional regulation, and academic achievement at 6-7 years. RESULTS: Improvements in task attentiveness between 2-3 and 6-7 years, adjusted for baseline levels of task attentiveness, child and family confounders, and children's receptive vocabulary and non-verbal reasoning skills at age 6-7 were associated with greater teacher-rated literacy [B = 0.05, 95% confidence interval (CI) = 0.04-0.06] and maths achievement (B = 0.04, 95% CI = 0.03-0.06) at 6-7 years. Improvements in emotional regulation, adjusting for baseline levels and covariates, were also associated with better teacher-rated literacy (B = 0.02, 95% CI = 0.01-0.04) but not with maths achievement (B = 0.01, 95% CI = -0.01-0.02) at 6-7 years. For literacy, improvements in task attentiveness had a stronger association with achievement at 6-7 years than improvements in emotional regulation. CONCLUSIONS: Our study shows that improved trajectories of task attentiveness from ages 2-3 to 6-7 years are associated with improved literacy and maths achievement during the early school years. Trajectories of improving emotional regulation showed smaller effects on academic outcomes. Results suggest that interventions that improve task attentiveness when children are aged 2-3 to 6-7 years have the potential to improve literacy and maths achievement during the early school years.

A missense mutation in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor in the spasmodic mouse.

Hereditary hyperekplexia, an autosomal dominant neurologic disorder characterized by an exaggerated startle reflex and neonatal hypertonia, can be caused by mutations in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor (GLRA1). Spasmodic (spd), a recessive neurologic mouse mutant, resembles hyperekplexia phenotypically, and the two disease loci map to homologous chromosomal regions. Here we describe a Glra1 missense mutation in spd that results in reduced agonist sensitivity in glycine receptors expressed in vitro. We conclude that spd is a murine homologue of hyperekplexia and that mutations in GLRA1/Glra1 can produce syndromes with different inheritance patterns.

Does an early childhood intervention affect cardiometabolic risk in adulthood? Evidence from a longitudinal study of preschool attendance in South Australia.

OBJECTIVES: There is an expectation that a positive social, cognitive and behavioural trajectory from early childhood developmental interventions will lead to improved population health and reduced health inequalities. However, there is limited direct evidence for this. The aim of this study was to assess the effect of participation in the South Australian Kindergarten Union preschool programme on adult cardiovascular biomedical risk factors. Kindergarten Union preschools delivered high-quality, comprehensive services to children aged 2-4 years and their families, including education, parenting and health services. STUDY DESIGN: Retrospective population-based cohort study. METHODS: The effect of attendance at a Kindergarten Union preschool on a range of cardiometabolic risk factors was assessed using data from the North West Adelaide Health Study 1999-2007. The study sample was taken from participants in the 2007 survey (n = 1064, 44.8% attended preschool) who lived in South Australia as children and were born during the years 1937-1969. RESULTS: Preschool attendance had a beneficial effect on hypertension in adulthood [prevalence ratio 0.82, 95% confidence interval (CI) 0.69-0.97] and an indication of benefit on hypercholesterolaemia (prevalence ratio 0.86, 95% CI 0.71-1.05), but had no effect on dyslipidaemia, central obesity, high fasting blood glucose or metabolic syndrome. CONCLUSIONS: This study found that preschool attendance was associated with reduced risk of hypertension in adulthood, but no effect was seen for the other cardiometabolic factors. These findings may reflect differing causal pathways and trajectories of these risk factors from childhood to adulthood, but confirmation from other studies is required.

Does attendance at preschool affect adult health? A systematic review.

