Iodine Nutrition in Children ≤2 years of Age in Norway.

BACKGROUND: As a component of the thyroid hormones (THs), iodine is vital for normal neurodevelopment during early life. However, both deficient and excess iodine may affect TH production, and data on iodine status in young children are scarce. OBJECTIVES: To describe iodine nutrition (iodine status and intake) in children ≤2 y of age in Innlandet County (Norway) and to describe the associations with maternal iodine nutrition. METHODS: A cross-sectional study was performed in a representative sample of mother-child pairs selected from 30 municipalities from November 2020 until October 2021. Iodine status [child urinary iodine concentration (UIC), maternal UIC, and breast milk iodine concentration (BMIC)] was measured. Child's iodine intake was estimated using 2 24-h dietary recalls (24-HR) and a food frequency questionnaire. The Multiple Source Method was used to estimate the usual iodine intake distributions from the 24-HR assessments. RESULTS: The median UIC in 333 children was 145 µg/L, indicating adequate iodine status according to the WHO cutoff (100 µg/L). The median usual iodine intake was 83 µg/d. Furthermore, 35% had suboptimal usual iodine intakes [below the proposed Estimated average requirement (72 µg/d)], whereas <1% had excessive usual iodine intakes [above the Upper intake level (200 µg/d)]. There was a positive correlation between children's iodine intake and BMIC (Spearman rank correlation coefficient r = 0.67, P < 0.001), and between children's UIC and BMIC (r = 0.43, P < 0.001), maternal UIC (r = 0.23, P = 0.001), and maternal iodine intake (r = 0.20, P = 0.004). CONCLUSION: Despite a median UIC above the cutoff for iodine sufficiency, more than a third of the children had suboptimal usual iodine intakes. Our findings suggest that many children will benefit from iodine fortification and that risk of iodine excess in this age group is low.

Inadequate Iodine Intake in Mothers of Young Children in Innlandet County, Norway.

Background: Iodine has an essential role in child growth and brain development. Thus, sufficient iodine intake is particularly important in women of childbearing age and lactating women. Objectives: This cross-sectional study aimed to describe iodine intake in a large random sample of mothers of young children (aged ≤2 y) living in Innlandet County, Norway. Methods: From November 2020 to October 2021, 355 mother-child pairs were recruited from public health care centers. Dietary data were obtained using two 24-h dietary recalls (24-HRs) per woman and an electronic FFQ. The Multiple Source Method was used to estimate the usual iodine intake from the 24-HR assessment. Results: Based on the 24-HRs, the median (P25, P75) usual iodine intake from food was 117 µg/d (88, 153) in nonlactating women and 129 µg/d (95, 176) in lactating women. The median (P25, P75) total usual iodine intake (from food combined with supplements) was 141 µg/d (97, 185) in nonlactating women and 153 µg/d (107, 227) in lactating women. Based on the 24-HRs, 62% of the women had a total iodine intake below the recommendations (150 µg/d in nonlactating women and 200 µg/d in lactating women), and 23% of them had an iodine intake below the average requirement (100 µg/d). The reported use of iodine-containing supplements was 21.4% in nonlactating women and 28.9% in lactating women. In regular users of iodine-containing supplements (n = 63), supplements contributed to an average of 172 µg/d of iodine. Among regular iodine supplement users, 81% reached the recommendations compared with 26% of nonsupplement users (n = 237). The iodine intake estimated by FFQ was substantially higher than that estimated by 24-HRs. Conclusions: Maternal iodine intake in Innlandet County was inadequate. This study confirms the need for action to improve iodine intake in Norway, particularly among women of childbearing age.

Vitamin B12 status in infancy and the effect of a vitamin B12 injection in infants with subclinical vitamin B12 deficiency: study protocol for a register-based randomised controlled trial.

