Second primary uterine malignancies after radiation therapy for cervical cancer.

PURPOSE: Radiation exposure has long been established as a risk factor for cancer development. The purpose of this study is to assess the risk of uterine malignancy in patients previously treated for cervical cancer with radiation therapy. METHODS: A population-based cohort of 9092 patients diagnosed with cervical cancer who did not undergo surgery and received radiation therapy between 1973 and 2008 was identified from the Surveillance, Epidemiology and End Results Program database (SEER 9). Patients in this cohort who developed endometrial cancer after treatment of cervical cancer were identified. 55,140 patients with endometrial cancer were also identified. The distribution of the different histologic types of endometrial cancer was determined for each of these cohorts. RESULTS: 54 patients (0.6%) were diagnosed with an endometrial cancer more than 12 months after diagnosis of cervical cancer. The average latency to endometrial cancer diagnosis was 160 months, with a range of 14-374 months. The average age of cervical cancer diagnosis was 52 years and the average age at subsequent endometrial cancer diagnosis was 66 years. Only 40% of the endometrial cancers diagnosed following treatment of cervical cancer were endometrioid. The majority were clear-cell adenocarcinomas (42%), 9% were carcinosarcomas and 5.5% were leiomyosarcomas. Of the 55,140 endometrial cancer patients in the database, a vast majority were endometrioid adenocarcinomas (91%), and only 2.3% clear-cell adenocarcinoma, 2.3% carcinosarcoma and 0.5% leiomyosarcoma. The difference in histologic type distribution between these two cohorts is highly significant (p < 0.01). CONCLUSION: A small proportion of women who receive radiation for cervical cancer go on to develop endometrial cancer. These are predominantly of the more aggressive histologic types when compared to primary endometrial cancers. The latency from cervical cancer diagnosis to endometrial cancer diagnosis is over a decade. In a patient who still has a uterus after receiving pelvic radiation, vaginal bleeding should be investigated.

The Effect of Hospital Volume on Breast Cancer Mortality.

OBJECTIVE: The aim of this study was to determine whether hospital volume was associated with mortality in breast cancer, and what thresholds of case volume impacted survival. BACKGROUND: Prior literature has demonstrated improved survival with treatment at high volume centers among less common cancers requiring technically complex surgery. METHODS: All adults (18 to 90 years) with stages 0-III unilateral breast cancer diagnosed from 2004 to 2012 were identified from the American College of Surgeons National Cancer Data Base (NCDB). A multivariable Cox proportional hazards model with restricted cubic splines was used to examine the association of annual hospital volume and overall survival, after adjusting for measured covariates. Intergroup comparisons of patient and treatment characteristics were conducted with X and analysis of variance (ANOVA). The log-rank test was used to test survival differences between groups. A multivariable Cox proportional hazards model was used to estimate hazard ratios (HRs) associated with each volume group. RESULTS: One million sixty-four thousand two hundred and fifty-one patients met inclusion criteria. The median age of the sample was 60 (interquartile range 50 to 70). Hospitals were categorized into 3 groups using restricted cubic spline analysis: low-volume (<148 cases/year), moderate-volume (148 to 298 cases/year), and high-volume (>298 cases/year). Treatment at high volume centers was associated with an 11% reduction in overall mortality for all patients (HR 0.89); those with stage 0-I, ER+/PR+ or ER+/PR- breast cancers derived the greatest benefit. CONCLUSIONS: Treatment at high volume centers is associated with improved survival for breast cancer patients regardless of stage. High case volume could serve as a proxy for the institutional infrastructure required to deliver complex multidisciplinary breast cancer treatment.

Potential of Lactobacillus curvatus LFC1 to produce slits in Cheddar cheese.

