Utility of frozen section in pediatric and adolescent malignant ovarian nonseminomatous germ cell tumors: A report from the children's oncology group.

PURPOSE: In adult women, most malignant ovarian tumors are epithelial in origin. The use of intra-operative frozen section to distinguish between benign and malignant histology is reliable in guiding operative decision-making to determine the extent of surgical staging required. Pediatric and adolescent patients with ovarian masses have a much different spectrum of pathology with most tumors arising from germ cell precursors. This review was undertaken to assess the concordance between the intra-operative frozen section and the final diagnosis as an aid to guide extent of surgical staging in a group of pediatric and adolescent patients with malignant ovarian germ cell tumors. METHODS: Records of patients aged 0 to 20 years with malignant ovarian germ cell tumors enrolled on Children's Oncology Group study AGCT0132 were reviewed. Pathology reports from patients who had both intra-operative frozen section diagnosis and final paraffin section diagnosis were compared using descriptive statistics. By inclusion criteria for the study, all patients had a final diagnosis of malignancy with required yolk sac tumor, choriocarcinoma or embryonal carcinoma histology. Available central review of pathology final paraffin section slides were compared with final institution pathology reports. RESULTS: Of 131 eligible patients with ovarian germ cell tumors, 60 (45.8%) had both intra-operative frozen section and final paraffin section diagnoses available. Intra-operative frozen section diagnoses were classified as: incorrect diagnosis of benign tumor (13.3%), confirmation of malignancy (61.7%), immature teratoma (16.7%), germ cell tumor not otherwise specified (5%) and no diagnosis provided (3.3%). Intra-operative frozen section was incorrect in 23 of 60 (38.3%) patients evaluated. Central pathology review was concordant with the final institution pathology diagnosis in 76.3% of patients. Central pathology review identified additional germ cell tumor components in 23.7% of patients. CONCLUSIONS: In pediatric and adolescent patients with a confirmed final diagnosis of ovarian germ cell malignancy, intra-operative frozen section diagnosis is not reliable to inform the extent of surgical staging required. Central review by an expert germ cell tumor pathologist provides important additional information to guide therapy.

Development of paediatric non-stage prognosticator guidelines for population-based cancer registries and updates to the 2014 Toronto Paediatric Cancer Stage Guidelines.

Population-based cancer registries (PBCRs) generate measures of cancer incidence and survival that are essential for cancer surveillance, research, and cancer control strategies. In 2014, the Toronto Paediatric Cancer Stage Guidelines were developed to standardise how PBCRs collect data on the stage at diagnosis for childhood cancer cases. These guidelines have been implemented in multiple jurisdictions worldwide to facilitate international comparative studies of incidence and outcome. Robust stratification by risk also requires data on key non-stage prognosticators (NSPs). Key experts and stakeholders used a modified Delphi approach to establish principles guiding paediatric cancer NSP data collection. With the use of these principles, recommendations were made on which NSPs should be collected for the major malignancies in children. The 2014 Toronto Stage Guidelines were also reviewed and updated where necessary. Wide adoption of the resultant Paediatric NSP Guidelines and updated Toronto Stage Guidelines will enhance the harmonisation and use of childhood cancer data provided by PBCRs.

Risk of second malignant neoplasms in women and girls with germ cell tumors.

Background: While an elevated risk of second malignant neoplasms (SMNs) has been observed in men treated for germ cell tumors (GCTs), risk of SMNs have not been quantified in adult women or in girls treated for GCTs. Patients and methods: One-year survivors of primary GCTs diagnosed between January 1980 and December 2012 were identified from Surveillance, Epidemiology, and End Results (SEER 9) registries. Risk of SMNs was calculated using SEER*Stat. Results: Among 1507 patients, a total of 47 SMNs were identified. The overall risk of SMNs was not elevated in females overall or in females treated for GCT during adulthood although SMN sites (pancreas, soft tissue, bladder, kidney, and thyroid) and trends were comparable with those in men. There were too few childhood GCT cases with SMNs for further analysis. Conclusions: Unlike men, women treated for GCTs did not have a statistically significant elevated risk of SMNs [standardized incidence ratio = 1.11; 95% confidence interval (CI) = 0.81-1.47]. The fact that SMNs in women occur in sites similar to those observed in men indicate that long-term follow-up of a larger cohort of females treated for GCT is warranted.