BACKGROUND: Early child development interventions can set children on positive social and educational trajectories. The aim of this review was to examine the evidence for the adult health impacts of centre-based preschool interventions for preschoolers. METHODS: Medline, Embase, ERIC, Psych Info, Sociological Abstracts, the Cochrane Library, C2-SPECTR and the Head Start database were searched (1980-2008), and reference lists were searched for articles missed by the electronic search. RESULTS: The 12 eligible articles reviewed reported multi-faceted interventions and involved disadvantaged populations in all but one study. Limitations included a restricted range of health outcomes, reliance on self-report measures (11 studies), small sample sizes (nine studies with <100 in each arm) and a relatively young adult age at follow-up. There were positive intervention effects across the majority of behavioural outcomes, and a suggestion of a reduction in symptoms of depression. Non-communicable disease outcomes (e.g. diabetes mellitus) tended to have adverse or near-zero effect estimates. CONCLUSIONS: The reviewed articles provide some support for the role of early childhood interventions to improve health behaviours but not chronic disease outcomes. Population health researchers should become more involved in the evaluation of preschool interventions as there is great potential for broad population health benefit.

Mutation of an arginine residue in the human glycine receptor transforms beta-alanine and taurine from agonists into competitive antagonists.

Agonist binding to the inhibitory glycine receptor (GlyR) initiates the opening of a chloride-selective channel that modulates the neuronal membrane potential. Point mutations of the GlyR, substituting Arg-271 with either Leu or Gln, have been shown to underlie the inherited neurological disorder startle disease (hyperekplexia). We show that these substitutions result in the redistribution of GlyR single-channel conductances to lower conductance levels. Additionally, the binding of the glycinergic agonists beta-alanine and taurine to mutated GlyRs does not initiate a chloride current, but instead competitively antagonizes currents activated by glycine. These findings are consistent with mutations of Arg-271 resulting in the uncoupling of the agonist binding process from the channel activation mechanism of the receptor.

Cesarean birth is not associated with early childhood body mass index.

Cesarean birth leads to a markedly different microbiome compared to vaginal birth, and the microbiome has been implicated in childhood obesity. Among mothers who had a previous cesarean, we compared anthropometry of 3- to 6-year-old children who were subsequently born by cesarean section versus vaginal birth. This large population-based study involved linking de-identified administrative perinatal and anthropometric data. Children's weight and height were collected at community-based clinics and converted to age- and sex-adjusted z-scores of height-for-age (HFAz), weight-for-age (WFAz) and BMI-for-age (BMIz). The average treatment effect (ATE) of cesarean versus vaginal birth was calculated from augmented inverse probability weighted analyses accounting for a wide range of confounding variables. There was little evidence of an effect of cesarean birth on HFAz (ATE = 0.26 95%CI -0.35, 0.87, n = 3993), WFAz (ATE = 0.35, 95%CI -0.19, 0.89, n = 4817) or BMIz (ATE = 0.11, 95%CI -0.25, 0.46, n = 3909). Cesarean section was not associated with anthropometry among children aged 3-6 years.

The "Americanisation" of migrants: evidence for the contribution of ethnicity, social deprivation, lifestyle and life-course processes to the mid-20th century Coronary Heart Disease epidemic in the US.

We investigated the contribution of the large-scale immigration of White Europeans into the US between 1850 and 1930 to the timing and extent of the epidemic pattern of heart disease between 1900 and 1980. The analyses are based on data collected through the United States Federal Census from 1850 to the present. The hardcopy historical record confirms that census reports themselves and related monographs were concerned from 1850 with excessive mortality from heart disease of immigrants, particularly of Northern European origin and initially at least, their first-generation native-born children. Our analysis of the electronic database indicates a strong relationship between the percentage of US population foreign born and native born of foreign parentage and age adjusted mortality from heart disease. We identified a lag of 50 years giving the maximum linear correlation coefficient for men (r(2) = 0.92), and for women a shorter lag of 38 years and an earlier decline in Coronary Heart Disease (CHD) rates (r(2) = 0.96). Both the rise and fall of the CHD epidemic over an 80-year period correspond closely to the rise and fall of the foreign population in previous years. For the foreign born only, age adjusted negative binomial general estimated equation (GEE) models calculate the relative risk of dying of heart disease per 10% increase in proportion foreign born. There is an independent influence for men until 1930 and for women throughout the period from 1910 onwards. We conclude there is an impact of immigration on the pattern of the epidemic, mediated through a combination of factors, such as accumulated life-course susceptibility, deprived socio-economic conditions upon arrival, and the enthusiastic uptake of behaviours related to the classic risk factors of smoking, high saturated fat and salt diet. Our analysis provides a more contextualised understanding of the scale and timing of the epidemic of CHD in the US.