Defects in Cheddar cheese resulting from undesired gas production are a sporadic problem that results in significant financial losses in the cheese industry. In this study, we evaluate the potential of a facultatively heterofermentative lactobacilli, Lactobacillus curvatus LFC1, to produce slits, a gas related defect in Cheddar cheese. The addition of Lb. curvatus LFC1 to cheese milk at log 3 CFU/ml resulted in the development of small slits during the first month of ripening. Chemical analyses indicated that the LFC1 containing cheeses had less galactose and higher levels of lactate and acetate than the control cheeses. The composition the cheese microbiota was examined through a combination of two culture independent approaches, 16S rRNA marker gene sequencing and automated ribosomal intergenic spacer analysis; the results indicated that no known gas producers were present and that high levels of LFC1 was the only significant difference between the cheese microbiotas. A ripening cheese model system was utilized to examine the metabolism of LFC1 under conditions similar to those present in cheeses that exhibited the slit defect. The combined cheese and model system results indicate that when Lb. curvatus LFC1 was added to the cheese milk at log 3 CFU/ml it metabolized galactose to lactate, acetate, and CO2. For production of sufficient CO2 to result in the formation of slits there needs to be sufficient galactose and Lb. curvatus LFC1 present in the cheese matrix. To our knowledge, facultatively heterofermentative lactobacilli have not previously been demonstrated to result in gas-related cheese defects.

Effect of various high-pressure treatments on the properties of reduced-fat Cheddar cheese.

A major problem with reduced-fat cheese is the difficulty in attaining the characteristic flavor and texture of typical full-fat versions. Some previous studies have suggested that high hydrostatic pressure (HHP) can accelerate the ripening of full-fat cheeses. Our objective was to investigate the effect of HHP on reduced-fat (~7.3% fat) Cheddar cheese, with the goal of improving its flavor and texture. We used a central composite rotatable design with response surface methodology to study the effect of pressure and holding time on the rheological, physical, chemical, and microbial characteristics of reduced-fat Cheddar cheese. A 2-level factorial experimental design was chosen to study the effects of the independent variables (pressure and holding time). Pressures were varied from around 50 to 400 MPa and holding times ranged from 2.5 to 19.5 min. High pressure was applied 1 wk after cheese manufacture, and analyses were performed at 2 wk, and 1, 3, and 6 mo. The insoluble calcium content as a percentage of total Ca in cheeses were not affected by pressure treatment. Pressure applications ≥ 225 MPa resulted in softer cheese texture during ripening. Pressures ≥ 225 MPa increased melt, and resulted in higher maximum loss tangent values at 2 wk. Pressure treatment had a greater effect on cheese microbial and textural properties than holding time. High-pressure-treated cheeses also had higher pH values than the control. We did not observe any significant difference in rates of proteolysis between treatments. In conclusion, holding times of around 5 min and pressures of ≥ 225 MPa could potentially be used to improve the excessively firm texture of reduced-fat cheese.

Zebrafish developmental screening of the ToxCast™ Phase I chemical library.

Zebrafish (Danio rerio) is an emerging toxicity screening model for both human health and ecology. As part of the Computational Toxicology Research Program of the U.S. EPA, the toxicity of the 309 ToxCast™ Phase I chemicals was assessed using a zebrafish screen for developmental toxicity. All exposures were by immersion from 6-8 h post fertilization (hpf) to 5 days post fertilization (dpf); nominal concentration range of 1 nM-80 µM. On 6 dpf larvae were assessed for death and overt structural defects. Results revealed that the majority (62%) of chemicals were toxic to the developing zebrafish; both toxicity incidence and potency was correlated with chemical class and hydrophobicity (logP); and inter-and intra-plate replicates showed good agreement. The zebrafish embryo screen, by providing an integrated model of the developing vertebrate, compliments the ToxCast assay portfolio and has the potential to provide information relative to overt and organismal toxicity.

Effect of heat treatment of milk on activation of Bacillus spores.

The quality and shelf life of fluid milk products are dependent on the amount and type of microorganisms present following pasteurization. This study evaluated the effects of different pasteurization processes on the microbial populations in fluid milk. The objective was to determine whether certain pasteurization processes lead to an increase in the amount of bacteria present in pasteurized milk by activating Bacillus spores. Samples of raw milk were collected on the day of arrival at the dairy plant. The samples were pasteurized at 63 degrees C for 30 min (low temperature, long time), 72 degrees C for 15 s (high temperature, short time), 76 degrees C for 15 s, and 82 degrees C for 30 min. The pasteurized samples were then stored at 6 and 10 degrees C for 14 days. The samples were analyzed for standard plate count and Bacillus count immediately after pasteurization and after 14 days of storage. Pasteurization of milk at 72 and 76 degrees C significantly (P < 0.05) increased the amount of Bacillus spore activation over that of 63 degrees C. There was no detection of Bacillus in initial samples pasteurized at 82 degrees C for 30 min, but Bacillus was present in samples after storage for 14 days, indicating that injury and recovery time preceded growth. The majority of isolates were characterized as Bacillus mycoides and not Bacillus cereus, suggesting that this organism might be more a cause of sweet curdling of fluid milk than previously reported.