Sugar-sweetened beverage consumption and age at menarche in a prospective study of US girls.

STUDY QUESTION: Is sugar-sweetened beverage (SSB) consumption associated with age at menarche? SUMMARY ANSWER: More frequent SSB consumption was associated with earlier menarche in a population of US girls. WHAT IS KNOWN ALREADY: SSB consumption is associated with metabolic changes that could potentially impact menarcheal timing, but direct associations with age at menarche have yet to be investigated. STUDY DESIGN, SIZE, DURATION: The Growing up Today Study, a prospective cohort study of 16 875 children of Nurses' Health Study II participants residing in all 50 US states. This analysis followed 5583 girls, aged 9-14 years and premenarcheal at baseline, between 1996 and 2001. During 10 555 person-years of follow-up, 94% (n = 5227) of girls reported their age at menarche, and 3% (n = 159) remained premenarcheal in 2001; 4% (n = 197) of eligible girls were censored, primarily for missing age at menarche. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cumulative updated SSB consumption (composed of non-carbonated fruit drinks, sugar-sweetened soda and iced tea) was calculated using annual Youth/Adolescent Food Frequency Questionnaires from 1996 to 1998. Age at menarche was self-reported annually. The association between SSB consumption and age at menarche was assessed using Cox proportional hazards regression. MAIN RESULTS AND THE ROLE OF CHANCE: More frequent SSB consumption predicted earlier menarche. At any given age between 9 and 18.5 years, premenarcheal girls who reported consuming >1.5 servings of SSBs per day were, on average, 24% more likely [95% confidence interval (CI): 13, 36%; P-trend: <0.001] to attain menarche in the next month relative to girls consuming ≤2 servings of SSBs weekly, adjusting for potential confounders including height, but not BMI (considered an intermediate). Correspondingly, girls consuming >1.5 SSBs daily had an estimated 2.7-month earlier menarche (95% CI: -4.1, -1.3 months) relative to those consuming ≤2 SSBs weekly. The frequency of non-carbonated fruit drink (P-trend: 0.03) and sugar-sweetened soda (P-trend: 0.001), but not iced tea (P-trend: 0.49), consumption also predicted earlier menarche. The effect of SSB consumption on age at menarche was observed in every tertile of baseline BMI. Diet soda and fruit juice consumption were not associated with age at menarche. LIMITATIONS, REASONS FOR CAUTION: Although we adjusted for a variety of suspected confounders, residual confounding is possible. We did not measure SSB consumption during early childhood, which may be an important window of exposure. WIDER IMPLICATIONS OF THE FINDINGS: More frequent SSB consumption may predict earlier menarche through mechanisms other than increased BMI. Our findings provide further support for public health efforts to reduce SSB consumption. STUDY FUNDING/COMPETING INTERESTS: The Growing up Today Study is supported by grant R03 CA 106238. J.L.C. was supported by the Breast Cancer Research Foundation; Training Grant T32ES007069 in Environmental Epidemiology from the National Institute of Environmental Health Sciences, National Institutes of Health; and Training Grant T32HD060454 in Reproductive, Perinatal and Pediatric Epidemiology from the National Institute of Child Health and Human Development, National Institutes of Health. A.L.F. is supported by the American Cancer Society, Research Scholar Grant in Cancer Control. K.B.M. was supported in part by the National Cancer Institute at the National Institutes of Health (Public Health Service grants R01CA158313 and R03CA170952). There are no conflicts of interest to declare.

Identification of testicular cancer driver genes by a cross-species comparative oncology approach.