INTRODUCTION: Vitamin B12 (cobalamin) is crucial for optimal child development and growth, yet deficiency is common worldwide. The aim of this study is twofold; (1) to describe vitamin B12 status and the status of other micronutrients in Norwegian infants, and (2) in a randomised controlled trial (RCT), investigate the effect of vitamin B12 supplementation on neurodevelopment in infants with subclinical vitamin B12 deficiency. METHODS AND ANALYSIS: Infant blood samples, collected at public healthcare clinics, are analysed for plasma cobalamin levels. Infants with plasma cobalamin <148 pmol/L are immediately treated with hydroxocobalamin and excluded from the RCT. Remaining infants (cobalamin ≥148 pmol/L) are randomly assigned (in a 1:1 ratio) to either a screening or a control group. In the screening group, baseline samples are immediately analysed for total homocysteine (tHcy), while in the control group, the baseline samples will be analysed after 12 months. Screening group infants with plasma tHcy >6.5 µmol/L, are given an intramuscular injection of hydroxocobalamin (400 µg). The primary outcomes are cognitive, language and motor development assessed using the Bayley Scales of Infant and Toddler Development at 12 months of age. ETHICS AND DISSEMINATION: The study has been approved by the Regional Committee for Medical and Health Research Ethics (ref: 186505). Investigators who meet the Vancouver requirements will be eligible for authorship and be responsible for dissemination of study findings. Results will extend current knowledge on consequences of subclinical vitamin B12 deficiency during infancy and may inform future infant feeding recommendations. TRIAL REGISTRATION NUMBER: NCT05005897.

Experiences with energy drink consumption among Norwegian adolescents.

The objective of the present study was to describe adolescents' habits and experiences with energy drink (ED) consumption and the relation to the amount of ED consumed. We used the national cross-sectional study Ungdata, conducted in 2015-16 in Norway. A total of 15 913 adolescents aged 13-19 years answered questions about ED consumption related to the following topics: reasons for, experiences with, habits and parental attitudes. The sample comprised only adolescents reporting to be ED consumers. We estimated the association between the responses and the average daily consumption of ED in multiple regression models. Those who consumed ED 'to concentrate' or 'to perform better in school' consumed on average 73⋅1 (CI 65⋅8, 80⋅3) and 112⋅0 (CI 102⋅7, 121⋅2) ml more daily, respectively, than those who did not consume ED for these reasons. Up to 80 % of the adolescents reported that 'my parents think it is OK that I drink energy drink', but at the same time almost 50 % reported that 'my parents say that I shouldn't drink energy drink'. Apart from increased endurance and feeling stronger, both desired and adverse effects of ED consumption were reported. Our findings indicate that the expectation created by the ED companies have great influence on the adolescents' consumption rate and that parental attitudes towards ED have little to no influence on the adolescents' consumption rate.

Current outcomes of live-born children with double outlet right ventricle in Norway.

OBJECTIVES: This population-based, comprehensive, retrospective study presented the clinical outcomes of all children born in Norway between 2003 and 2017 with double outlet right ventricle (DORV). METHODS: All children born with DORV between 2003 and 2017 were identified in the Oslo University Hospital registry. Patients' characteristics, interventions, complications and deaths were recorded. Echocardiographic data were reviewed for classification according to current standards. We investigated time-dependent surgical reintervention and mortality using Kaplan-Meier analyses and determinants of treatment complications, reintervention and death using regression analyses. RESULTS: Ninety-three children with DORV represented an annual median prevalence of 1.18 per 10 000 births in Norway. Six children received palliative care. With an intention to treat, a surgical route with the primary biventricular repair was followed for 62 children, staged biventricular repair for 15 and univentricular repair for 10 children. Major complications occurred in 1.0% and 6.2% of children following catheter or surgical intervention, respectively. No significant determinants of the complications were identified. Overall survival following treatment was 91.9%, 90.8%, 89.5% and 89.5% and corresponding freedom from surgical reintervention was 88.0%, 79.0%, 74.9% and 69.4% at 1, 2, 5 and 10 years, respectively. The presence of atrioventricular septal defect predicted an increased risk of mortality (hazard ratio: 7.16) but did not increase the risk of surgical reintervention. CONCLUSIONS: In Norway, most children receive tailored treatment for DORV with low rates of complications, surgical reinterventions and mortality. However, atrioventricular septal defect remains a potential determinant of postoperative death.

Modifiable and non-modifiable risk factors for obstetric anal sphincter injury in a Norwegian Region: a case-control study.