Influence of adjunct use and cheese microenvironment on nonstarter bacteria in reduced-fat cheddar-type cheese.

This study investigated population dynamics of starter, adjunct, and nonstarter lactic acid bacteria (NSLAB) in reduced-fat Cheddar and Colby cheese made with or without a Lactobacillus casei adjunct. Duplicate vats of cheese were manufactured and ripened at 7 degrees C. Bacterial populations were monitored periodically by plate counts and by DNA fingerprinting of cheese isolates with the random amplified polymorphic DNA technique. Isolates that displayed a unique DNA fingerprint were identified to the species level by partial nucleotide sequence analysis of the 16S rRNA gene. Nonstarter biota in both cheese types changed over time, but populations in the Colby cheese showed a greater degree of species heterogeneity. The addition of the L. casei adjunct to cheese milk at 10(4) cfu/ml did not completely suppress "wild" NSLAB populations, but it did appear to reduce nonstarter species and strain diversity in Colby and young Cheddar cheese. Nonetheless, nonstarter populations in all 6-mo-old cheeses were dominated by wild L. casei. Interestingly, the dominant strains of L. casei in each 6-mo-old cheese appeared to be affected more by adjunct treatment and not cheese variety.

Influence of ovine milk in mixture with bovine milk on the quality of reduced fat Muenster-type cheese.

Reduced fat Muenster-type cheeses were manufactured from a mixture of bovine skim milk and ovine whole milk and from bovine milk only (control). Cheeses were evaluated at 15, 30, 60, 90, 120, and 180 d of age for numbers and type of microflora, casein hydrolysis, and amounts of free fatty acids. alpha(s1)-Casein degradation was similar for both cheeses during the aging period, but beta-casein degradation proceeded at a faster rate in the control cheese. The total amounts of free fatty acids remained constant throughout the ripening time; however, the cheeses produced with bovine/ovine milk yielded a significantly larger amount of caprylic (C8:0) and capric (C10:0) acids compared with the bovine milk cheeses. Lactobacilli increased during the aging period, while the populations of lactic acid bacteria, yeast and molds, and lipolytic organisms did not increase. Both cheeses had comparable cheese flavor intensity, but the bovine/ovine milk cheese had a greater occurrence of off flavors. The bovine/ovine milk cheeses were firmer than the bovine cheeses throughout the aging period.

Influence of salting procedure on the composition of Muenster-type cheese.

Muenster-type cheeses were salted with a traditional saturated brine solution or by direct addition of salt to the curd. Cheeses were evaluated at 0, 30, 60, 90, 120, and 180 d of age for numbers and type of microflora, casein hydrolysis, and amounts of free fatty acids. No significant differences were found in the populations of starter, lactobacilli, or yeast for the brine- and direct-salted cheeses. The amounts of free fatty acids liberated were similar for both cheeses. The hydrolysis of alpha s1-casein was complete at 90 d of age, whereas only 40% of the beta-casein was hydrolyzed at 180 d of age. The inner layer of the brine-salted cheeses had the highest number of starter microorganisms, followed by the middle and outer layers, respectively. The salt concentrations were similar in the three layers after 4 mo of age. Results of this study showed that comparable Muenster-type cheese could be produced with either of the salting procedures. With direct salt addition to curd, a 59% reduction was observed in salt emissions from the Muenster manufacturing process.

Addition of supplementary foods and infant growth (2 to 24 months).