BACKGROUND: Germ cell tumors arise in the testis, ovary, or extragonadal locations and have a wide range of histopathological and clinical presentations. The relative lack of animal models of germ cell tumors has impeded functional assessment of candidate driver genes. Previously, we described the development of testicular germ cell tumors in zebrafish carrying a mutation in bmpr1bb, a BMP family receptor, and demonstrated that human germ cell tumors have defects in BMP signaling. OBJECTIVE: To further credential the zebrafish model for studies of human germ cell tumor, and to elucidate conserved genetic programs underlying the development of germ cell tumor. MATERIALS AND METHODS: We used genetic techniques to ablate the germ cell lineage in developing fish and tested tumors for loss-of-heterozygosity of the wild-type allele of bmpr1bb. We performed comparative gene expression profiling of zebrafish and human germ cell tumors and carried out functional studies of selected genes. RESULTS: Ablation of germ cells completely prevents testis tumor formation in the fish, definitively establishing the germ cell origin of the tumors. Germ cell tumors in bmpr1bb heterozygous mutants retain the wild-type allele, indicating haploinsufficiency of bmpr1bb as the mechanism of tumor formation. Comparison of RNA-Seq and microarray data from human and zebrafish germ cell tumors revealed a unique overlapping signature shared by the zebrafish tumors with human seminomas, yolk sac tumors, and embryonal carcinomas. The most highly conserved gene set in this cross-species analysis included potential driver genes such as JUP, which we show to be essential for germ cell tumor cell growth. CONCLUSION: Our findings highlight the value of cross-species comparative oncology for the identification of candidate human cancer genes.

Identification and characterisation of a human calmodulin-stimulated phosphodiesterase PDE1B1.

A cDNA encoding a calmodulin-stimulated 3',5'-cyclic nucleotide phosphodiesterase (PDE) was isolated from a human brain cDNA library. The cDNA, designated HSPDE1B1, encoded a protein of 536 amino acids that shared 96% sequence identity with the bovine "63 kDa" calmodulin-stimulated PDE. The recombinant protein had cyclic nucleotide phosphodiesterase activity that was stimulated approximately 2-fold by Ca2+/calmodulin and preferred cGMP as substrate. In addition, the enzymatic activity of HSPDE1B1 was inhibited by phosphodiesterase inhibitors with potencies similar to that displayed toward the bovine PDE1 enzymes: IBMX approximately equal to 8-methoxymethyl-IBMX > vinpocetine approximately equal to zaprinast > cilostamide > rolipram. HSPDE1B1 mRNA was found predominantly in the brain. Lower mRNA levels were found in heart and skeletal muscle. In situ hybridisation of brain revealed expression of HSPDE1B1 predominately in neuronal cells of the cerebellum, hippocampus and caudate. The HSPDE1B1 gene was mapped to human chromosome 12. A partial genomic sequence of HSPDE1B1 was isolated and shown to contain two splice junctions that are conserved in the rat PDE4 and the Drosophila dunce genes.

Isolation of TSH and LH/CG receptor cDNAs from human thyroid: regulation by tissue specific splicing.

A TSH receptor (TSH-R) cDNA has been isolated from a human thyroid lambda GT11 library. Unexpectedly, several cDNAs encoding the human LH/CG receptor (LH/CG-R), previously thought to be expressed solely in gonadal cells, were also isolated from the thyroid library. The receptors are structurally related, consisting of a signal sequence, a large extracellular amino terminal domain, seven membrane spanning domains, and a short carboxyl-terminal portion. The TSH-R is encoded by a single 4.2 kilobase mRNA specific to the thyroid. Introns were not present in any hTSH-R cDNAs examined, however, sequencing of several LH/CG-R cDNAs and RNase protection experiments demonstrated that the majority of hLH/CG-R mRNA in the thyroid is incompletely spliced. Consequently, tissue-specific splicing may be an important step in the regulation of the glycoprotein hormone receptor family.

The interaction of signal transduction pathways in FRTL5 thyroid follicular cells: studies with stable expression of beta 2-adrenergic receptors.