The surface accessibility of the glycine receptor M2-M3 loop is increased in the channel open state.

Mutations in the extracellular M2-M3 loop of the glycine receptor (GlyR) alpha1 subunit have been shown previously to affect channel gating. In this study, the substituted cysteine accessibility method was used to investigate whether a structural rearrangement of the M2-M3 loop accompanies GlyR activation. All residues from R271C to V277C were covalently modified by both positively charged methanethiosulfonate ethyltrimethylammonium (MTSET) and negatively charged methanethiosulfonate ethylsulfonate (MTSES), implying that these residues form an irregular surface loop. The MTSET modification rate of all residues from R271C to K276C was faster in the glycine-bound state than in the unliganded state. MTSES modification of A272C, L274C, and V277C was also faster in the glycine-bound state. These results demonstrate that the surface accessibility of the M2-M3 loop is increased as the channel transitions from the closed to the open state, implying that either the loop itself or an overlying domain moves during channel activation.

Properties of transient K+ currents and underlying single K+ channels in rat olfactory receptor neurons.

The transient potassium current, IK(t), of enzymatically dissociated rat olfactory receptor neurons was studied using patch-clamp techniques. Upon depolarization from negative holding potentials, IK(t) activated rapidly and then inactivated with a time course described by the sum of two exponential components with time constants of 22.4 and 143 ms. Single-channel analysis revealed a further small component with a time constant of several seconds. Steady-state inactivation was complete at -20 mV and completely removed at -80 mV (midpoint -45 mV). Activation was significant at -40 mV and appeared to reach a maximum conductance at +40 mV (midpoint -13 mV). Deactivation was described by the sum of two voltage-dependent exponential components. Recovery from inactivation was extraordinarily slow (50 s at -100 mV) and the underlying processes appeared complex. IK(t) was reduced by 4-aminopyridine and tetraethylammonium applied externally. Increasing the external K+ concentration ([K+]o) from 5 to 25 mM partially removed IK(t) inactivation, usually without affecting activation kinetics. The elevated [K+]o also hyperpolarized the steady-state inactivation curve by 9 mV and significantly depolarized the voltage dependence of activation. Single transient K+ channels, with conductances of 17 and 26 pS, were observed in excised patches and often appeared to be localized into large clusters. These channels were similar to IK(t) in their kinetic, pharmacological, and voltage-dependent properties and their inactivation was also subject to modulation by [K+]o. The properties of IK(t) imply a role in action potential repolarization and suggest it may also be important in modulating spike parameters during neuronal burst firing. A simple method is also presented to correct for errors in the measurement of whole-cell resistance (Ro) that can result when patch-clamping very small cells. The analysis revealed a mean corrected Ro of 26 G omega for these cells.

Cyclic nucleotide-gated channels of rat olfactory receptor cells: divalent cations control the sensitivity to cAMP.

cAMP-gated channels were studied in inside-out membrane patches excised from the apical cellular pole of isolated olfactory receptor cells of the rat. In the absence of divalent cations the dose-response curve of activation of patch current by cAMP had a KM of 4.0 microM at -50 mV and of 2.5 microM at +50 mV. However, addition of 0.2 or 0.5 mM Ca2+ shifted the KM of cAMP reversibly to the higher cAMP concentrations of 33 or 90 microM, respectively, at -50 mV. Among divalent cations, the relative potency for inducing cAMP affinity shifts was: Ca2+ > Sr2+ > Mn2+ > Ba2+ > Mg2+, of which Mg2+ (up to 3 mM) did not shift the KM at all. This potency sequence corresponds closely to that required for the activation of calmodulin. However, the Ca(2+)-sensitivity is lower than expected for a calmodulin-mediated action. Brief (60 s) transient exposure to 3 mM Mg2+, in the absence of other divalent cations, had a protective effect in that following washout of Mg2+, subsequent exposure to 0.2 mM Ca2+ no longer caused affinity shifts. This protection effect did not occur in intact cells and was probably a consequence of patch excision, possibly representing ablation of a regulatory protein from the channel cyclic nucleotide binding site. Thus, the binding of divalent cations, probably via a regulatory protein, controls the sensitivity of the cAMP-gated channels to cAMP. The influx of Ca2+ through these channels during the odorant response may rise to a sufficiently high concentration at the intracellular membrane surface to contribute to the desensitization of the odorant-induced response. The results also indicate that divalent cation effects on cyclic nucleotide-gated channels may depend on the sequence of pre-exposure to other divalent cations.