BACKGROUND: Obstetric anal sphincter injury (OASI) is a common and severe complication of vaginal delivery and may have short- and long-term consequences, including anal incontinence, sexual dysfunction and reduced quality of life. The rate of OASI varies substantially between studies and national birth statistics, and a recent meta-analysis concluded that there is a need to identify unrecognized risk factors. Our aim was therefore to explore both potential modifiable and non-modifiable risk factors for OASI. METHODS: We performed a case-control study in a single center maternity clinic in South-Eastern Norway. Data were extracted retrospectively from an institutional birth registry. The main outcome measure was the occurrence of the woman's first-time 3rd or 4th degree perineal lesion (OASI) following singleton vaginal birth after 30 weeks' gestation. For each woman with OASI the first subsequent vaginal singleton delivery matched for parity was elected as control. The study population included 421 women with OASI and 421 matched controls who gave birth during 1990-2002. Potential risk factors for OASI were assessed by conditional logistic regression analyses. RESULTS: The mean incidence of OASI was 3.4% of vaginal deliveries, but it increased from 1.9% to 5.8% during the study period. In the final multivariate regression model, higher maternal age and birthweight for primiparous women, and higher birthweight for the multiparous women, were the only non-modifiable variables associated with OASI. Amniotomy was the strongest modifiable risk factor for OASI in both primi- (odds ratio [OR] 4.84; 95% confidence interval [CI] 2.60-9.02) and multiparous (OR 3.76; 95% CI 1.45-9.76) women, followed by augmentation with oxytocin (primiparous: OR 1.63; 95% CI 1.08-2.46, multiparous: OR 3.70; 95% CI 1.79-7.67). Vacuum extraction and forceps delivery were only significant risk factors in primiparous women (vacuum: OR 1.91; 95% CI 1.03-3.57, forceps: OR 2.37; 95% CI 1.14-4.92), and episiotomy in multiparous women (OR 2.64; 95% CI 1.36-5.14). CONCLUSIONS: Amniotomy may be an unrecognized independent modifiable risk factor for OASI and should be further investigated for its potential role in preventive strategies.

Sleep and energy drink consumption among Norwegian adolescents - a cross-sectional study.

BACKGROUND: Adolescents are recommended to get 8-10 h of sleep at night, yet more than 80% fail to obtain this goal. Energy drink (ED) consumption has been linked to later bedtime in adolescents. Therefore, we aimed to investigate the potential association between ED consumption and sleep duration, and shuteye latency among adolescents in Norway. METHODS: This study was based on data from 15- to 16-year-old adolescents living in Oppland County in 2017. In total, 1353 adolescents were included in the analysis. Multiple regression models were used to estimate the associations between the frequency of ED consumption with sleep duration, shuteye latency, and getting 8 h of sleep. RESULTS: Forty-six point five percent of the adolescents reported sleeping more than 8 h at night. Those who reported ED consumption at any frequency had significantly shorter sleep duration than those who did not. On average, high consumers of ED (consuming ED ≥ 4 times a week) had 0.95 (95% CI: 0.61, 1.28) hours (i.e., 57 min) less sleep than those who never consumed ED. In addition, high consumers had more than 25 min (95% CI: 13.95, 36.92) longer shuteye period than those who never consumed ED. CONCLUSION: Most ED consumers fail to obtain the recommended 8 h of sleep at night, which could be a consequence of shorter sleep duration and longer shuteye latency. We found a dose-response relationship between frequency of ED consumption and reduced sleep. Yet, the potential long-term effects of both ED consumption and insufficient sleep among adolescents remain unclear.

Social determinants and changes in energy drink consumption among adolescents in Norway, 2017-2019: a cross-sectional study.