Multiple signal transduction pathways interact in FRTL5 cells to promote thyroid follicular cell differentiated function and cell proliferation. In these cells, TSH is a tissue-specific mitogen that promotes DNA synthesis primarily through activation of adenylate cyclase. To further test the role of adenylate cyclase in regulating cell growth and differentiated function we have introduced into FRTL5 the human beta 2-adrenergic receptor (BAR) complementary DNA and have studied the ability of isoproterenol, alone and in combination with insulin-like growth factor I (IGF-I), to stimulate cAMP accumulation, iodide transport, [3H]thymidine incorporation into DNA, and cell growth. Wild-type FRTL5 were infected with a PLJ retroviral construct containing the BAR in either a sense (FRTL BAR) or antisense (FRTL RBAR) orientation, and cell populations were selected on the basis of resistance to the antibiotic geneticin. FRTL BAR expressed approximately 1.3 x 10(5) high affinity binding sites per cell for the beta 2-specific ligand, CGP-12177, while neither FRTL5 wild-type nor RBAR cells demonstrated any specific binding. FRTL BAR had significantly higher levels of intracellular cAMP, [3H]thymidine incorporation, and iodide uptake in the absence of added isoproterenol than FRTL RBAR or wild-type cells. In FRTL BAR, but not RBAR cells, isoproterenol stimulated a dose-dependent accumulation of cAMP, iodide uptake, [3H]thymidine incorporation, and cell growth. FRTL BAR and RBAR cells were equally responsive to TSH and to IGF-I. Isoproterenol enhanced the ability of IGF-I to stimulate [3H]thymidine incorporation in BAR but not RBAR cells. Isoproterenol partially inhibited the ability of TSH to stimulate cAMP generation and DNA synthesis. These studies demonstrate that activation of adenylate cyclase through the BAR introduced into FRTL5 cells by retroviral infection reproduces the range of biological effects in these cells stimulated by TSH and suggest that activation of adenylate cyclase is sufficient to stimulate thyroid differentiated function and cell growth. FRTL BAR cells will provide an interesting model system with which to study the heterologous regulation of both TSH and BARs through activation of a common signal transduction pathway, adenylate cyclase.

Models of breast cancer show that risk is set by events of early life: prevention efforts must shift focus.

We have recently published a mathematical model of the etiology of breast cancer based on the data from the Nurses Health Study that extends the Pike model of breast cancer (see Appendix). The most salient feature of the model is that it identifies the years before the first birth of a child as the most crucial in establishing future risk of breast cancer. The extended model includes several additional details of reproductive risk factors, allowing us to quantify the relative importance of each of the reproductive risk factors and to estimate the effect of changes in key determinants of breast cancer. In this review, we present the evidence from both animal studies and epidemiological research that corroborate the critical importance of the exposures that occur before first birth. We argue that research and preventive interventions should now focus on youth. Population-wide prevention strategies are necessary because the inherited genetic risk for breast cancer accounts for no more than 10-15% of all breast cancer cases, leaving 85% of cases diagnosed among women who are not in this high-risk subgroup of the population. An example of a population-based intervention would be the promotion of increased physical activity among young girls that could result in the delay of menarche. An example of additional research that focuses on the importance of early life exposures would be an analysis of the relation between diet and other lifestyle factors during adolescence and the subsequent risk of breast cancer and studies of precursor lesions (atypical hyperplasia). Shifting the focus of breast cancer prevention to this age group is urgently needed.

Weight concerns, weight control behaviors, and smoking initiation.