OBJECTIVE: To determine the effect of adding supplementary foods on infant growth 2 to 8 and 12 to 24 months. METHODS: Length (cm/month) and weight (kg/month) of white infants (n = 94) were measured five to nine times from 2 to 24 months of age. Mothers reported birth weights, infants' ages at first introduction of supplementary food, illnesses and information sources about infant feeding. Simple linear regression equations were used to compute slopes for each child (unit changes in length and in weight by age). Stepwise linear regression was used to determine the effect on weight and length slopes by the introduction of supplementary foods (e.g., an infant's age when cereal, fruit, juice, vegetables and a meat cluster were first added) to the diet. Breast feeding (months duration or ever fed), illness scores and gender were covariates in the regression models. RESULTS: A significant model (F = 10.09, p = .002) for weight gain (2 to 8 months) showed that gender explained 10% of the variance; for length slope, the model was non-significant and gender explained 3% of the variance. Females had a slower weight gain compared to that of males. None of the covariates or supplementary foods were retained in the models. Weight prior to 12 months was the best predictor (p = .0001, 54% of the variance) of weight gain 12 to 24 months. CONCLUSIONS: Unit changes in weight or length for an infant's age were not statistically associated with the timing of when supplementary foods were first added to the diet 2 to 8 or 12 to 24 months. Weight prior to 12 months was a significant predictor of weight gain 12 to 24 months.

Borderline tumors of the ovary: correlation of frozen and permanent histopathologic diagnosis.

OBJECTIVE: To evaluate the correlation between the diagnosis of borderline tumor of the ovary by frozen and permanent pathology. METHODS: All pathology reports with diagnoses of borderline tumor of the ovary between 1980 and 1998 at Massachusetts General Hospital were reviewed. Univariate and multivariable logistic regression models were constructed for patient age, tumor size, histology, presence of bilateral or extraovarian disease, and concurrent diagnosis of endometriosis or endosalpingiosis. RESULTS: We reviewed 140 cases. The average age of patients was 52.3 years. Eighty tumors were serous, 47 mucinous, 11 mixed, and two endometrioid. The mean diameter overall was 13.7 cm (range 1-70 cm), 10.2 cm for serous, and 20.1 cm for mucinous. Diagnoses of borderline tumors by frozen and permanent pathology were consistent in 60% of cases. Frozen section interpreted a benign lesion as malignant (overdiagnosed) in 10.7% of cases, and interpreted a malignant lesion as benign (underdiagnosed) in 29.3%. No variable was a significant predicator of overdiagnosis. In univariate analysis, underdiagnosis was more likely for other types of tumors than serous (P <.001), tumors larger than 20 cm (P =.039), and tumors confined to the ovaries (P =. 009). When all variables were included in a multiple regression model, only histology was a significant predictor of underdiagnosis (P =.039). CONCLUSION: Frozen or permanent pathology reports of diagnoses of borderline tumor were consistent 60% of the time, whereas the positive predictive value of borderline by frozen section was 89.3%. Tumors other than serous are more likely to be misinterpreted.

Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression.

The PTEN tumor suppressor gene is frequently inactivated in human prostate cancers, particularly in more advanced cancers, suggesting that the AKT/protein kinase B (PKB) kinase, which is negatively regulated by PTEN, may be involved in human prostate cancer progression. We now show that AKT activation and activity are markedly increased in androgen-independent, prostate-specific antigen-positive prostate cancer cells (LNAI cells) established from xenograft tumors of the androgen-dependent LNCaP cell line. These LNAI cells show increased expression of integrin-linked kinase, which is putatively responsible for AKT activation/Ser-473 phosphorylation, as well as for increased phosphorylation of the AKT target protein, BAD. Furthermore, expression of the p27(Kip1) cell cycle regulator was diminished in LNAI cells, consistent with the notion that AKT directly inhibits AFX/Forkhead-mediated transcription of p27(Kip1). To assess directly the impact of increased AKT activity on prostate cancer progression, an activated hAKT1 mutant was overexpressed in LNCaP cells, resulting in a 6-fold increase in xenograft tumor growth. Like LNAI cells, these transfectants showed dramatically reduced p27(Kip1) expression. Together, these data implicate increased AKT activity in prostate tumor progression and androgen independence and suggest that diminished p27(Kip1) expression, which has been repeatedly associated with prostate cancer progression, may be a consequence of increased AKT activity.

Conditional transformation of rat embryo fibroblast cells by a cyclin D1-cdk4 fusion gene.