OBJECTIVES: To describe the social determinants and development in energy drink consumption among Norwegian adolescents in 2017, 2018 and 2019. DESIGN: Cross-sectional, online, annual, nationwide surveys (Ungdata). SETTING: Responses collected online from January 2017 to December 2019. PARTICIPANTS: Lower and upper secondary school students (n=297 102) aged 12-19 years who responded in 2017, 2018 and 2019. MAIN OUTCOME MEASURES: Frequency of energy drink consumption. RESULTS: Over the 3-year period, 66.4% of the men and 41.8% of the women had consumed energy drink once a week or more. The proportion of female high consumers (consuming energy drink more than four times a week) increased from 3.3% to 4.9% between 2017 and 2019; for male, the increase was from 9.8% to 11.5%. In females, the proportion of high consumers increased with 24% (relative risk; CI) (1.24; 1.09 to 1.41) from 2017 to 2018 and 46% (1.46; 1.31 to 1.62) from 2017 to 2019. The corresponding increases in males were 10% (1.10; 1.01 to 1.20) from 2017 to 2018 and 12% (1.12; 1.05 to 1.19) from 2017 to 2019. Any energy drink consumption as well as high energy drink consumption were independently associated with school level, less central residency, low socioeconomic status, physical inactivity and high leisure screen time. CONCLUSION: We found an increase in high consumers among both boys and girls between 2017 and 2019. The observed increase in energy drink consumption among adolescents can explain some of the increased sales of energy drink in Norway.

Health-Related Behaviors in Adolescents Mediate the Association between Subjective Social Status and Body Mass Index.

The aim of this study was to explore the association between adolescent subjective social status (SSS) and body mass index (BMI) at two different time points and to determine whether this association was mediated by health-related behaviors. In 2002 (n = 1596) and 2017 (n = 1534), tenth-grade students (15-16 years old) in schools in the District of Oppland, Norway, completed a survey. Four categories of perceived family economy were measured as SSS, and structural equation modeling was performed, including a latent variable for unhealthy behavior derived from cigarette smoking, snuff-use, and alcohol-drinking as well as dietary and exercise as mediators. No linear association was found between SSS and BMI in 2002 (standardized ß -0.02, (95% confidence interval (CI) -0.07, 0.03)). However, an association was present in 2017 (standardized ß -0.05 (95% CI -0.10, -0.001)), indicating that BMI decreased by 0.05 standard deviations (0.05 × 3.1 = 0.16 BMI unit) for every one-category increase in SSS. This association was mediated by exercise (standardized ß -0.013 (95% CI -0.02, -0.004) and unhealthy behavior (standardized ß -0.009 (95% CI -0.002, -0.04)). In conclusion, a direct association between SSS and BMI was found in 2017 in this repeated cross-sectional survey of 15-16-year-old Norwegian adolescents. This association was mediated through health-related behavior.

A Cross-Sectional Study of the Relationship Between Mental Health Problems and Overweight and Obesity in Adolescents.

Background: There is a suggested coexistence between obesity and mental health discomfort in adolescence. The objective of this study was to explore if mental health indices covaried with body mass index (BMI) in adolescence and if there were gender-related disparities. Methods: Data were collected in two cross-sectional surveys of 10th-grade students (15 to 16 years old) carried out in 2002 and 2017. The questionnaires included self-reported height and weight, questions covering mental health using the Strengths and Difficulties Questionnaire (SDQ), lifestyle, and sociodemographic variables. We estimated the associations between SDQ subscale scores and BMI and the prevalence of overweight and obesity in linear and logistic multivariable models. We also estimated the extent to which gender modified these associations. Results: BMI was positively associated with peer problems [beta (ß): 0.08, (95% confidence interval 0.01, 0.14)], indicating that for every point increase in peer problems subscore, BMI increased by 0.08 kg/m2. The association between internalizing (i.e., peer and emotional) problems and BMI and conduct problems and BMI was different for boys and girls (p < 0.05 for all effect modifications). Conclusion: In this repeated cross-sectional study across 15 years, we found that peer problems were associated with BMI in Norwegian adolescents. We also found that there is a possibility that adolescent boys and girls report different mental health symptoms related to increased BMI. This finding implicates a need for gender-specific attention when assessing risk factors for increased BMI in adolescents.

Vitamin D Status and Its Determinants in A Paediatric Population in Norway.