OBJECTIVE: To examine the cross-sectional relationships between weight concerns, weight control behaviors, and initiation of tobacco use among youths. STUDY DESIGN: Smoking status, weight concerns, and weight control behaviors were assessed in a cross-sectional sample of 16 862 children, 9 to 14 years of age, in 1996. Logistic regression was used to examine the relationship between weight concerns, weight control behaviors, and early stages of smoking initiation (precontemplation, contemplation, and experimentation). All analyses were adjusted for age, body mass index, and known predictors of initiation. RESULTS: Approximately 9% of participants had experimented with cigarettes, and 6% were contemplating cigarette smoking. Contemplation of tobacco use was associated with misperception of being overweight (boys: odds ratio [OR], 1.65; 95% confidence interval [CI], 1.10-2.48), unhappiness with appearance (girls: OR, 2.05; 95% CI, 1.48-2.84; boys: OR, 1.60; 95% CI, 1.05-2. 42), and a tendency to change eating patterns around peers (girls: OR, 2.87; 95% CI, 2.28-3.62; boys: OR, 1.83; 95% CI, 1.25-2.66). Experimentation with cigarettes was associated with daily exercise to control weight among boys (OR, 1.92; 95% CI, 1.07-3.43) and with monthly purging (OR, 2.54; 95% CI, 1.27-5.07) and daily dieting among girls (OR, 1.79; 95% CI, 1.09-2.96). CONCLUSIONS: Our findings suggest that, among both girls and boys, contemplation of smoking is positively related to weight concerns. Experimentation seems to be positively related to weight control behaviors. It is important for both pediatricians and comprehensive school health programs to address healthy methods of weight maintenance and to dispel the notion of tobacco use as a method of weight control.

Retrovirus-mediated transfer and long-term expression of HIV type 1 tat gene in murine hematopoietic tissues.

Replication of the human immunodeficiency virus (HIV) is regulated tightly by the tat and rev genes. The tat gene of HIV is a potent trans-activator of virus gene expression. trans-Activation is mediated through the tat-responsive element (TAR). Tat also has been shown to affect transcription of cellular genes and to trans-activate other viral promoters. In transgenic animals, tat expression in skin was implicated in the development of lesions resembling Kaposi's sarcoma (KS). More recently, evidence has been presented that suggests that Tat might play a role in the maintenance of KS cells. To study the possible role(s) of Tat in pathogenesis and disease progression, we have developed a retroviral vector for the transfer of tat into murine bone marrow cells. We used this transduced bone marrow to repopulate recipient animals, which expressed the tat gene in peripheral blood 6 months after transplantation as determined by PCR amplification of first-strand cDNA. Analysis of the hematopoietic tissues of mice 6 months posttransplantation indicated persistence of the tat gene and its expression in thymus, lymph nodes, spleen, bone marrow, and peripheral blood. Although tat expression was sustained in all hematopoietic tissues, no gross abnormalities were observed. The presence of tat in all hematopoietic tissues strongly suggests transduction of stem or multipotential progenitor cells.

Overweight, weight concerns, and bulimic behaviors among girls and boys.

OBJECTIVE: To assess the prevalence rates and correlates of overweight, concern with weight, and bulimic behaviors. METHOD: A survey was completed by a population-based sample of 16,114 boys and girls aged 9 to 14 years. RESULTS: Although fewer girls (19%) than boys (26%) were overweight, more girls (25% versus 22%) perceived themselves as overweight (p < .001). The proportion of girls reporting trying to lose weight increased with age (p < .001). The prevalence of binge eating at least monthly increased with age among the girls, but remained stable among the boys. The prevalence of purging was low (< or = 1%) and comparable between genders until age 13. Among the 13- and 14-year-olds, girls were significantly more likely than boys to report using laxatives or vomiting to control weight (p < or = .001). Purging was independently positively associated with stage of pubertal development (girls: odds ratio [OR] = 2.1, 95% confidence interval [CI] 1.6-2.7; boys: OR = 1.5, 95% CI 1.0-2.2) and overweight (girls: OR = 1.9, 95% CI 1.2-3.0; boys: OR = 2.7, 95% CI 1.4-5.1). CONCLUSIONS: Misperception of being overweight and concern with weight were common. Purging was a very rare behavior, but increased with pubertal development. Among the girls, the prevalence increased sharply around the onset of adolescence.