Cyclin D1 gene overexpression is a frequent event in a number of human cancers. These observations have led to the suggestion that cyclin D1 alterations might play a role in the etiology of cancer. This possibility is supported by the finding that transfection of mammalian cells with cyclin D1 can accelerate progression through the G1 phase of the cell cycle. Moreover, cyclin D1 can function as an oncogene by cooperating with activated Ha-ras to transform primary rat embryo fibroblasts (REFs). In addition, cyclin D1 transgenics develop hyperplasia and neoplasia of the thymus and mammary gland. We have constructed a novel fusion gene consisting of full-length human cyclin D1 and cdk4 genes. This fusion gene was expressed in insect cells and the fusion protein was shown to be enzymatically active. The fusion gene was expressed in mammalian cells under the control of tet-repressor. This fusion gene immortalized primary REFs, and cooperated with activated Ha-ras to transform primary REFs, in terms of anchorage-independent growth in vitro and formation of tumors in vivo. Utilizing a tet-regulated gene expression system, we have shown that proliferation of stably transfected primary REFs in vitro and in vivo is dependent on the continued expression of the cyclin D1-cdk4 fusion gene. These cell lines could be useful in the discovery of novel cancer therapeutics to modulate cyclin D1.cdk4 activity.

Longitudinal study of nutrient and food intakes of white preschool children aged 24 to 60 months.

OBJECTIVE: To determine nutrient and food intakes of 72 white preschool children primarily from families of middle and upper socioeconomic status and to compare children's nutrient intakes with current recommendations. DESIGN: Six in-home interviews were conducted with mothers when children were 24 to 60 months old; at each time mothers provided 3 days of dietary information on the child. Children and mothers independently provided information on the child's favorite and least favorite foods at 42 and 54 months. SUBJECTS: Preschool children (24 to 60 months old) participating in a longitudinal study. STATISTICAL ANALYSES: Mean nutrient intakes were compared with the most recent Recommended Dietary Allowances/Adequate Intakes. Differences over time were tested with repeated-measures analysis of variance; gender differences were determined with t tests. Food frequencies (i.e., percentage of children consuming specific foods) were determined from dietary recalls and food records. Dietary variety was assessed with the Variety Index for Toddlers or the Variety Index for Children. RESULTS: Means were consistently less than the RDA/AI for energy, zinc, folate, and vitamins D and E. Energy, carbohydrate, and fat intakes were highest (P < or = .01) at 60 months. Boys consumed more (P < or = .05) protein (10 g), calcium (197 mg), magnesium (35 mg), and pantothenic acid (0.8 mg) at 60 months than did girls. Foods most commonly eaten were fruit drink, carbonated beverages, 2% milk, and french fries. The vegetable group consistently had the lowest variety scores; vegetables also dominated least favorite foods lists. APPLICATIONS: Parents need to be encouraged to include more sources of zinc, folate, vitamin E, and vitamin D in children's diets. Parents should also encourage their children to eat more vegetables, zinc- and folate-fortified cereals, lean red meats, seafood, vegetable oils, and low-fat milk.

Fruit juice intake is not related to children's growth.

BACKGROUND: Excessive fruit juice intake (>12 ounces/day) has been reported to be associated with short stature and obesity in preschool children. OBJECTIVE: To confirm whether excess fruit juice intake was associated with short stature and obesity in preschool children, we assessed growth parameters and fruit juice intake in 105 white children, ages 24 to 36 months. METHODOLOGY: Mothers were interviewed twice by a registered dietitian when children were age 24, 28, or 32 months (interview 1) and when children were age 28, 32, or 36 months (interview 2); interviews were assigned randomly. At each interview mothers provided 3 days of dietary data (one 24-hour recall and a 2-day food record) and the registered dietitian weighed the child and measured his/her height. Dietary data were analyzed using Nutritionist IV software. Each child's body mass index (wt/ht2) and ponderal index (wt/ht3) were calculated for each interview. Growth parameters of children consuming <12 ounces/day 100% fruit juice were compared with those consuming >/=12 ounces/day using the Student's t test, chi2, Fisher's exact test, and mixed model repeated measures analyses (PROC MIXED). RESULTS: Results consistently indicated no statistically significant differences in children's height, body mass index, or ponderal index related to fruit juice intake. Intakes of soda pop were negatively related to intakes of milk and fruit juice although intakes of milk and fruit juice were not related. CONCLUSIONS: The consistent lack of relationship between children's fruit juice intake and growth parameters in our study does not support previous recommendations to limit the intake of 100% fruit juice to <12 ounces/day.