Recommendations for sufficient vitamin D intake in children were recently revised in Norway. However, optimal levels of vitamin D are still debated and knowledge on supplementation and vitamin D levels in healthy children in Norway is scarce. Therefore, we measured the plasma-concentration of 25-hydroxyvitamin D (25(OH)D) in children and adolescents attending the outpatient paediatric clinics in Innlandet Hospital Trust, Norway during two consecutive years (2015-2017). We recruited 301 children and adolescents aged 5 months to 18 years (mean 7.8, SD 4.4 years) for the study and obtained sample material for 25(OH)D measurements from 295 (98%). Information on diet, vitamin D supplementation, sun exposure, ethnicity, parental education and general health was collected by questionnaire. 25(OH)D levels were analysed and determinants for 25(OH)D were estimated by linear regression. 1.0% of the children had deficient levels (25(OH)D < 25 nmol/L) and 21.0% had insufficient levels (25-50 nmol/L). 25(OH)D levels ranging from 50 to 75 nmol/L were found among 38.3%, while 39.7% had levels above 75 nmol/L. The mean 25(OH)D level was 70.0 nmol/L (SD 23.4, range 17-142 nmol/L) with a significant seasonal variation with lowest levels in mid-winter and highest in late summer. In addition to seasonal variation independent determinants for 25(OH)D-levels were age of the child, parental ethnicity, vitamin D supplementation and soda consumption. Along with parental ethnicity other than Nordic, age was the strongest determinant of 25(OH)D, with adolescents having the lowest levels.

No significant associations between breastfeeding practices and overweight in 8-year-old children.

AIM: The aim was to examine if breastfeeding practices were associated with body mass index (BMI) and risk of overweight or obesity in third grade (8 years) of elementary school. METHODS: In a regional cohort, we related BMI z-scores and presence of overweight or obesity at 8 years of age with ever being breastfed and with duration of exclusive and partial breastfeeding after adjusting for potential confounders. Parents completed questionnaires on breastfeeding and sociodemographic and lifestyle factors at school entry, and public health nurses measured height and weight. For non-participants, the nurses anonymously reported these measurements together with sex and age. RESULTS: 90% of participants had been breastfed. In adjusted analyses, BMI z-scores were not significantly related to whether or not the child had been breastfed (P = .64), or to the duration of exclusive (P = .80) or partial breastfeeding (P = .94). Logistic regression also showed no significant association between breastfeeding measures and overweight or obesity. CONCLUSION: This study on 8-year-old Norwegian children did not support a commonly held notion that breastfeeding reduces the risk of overweight or obesity.

Sex-related change in BMI of 15- to 16-year-old Norwegian girls in cross-sectional studies in 2002 and 2017.

BACKGROUND: The prevalence of overweight and obesity (OWOB) has stabilized in some countries, but a portion of children with high body mass index (BMI) may have become heavier. This study aimed to describe the distributions of BMI and the point prevalence of OWOB in Norwegian adolescents in 2002 and 2017. METHODS: A cross-sectional study involving 15- to 16-year-old adolescents in Oppland, Norway, was undertaken in 2002 and 2017. We calculated their BMI, BMI z-scores (BMIz), and the prevalence of OWOB. RESULTS: The mean BMI increased from 20.7 to 21.4 (p < 0.001) for girls but remained unchanged at 21.5 vs 21.4 (p = 0.80) for boys. The prevalence of OWOB increased from 9 to 14% among girls (difference 5, 95% CI: 2, 8) and from 17 to 20% among boys (difference 3, 95% CI: - 1, 6%). The BMI density plots revealed similar shapes at both time points for both sexes, but the distribution for girls shifted to the right from 2002 to 2017. CONCLUSION: Contrary to previous knowledge, we found that the increase in OWOB presented a uniform shift in the entire BMI distribution for 15-16-year-old Norwegian girls and was not due to a larger shift in a specific subpopulation in the upper percentiles.

Consumption of energy drinks among adolescents in Norway: a cross-sectional study.