Comparing physical activity questionnaires for youth: seasonal vs annual format.

BACKGROUND: In large cohort studies of older children, self-report is the only practical way to assess physical activity. Assessing usual activity over the entire year is desirable, but children and adolescents may overestimate activities with high seasonal variability. Use of questionnaires in which individuals report each activity by season may improve accuracy. METHODS: A total of 6782 girls and 5110 boys, aged 9-14 years in 1996, completed self-administered activity questionnaires in 1996 and in 1997. In 1996, participants reported the average time spent in each of 17 activities during the previous 12 months; in 1997, we also asked for the average time spent in the previous year, but within each of the four seasons. RESULTS: Girls reported a median of 12.8 hours/week total activity in 1996 and 10.4 hours/week in 1997. For boys, the estimates were 15.5 hours/week and 13.4 hours/week, respectively. Girls and boys within 1-year age strata (e.g., comparison of 10-year olds in 1996 with 10-year olds in 1997) reported an average of 3.7 and 3.1 fewer hours per week, respectively, on the 1997 seasonal format versus the 1996 annual format questionnaire. In longitudinal analyses, the difference between the annual and the seasonal estimates was greater if participants did the activity in fewer seasons in 1997. CONCLUSIONS: In comparison to an annual format questionnaire, a seasonal format questionnaire may improve accuracy of self-report of physical activity by reducing over-reporting of activities in which pre-adolescents and adolescents engage in fewer seasons.

Physical activity and reduced risk of colon cancer: implications for prevention.

This paper reviews the consistency of the relation between increased physical activity and reduced risk of colon cancer, estimates the potential prevention benefit from increasing population levels of physical activity, and considers social strategies to increase activity levels. The published literature was reviewed systematically and supplemented by MEDLINE searches through March 1997. Studies that reported a measure of physical activity and outcomes of colon cancer or colorectal cancer were included. We excluded the first report of a study that was expanded subsequently by extended follow-up, and any study that did not report the methods for measurement of physical activity. Data were extracted including details on study size, methods of classifying physical activity, and outcomes. A consistent inverse relation was observed such that increased physical activity was associated with reduced risk of colon cancer. About a 50 percent reduction in incidence was observed among those with the highest level of activity across numerous studies that used different measures of activity (occupational or leisure-time activity). This association persisted in studies using multivariate analyses to control for diet and other known or suspected risk factors for colon cancer. Risk reduction was attenuated in those studies that combined colon and rectal cancer. This review indicates that greater attention should be placed on social strategies to increase physical activity as a means of preventing colon cancer.

Reproducibility of recall of adolescent diet: Nurses' Health Study (United States).

Although diet and alcohol consumption at a younger age have been hypothesized to play an etiologic role in adult malignancy, few studies have addressed these relations and few data exist on the ability to measure recalled diet during adolescence. We undertook a study to determine whether the recall of diet during high school 22 to 47 years later was reproducible within a prospective cohort of women. In 1986, participants in the Nurses' Health Study (United States), aged 40 to 65 years, reported their diet during high school using a 24-item food frequency questionnaire (FFQ). On the 1988 questionnaire, the participants recorded their alcohol consumption between the ages of 18 and 22. In 1994, a random sample of 275 women were asked to record again their high school diet and alcohol consumption. The average of Spearman correlations between the two recalls of high school diet was r = 0.57 (range = 0.38 to 0.74). For alcohol intake, the correlation for the time period queried was 0.66. The correlation between the two recalls of high school diet was higher than the correlation between the first recall and current diet in 1986 (average r = 0.25). There was no effect of age on reproducibility of recall. These data suggest that recall of diet from the very distant past, during a distinct time period such as high school, is reasonably reproducible. Although further studies of validity are needed, such information may be sufficiently precise to assess the influence of remote diet in epidemiologic studies.

Treatment of endodermal sinus tumor in children using a regimen that lacks bleomycin.