Properties of cyclic nucleotide-gated channels mediating olfactory transduction. Activation, selectivity, and blockage.

Cyclic nucleotide-gated channels (cng channels) in the sensory membrane of olfactory receptor cells, activated after the odorant-induced increase of cytosolic cAMP concentration, conduct the receptor current that elicits electrical excitation of the receptor neurons. We investigated properties of cng channels from frog and rat using inside-out and outside-out membrane patches excised from isolated olfactory receptor cells. Channels were activated by cAMP and cGMP with activation constants of 2.5-4.0 microM for cAMP and 1.0-1.8 for cGMP. Hill coefficients of dose-response curves were 1.4-1.8, indicating cooperativity of ligand binding. Selectivity for monovalent alkali cations and the Na/Li mole-fraction behavior identified the channel as a nonselective cation channel, having a cation-binding site of high field strength in the pore. Cytosolic pH effects suggest the presence of an additional titratable group which, when protonated, inhibits the cAMP-induced current with an apparent pK of 5.0-5.2. The pH effects were not voltage dependent. Several blockers of Ca2+ channels also blocked olfactory cng channels. Amiloride, D 600, and diltiazem inhibited the cAMP-induced current from the cytosolic side. Inhibition constants were voltage dependent with values of, respectively, 0.1, 0.3, and 1 mM at -60 mV, and 0.03, 0.02, and 0.2 mM at +60 mV. Our results suggest functional similarity between frog and rat cng channels, as well as marked differences to cng channels from photoreceptors and other tissues.

The glycine receptor.

The inhibitory glycine receptor (GlyR) is a member of the ligand-gated ion channel receptor superfamily. The GlyR comprises a pentameric complex that forms a chloride-selective transmembrane channel, which is predominantly expressed in the spinal cord and brain stem. We review the pharmacological and physiological properties of the GlyR and relate this information to more recent insights that have been obtained through the cloning and recombinant expression of the GlyR subunits. We also discuss insights into our understanding of GlyR structure and function that have been obtained by the genetic characterisation of various heritable disorders of glycinergic neurotransmission.

Weight gain and the risk of developing insulin resistance syndrome.

OBJECTIVE: Obesity and weight gain have been associated independently with hypertension, hyperinsulinemia, and dyslipidemia; however, prior research has not looked at the relation between weight gain from early adulthood to middle age and the development of this cluster of risk factors, known as insulin resistance syndrome. RESEARCH DESIGN AND METHODS: The association between weight gain over 30 years (defined as the difference between measured weight in middle age and participant recall of their weight at age 20) and the odds of developing insulin resistance syndrome at middle age was examined in a population-based sample of 2,272 eastern Finnish men. RESULTS: Each 5% increase in weight over the reported weight at age 20 was associated with nearly a 20% greater risk of insulin resistance syndrome by middle age, after adjustment for age and height. Moreover, there was a strong graded association between categories of weight gain and risk of insulin resistance syndrome. Men with weight increases of 10-19%, 20-29%, or > or =30% since age 20 were 3.0, 4.7, or 10.6 times more likely to have insulin resistance syndrome, respectively, by middle age, compared with men within 10% of their weight at age 20. Adjustments for age, height, physical activity, smoking, education, and parental history of diabetes did not alter these findings. CONCLUSIONS: The odds of having developed the hemodynamic and metabolic abnormalities that characterize insulin resistance syndrome by middle adulthood were increasingly higher the greater the weight gain over the preceding 30 years. This study adds to the literature identifying deleterious effects of weight gain from young to middle adulthood.