Quality of life in advanced ovarian cancer: identifying specific concerns.

PURPOSE: To identify issues affecting the quality of life (QoL) in women receiving palliative therapy for ovarian cancer. METHODS: Twenty women with advanced recurrent ovarian cancer were interviewed to establish what issues affect QoL. All patients were receiving palliative chemotherapy or other palliative therapy in the department of Gynecologic Oncology at the Massachusetts General Hospital, and were felt to have a life expectancy of 1 year or less by best clinical estimate. RESULTS: Twenty patients with an average age of 56.7 years participated. Psychosocial issues were more common than physical ones, and patients were more likely to mention issues that positively impact on QoL rather than those with a negative effect. Most patients noted that a sense of hope, enhanced appreciation for day to day life, and a strong support system had a significantly positive effect on QoL. Issues negatively impacting QoL included fear of their disease (90%) and concern for family and friends (100%), particularly children. Most common physical symptoms impacting QoL included fatigue (100%) and anorexia (55%). CONCLUSIONS: Little research has been done into QoL issues for ovarian cancer patients receiving palliative care. Available QoL studies tend to focus on the physical aspects of a disease or its treatment. This pilot study suggests that women with advanced, recurrent ovarian cancer feel that psychosocial issues play a greater role in determining QoL than do physical issues. Further QoL studies for these patients should include assessment of psychosocial realms. This information can then be used to design interventions to improve QoL.

The phenomenon of "picky eater": a behavioral marker in eating patterns of toddlers.

OBJECTIVE: To determine if toddlers who were considered "picky eaters" had lower dietary scores than non-picky eaters, and if family environment and socioeconomic status were significantly related to picky eater status and dietary scores. METHODS: An incomplete block design provided two interviews at randomly assigned times (24, 28, 32, or 36 months) of Caucasian mothers from upper socioeconomic (n=74) and lower socioeconomic status (n=44). Using trained interviewers, 6 days of food intake, two administrations of a questionnaire about toddler's eating behavior, and one administration of the Family Environment Scales were collected in the home. MANOVA, discriminant function analysis, and logistic regression procedures were used to determine significant differences between picky and non-picky eater groups. RESULTS: Picky eaters had lower dietary variety (p=.03) and diversity scores (p=.009) than non-picky eaters. Mothers of picky eaters compared to those of non-picky eaters used persuasion (p=.0001) and ranked their child's eating behaviors as more problematic (p=.0001). CONCLUSION: Toddlers perceived by their mothers as picky eaters had significantly lower dietary variety and diversity scores. Parents need information and strategies to increase the number of foods acceptable to their toddlers and to develop a sound feeding plan.

A Food Variety Index for Toddlers (VIT): development and application.

OBJECTIVE: To develop a variety index based on the Food Guide Pyramid that is specific to toddlers and is indicative of dietary adequacy. DESIGN: Subjects' mothers were assigned randomly to two in-home interviews with a registered dietitian at four possible collection periods: 24, 28, 32, or 36 months. Three days of dietary information were collected at each period. A Variety Index for Toddlers (VIT) was developed to assess variety within and among food groups based on the number of servings from the food groups in the Food Guide Pyramid. SUBJECTS: White children aged 24 to 36 months (n = 124) and their mothers who were participants in an ongoing longitudinal study. STATISTICAL ANALYSES: Descriptive statistical procedures were performed on VIT scores. Mean adequacy ratio (MAR) scores were calculated for all subjects and compared with VIT scores. RESULTS: Bread group scores were consistently the highest of the individual food groups (mean score = 0.94 to 0.96 on the 0.0 to 1.0 scale); the vegetable and meat groups were generally the lowest (mean score = 0.68 to 0.73 and 0.73 to 0.76, respectively). Mean VIT scores (an average of the five food group scores) over the four collection periods ranged from 0.79 +/- 0.14 to 0.81 +/- 0.15; a score of 1.00 represented intake of at least the minimum number of recommended servings from each food group. VIT scores were strongly correlated to the MAR score of nutrient adequacy (r = +.74, P < .01). APPLICATIONS: The VIT can provide a numeric description of dietary variety specific to toddlers. VIT scores can be compared with other characteristics of children, and this index has the potential to be adapted for use with other age groups and populations.