BACKGROUND: The EPO-VAC protocol was initiated to study 1) the efficacy of adding a cisplatin regimen (EPO) to VAC alone (the previous standard of care) and 2) the effect of replacing bleomycin with etoposide in the treatment of pediatric endodermal sinus tumors. METHODS: The eligibility requirements for entry included age <21 years at diagnosis, diagnosis of a primary gonadal or extragonadal tumor (excluding central nervous system tumors and stage I testicular tumors), and histological confirmation of endodermal sinus tumor. Children who met the eligibility criteria were treated with four courses of EPO (etoposide, cisplatin, vincristine) alternating with three courses of VAC (vincristine, dactinomycin, and cyclophosphamide). RESULTS: Eleven children were entered on the protocol. Six patients had extragonadal disease, five patients had ovarian primaries. Seven patients had low-stage tumor (I or II) and four had advanced-stage tumor (III or IV). Three of six evaluable patients attained a complete response at 21 weeks. Three patients with a residual soft tissue mass at restaging underwent further therapy. No patient has relapsed after a median of 51 (range 14-88) months of follow-up. CONCLUSIONS: The results of this protocol suggests that a cisplatin-containing regimen that lacks bleomycin is active in childhood endodermal sinus tumors.

Relation of childhood diet and body size to menarche and adolescent growth in girls.

Adolescent growth and development may be affected by factors such as dietary intake and body size from much earlier in childhood. In a longitudinal study of 67 Caucasian girls in Boston, Massachusetts, data were collected prospectively from birth during the 1930s and 1940s. Heights and weights were measured semiannually, and dietary history interviews were conducted with mothers. Stepwise linear regression methods were used to seek factors which best predicted age at menarche, adolescent peak height growth velocity, and the age at which peak growth velocity occurred. Girls who consumed more (energy-adjusted) animal protein and less vegetable protein at ages 3-5 years had earlier menarche, and girls aged 1-2 years with higher dietary fat intakes and girls aged 6-8 years with higher animal protein intakes became adolescents with earlier peak growth. Controlling for body size, girls who consumed more calories and animal protein 2 years before peak growth had higher peak growth velocity. These findings may have implications regarding adult diseases whose risks are associated with adolescent growth and development factors.

Association of adolescent cigar use with other high-risk behaviors.

OBJECTIVES: To describe the association of cigar use with use of cigarettes, smokeless tobacco, and alcohol among adolescents; and to examine the association of self-esteem, physical activity, and use of tobacco promotional items with cigar use. METHODS: A cross-sectional study of 7104 girls and 5499 boys 10 to 15 years of age in 1997. Data were collected from self-report questionnaires. RESULTS: The prevalence of cigar use increased with age among both girls and boys. Among 11-year-olds, only 1% of girls and 3% of boys had used a cigar, whereas among 15-year-olds, 11% of girls and 25% of boys had used a cigar. Cigar users were much more likely than nonusers to have experimented with cigarettes (girls, odds ratio [OR]: 23.6; 95% confidence interval [CI]: 17.2-32.3; boys, OR: 21.3; 95% CI: 17.1-26.6), smokeless tobacco (girls, OR: 7.5; 95% CI: 4. 5-12.4; boys, OR: 13.0; 95% CI: 9.8-17.4), and alcohol (girls, OR: 6. 6; 95% CI: 4.8-9.1; boys, OR: 6.8; 95% CI: 5.3-8.8). There was a strong association between cigar use and binge drinking, especially among boys (girls, OR: 11.6; 95% CI: 7.9-16.9; boys, OR: 34.8; 95% CI: 19.4-62.3). Cigar users reported more hours of weekly physical activity than did nonusers. Additionally, cigar users were more likely to report high social self-esteem and to possess a tobacco promotional item. CONCLUSIONS: Adolescents who use cigars are more likely to use other tobacco products and alcohol, to report high social self-esteem, and to possess tobacco promotional items. Health care professionals and teachers should include cigar use in discussions with adolescents addressing substance use.