Stress-induced blood pressure reactivity and incident stroke in middle-aged men.

BACKGROUND AND PURPOSE: Exaggerated blood pressure reactivity to stress is associated with atherosclerosis and hypertension, which are known stroke risk factors, but its relation to stroke is unknown. Previous work also indicates that the association between reactivity and cardiovascular diseases may be influenced by socioeconomic status. METHODS: The impact of blood pressure reactivity and socioeconomic status on incident stroke was examined in 2303 men (mean age, 52.8+/-5.1 years) from a population-based, longitudinal study of risk factors for ischemic heart disease in eastern FINLAND: Reactivity was calculated as the difference between blood pressure measured during the anticipatory phase of an exercise tolerance test (before exercise) and resting blood pressure, measured 1 week earlier. Mean systolic reactivity was 20 mm Hg (+/-15.9), and mean diastolic reactivity was 8.6 mm Hg (+/-8.5). Socioeconomic status was assessed as years of education. One hundred thirteen incident strokes (90 ischemic) occurred in 11.2 (+/-1.6) years of follow-up. RESULTS: Men with exaggerated systolic reactivity (>/=20 mm Hg) had 72% greater risk of any stroke (relative hazard ratio [RH], 1.72; 95% CI, 1.17 to 2.54) and 87% greater risk of ischemic stroke (RH, 1.87; 95% CI, 1.20 to 2.89) relative to less reactive men. Moreover, men who were high reactors and poorly educated were nearly 3 times more likely to suffer a stroke than better educated, less reactive men (RH, 2.90; 95% CI, 1.66 to 5.08). Adjustment for stroke risk factors had little impact on these associations. Diastolic reactivity was unrelated to stroke risk. CONCLUSIONS: Excessive sympathetic reactivity to stress may be etiologically important in stroke, especially ischemic strokes, and low socioeconomic status confers added risk.

Is comprehensive lymphatic irradiation for low-grade non-Hodgkin's lymphoma curative therapy? Long-term experience at a single institution.

PURPOSE: This study reports 21 patients with Stage I-III low-grade non-Hodgkin's lymphoma who were treated with comprehensive lymphatic irradiation (CLI) at the University of Florida between 1966 and 1992. METHODS AND MATERIALS: Sites clinically involved with disease were treated with 30 Gy, whereas clinically uninvolved sites were treated with 25 Gy. Median follow-up for the group was 14 years (24.5 years for Stage III patients). RESULTS: Overall absolute survival rates at 5, 10, and 15 years were 84%, 68%, and 34%. Cause-specific survival rates at 5, 10, and 15 years were 84%, 68%, and 56%. Freedom-from-relapse rates at 5, 10, and 15 years were 75%, 58%, and 58%, with no relapses noted after 10 years. Bulky disease (>6 cm) was a significant indicator of poor prognosis for cause-specific survival (p = .01). CONCLUSION: These data support findings from other institutions suggesting a role for CLI as potentially curative therapy with acceptable toxicity and a short treatment time for patients with Stages I and II and limited Stage III disease.

Is combined modality therapy necessary for advanced Hodgkin's disease?

PURPOSE: To determine whether single-modality therapy is optimal management for patients with Stage III-IV Hodgkin's disease. METHODS AND MATERIALS: All patients with advanced (Stage III and IV) Hodgkin's disease treated at the University of Florida from 1964 through 1989 (n = 141) were studied retrospectively for factors predictive of good outcome with single-modality therapy. Treatment modalities varied and were distributed as follows: combined-modality therapy (CMT), 55 patients; chemotherapy alone (CX), 50 patients; and radiotherapy alone (RT), 36 patients. RESULTS: Ten-year rates of freedom from relapse and overall survival for all Stage III patients were 66% and 59% compared with 36% and 35% for Stage IV patients. The RT subset was highly selected with the majority of patients having nonbulky Stage IIIA disease. Within the RT group, multivariate analysis identified the degree of splenic involvement and age as the factors most associated with freedom from relapse. In patients treated with CX, multivariate analysis identified bulky tumor (maximum transverse tumor dimension > 6 cm) as the most important prognostic factor for relapse. In patients without bulky disease (< or = 6 cm), the probabilities of freedom from relapse and overall survival at 10 years, respectively, according to treatment group were 53% and 58% for RT patients, 60% and 56% for CX patients, and 83% and 71% for CMT patients. For patients without bulky disease, the probability of freedom from relapse was significantly better for the CMT group than for CX patients (p = 0.03) or RT patients (p = 0.04), but there was no statistical difference in overall survival among the three groups. In patients with bulky disease (> 6 cm), the probabilities of freedom from relapse and overall survival at 10 years were 44% and 45% for RT patients, 9% and 0% for CX patients, and 72% and 58% for CMT patients. Freedom from relapse and overall survival were significantly better (p = 0.0001) for CMT patients compared with CX patients. Fatal hematopoietic disorders developed in 10 patients: 2 of 36 RT patients, 2 of 50 CX patients, and 6 of 55 CMT patients. Nine patients had received chemotherapy, and eight had six or more cycles of alkylator-based chemotherapy. CONCLUSION: This retrospective study suggests that combined-modality therapy is preferable to single-modality therapy in the majority of patients with advanced Hodgkin's disease.

The impact of radiotherapy dose and other treatment-related and clinical factors on in-field control in stage I and II non-Hodgkin's lymphoma.

PURPOSE/OBJECTIVE: To assess local (in-field) disease control, identify potential prognostic factors, and elucidate the optimal radiotherapy dose in various clinical settings of Stage I and II non-Hodgkin's lymphoma (non-CNS). MATERIALS & METHODS: A total of 285 consecutive patients with Stage I and II non-Hodgkin's lymphoma were treated with curative intent, including 159 with radiotherapy (RT) alone and 126 with combined-modality therapy (CMT). Of these, 72 patients had low-grade lymphomas (LGL), 92 had intermediate or high-grade lymphomas (I/HGL), and 21 had unclassified lymphomas. Clinical and treatment variables with potential prognostic significance for in-field disease control, freedom from relapse (FFR), and absolute survival (AS) were evaluated by univariate and multivariate analyses. RESULTS: The 5-, 10-, and 20-year actuarial AS rates were 73%, 46%, and 33% for patients with LGL and 64%, 44%, and 18% for patients with I/HGL, respectively. The 5-, 10-, and 20-year actuarial FFR rates were 62%, 59%, and 49% for patients with LGL and 66%, 57%, and 57% for patients with I/HGL, respectively. Significant prognostic factors identified by the multivariate analysis were age, tumor size, and histology for AS; tumor size and treatment for FFR; and only tumor size for in-field disease control. There were 95 total failures, with only 12 occurring infield. Most failures (65%) were in contiguous unirradiated sites. All 4 in-field failures in patients with LGL occurred after RT doses < 30 Gy, although none occurred in 10 patients with small-volume LGL of the orbit treated with doses < 30 Gy. The 8 in-field failures in patients with I/HGL were distributed evenly throughout the RT dose range; 5 occurred in patients treated with CMT, all with tumors > 6 cm, and 4 with less than a complete response (CR) to chemotherapy. CONCLUSION: Our analysis suggests that the overwhelming problem in the treatment of non-Hodgkin's lymphoma is not in-field failure but, rather, failure in contiguous unirradiated sites. A dose of 20-25 Gy may be sufficient for small-volume LGL of the orbit. A dose of 30 Gy is sufficient for LGL in general, as well as for patients with nonbulky (< or = 6 cm) I/HGL treated with CMT who have a CR. However, patients with I/HGL treated with CMT for tumors > 6 cm and/or without a CR may benefit from doses > or = 40 Gy.