Specific suppression of human CD4 surface expression by Nef from the pathogenic simian immunodeficiency virus SIVmac239open.

HIV-1 Nef down-modulates expression of human CD4, the human immunodeficiency virus (HIV) receptor, at the cell surface. Down-modulation of retrovirus receptors has been shown to be important in the survival of infected cells. To relate this observation to AIDS pathogenesis, we compared the ability of Nef from the SIVmac239open and HIV-1 SF2 isolates to suppress CD4 surface levels. We first obtained the simian immunodeficiency virus (SIV)nef gene by PCR and cloned it into the retroviral vector pLXSN. We then established high titer (1 x 10(6) CFU/ml) amphotropic retrovirus producer lines (PA317/LSnefSN). Using LSnefSN we obtained populations of CD4+ human and mouse T-cells, human B-cells, and mouse fibroblasts that expressed SIV or HIV Nef. In the two human cell lines, both HIV and SIV Nef expression correlated with a significant decrease in CD4 cell surface levels. However, Nef expression did not alter the cell surface levels of CD3, CD18, and MHC class I. Both Nef proteins also suppressed human CD4 surface expression in mouse fibroblasts. Interestingly, SIV Nef failed to suppress cell surface expression of mouse CD4 under conditions where HIV-1 Nef did. Human CD4 down-modulation is a conserved function of SIV and HIV Nef likely to be important for pathogenesis.

Cost-effectiveness of screening for colorectal cancer in the general population.

CONTEXT: A recent expert panel recommended that persons at average risk of colorectal cancer (CRC) begin screening for CRC at age 50 years using 1 of several strategies. However, many aspects of different CRC screening strategies remain uncertain. OBJECTIVE: To assess the consequences, costs, and cost-effectiveness of CRC screening in average-risk individuals. DESIGN: Cost-effectiveness analysis from a societal perspective using a Markov model. SUBJECTS: Hypothetical subjects representative of the 50-year-old US population at average risk for CRC. SETTING: Simulated clinical practice in the United States. MAIN OUTCOME MEASURES: Discounted lifetime costs, life expectancy, and incremental cost-effectiveness (CE) ratio, compared used 22 different CRC screening strategies, including those recommended by the expert panel. RESULTS: In 1 base-case analysis, compliance was assumed to be 60% with the initial screen and 80% with follow-up or surveillance colonoscopy. The most effective strategy for white men was annual rehydrated fecal occult blood testing (FOBT) plus sigmoidoscopy (followed by colonoscopy if either a low- or high-risk polyp was found) every 5 years from age 50 to 85 years, which resulted in a 60% reduction in cancer incidence and an 80% reduction in CRC mortality compared with no screening, and an incremental CE ratio of $92,900 per year of life gained compared with annual unrehydrated FOBT plus sigmoidoscopy every 5 years. In a base-case analysis in which compliance with screening and follow-up is assumed to be 100%, screening more often than every 10 years was prohibitively expensive; annual rehydrated FOBT plus sigmoidoscopy every 5 years had an incremental CE ratio of $489,900 per life-year gained compared with the same strategy every 10 years. Other strategies recommended by the expert panel were either less effective or cost more per year of life gained than the alternatives. Colonoscopy every 10 years was less effective than the combination of annual FOBT plus sigmoidoscopy every 5 years. However, a single colonoscopy at age 55 years achieves nearly half of the reduction in CRC mortality obtainable with colonoscopy every 10 years. Because of increased life expectancy among white women and increased cancer mortality among blacks, CRC screening was even more cost-effective in these groups than in white men. CONCLUSIONS: Screening for CRC, even in the setting of imperfect compliance, significantly reduces CRC mortality at costs comparable to other cancer screening procedures. However, compliance rates significantly affect the incremental CE ratios. In this model of CRC, 60% compliance with an every 5-year schedule of screening was roughly equivalent to 100% compliance with an every 10-year schedule. Mathematical modeling used to inform clinical guidelines needs to take into account expected compliance rates. JAMA. 2000;284:1954-1961.