BACKGROUND: Energy drink (ED) consumption is increasing all over the world. We sought to describe the consumption of EDs among adolescents in Norway, and to explore the determinants of daily and high consumption. METHODS: Population-based cross-sectional data were collected from a sample of 31,091 secondary school students in grade 8-13 aged 12-19 years. School grade, residency, socioeconomic status (SES), physical activity and leisure screen time were included in multiple regression analyses, in order to investigate their associations with daily and high (≥four times weekly) ED consumption. RESULTS: 52.3% of the respondents were ED consumers and 3.5% were high consumers. Boys consumed twice as much ED as girls (boys: 36.3 ml/day, girls: 18.5 ml/day, geometric means), and the proportion of male high consumers was 3.7-times higher than that of females. The adjusted odd ratio (OR) of upper secondary school (grades 11-13, ages 15-19) students being high ED consumers were higher than for lower secondary school (grades 8-10, ages 12-15) students (OR 1.1(confidence interval (CI):1.0-1.3)), as well as higher for rural than urban residents (OR 1.3 (CI: 1.1-1.5)). Gradients for the increased ORs of being a high ED consumer were found for decreased SES, decreased frequency of physical activity and increased daily leisure screen time. CONCLUSIONS: More than half of the respondents reported that they were ED consumers. Daily and high consumption were independently associated with male gender, physical inactivity, high leisure screen time, low socioeconomic status and rural residency.

[An 11-month-year-old girl with repeated respiratory infections]. / En 11 måneder gammel jente med gjentatte luftveisinfeksjoner.

Hidden behind subtle symptoms and unspecific signs, heart failure in children can pose a significant challenge regarding diagnostic approach as well as treatment strategy. A case report is presented for an 11-month-year-old girl with recurrent airway infections and signs of cardiac failure as a consequence of ventricular non-compaction. This disease is morphologically distinct; most likely a developmental defect of the ventricular myocardium. It is characterized by heterogeneity regarding both heredity, age of presentation, symptoms, hemodynamic disturbances, prognosis and therapeutic approach. In general, a symptomatic child with non-compaction has a poor prognosis with a prospect of severe cardiac failure and death. The article summarises how to approach a child presenting with cardiac failure; i.e. initial evaluation, diagnostic and initial stabilizing procedures and alternative treatment strategies. We also discuss specific treatment of ventricular non-compaction and briefly report on children with non-compaction at the largest pediatric cardiology centre in Norway.

National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers.

BACKGROUND: Updated National Academy of Clinical Biochemistry (NACB) Laboratory Medicine Practice Guidelines for the use of tumor markers in the clinic have been developed. METHODS: Published reports relevant to use of tumor markers for 5 cancer sites--testicular, prostate, colorectal, breast, and ovarian--were critically reviewed. RESULTS: For testicular cancer, alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase are recommended for diagnosis/case finding, staging, prognosis determination, recurrence detection, and therapy monitoring. alpha-Fetoprotein is also recommended for differential diagnosis of nonseminomatous and seminomatous germ cell tumors. Prostate-specific antigen (PSA) is not recommended for prostate cancer screening, but may be used for detecting disease recurrence and monitoring therapy. Free PSA measurement data are useful for distinguishing malignant from benign prostatic disease when total PSA is <10 microg/L. In colorectal cancer, carcinoembryonic antigen is recommended (with some caveats) for prognosis determination, postoperative surveillance, and therapy monitoring in advanced disease. Fecal occult blood testing may be used for screening asymptomatic adults 50 years or older. For breast cancer, estrogen and progesterone receptors are mandatory for predicting response to hormone therapy, human epidermal growth factor receptor-2 measurement is mandatory for predicting response to trastuzumab, and urokinase plasminogen activator/plasminogen activator inhibitor 1 may be used for determining prognosis in lymph node-negative patients. CA15-3/BR27-29 or carcinoembryonic antigen may be used for therapy monitoring in advanced disease. CA125 is recommended (with transvaginal ultrasound) for early detection of ovarian cancer in women at high risk for this disease. CA125 is also recommended for differential diagnosis of suspicious pelvic masses in postmenopausal women, as well as for detection of recurrence, monitoring of therapy, and determination of prognosis in women with ovarian cancer. CONCLUSIONS: Implementation of these recommendations should encourage optimal use of tumor markers.

Primary tumor levels of tissue inhibitor of metalloproteinases-1 are predictive of resistance to chemotherapy in patients with metastatic breast cancer.

PURPOSE: Only about 50% of metastatic breast cancer patients benefit from cytotoxic chemotherapy. Today, no validated markers exist for prediction of chemotherapy sensitivity/resistance in this patient group. Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to protect against apoptosis, and the purpose of the present study was to test the hypothesis that tumors expressing high levels of TIMP-1 are protected against apoptosis-inducing agents and thus less sensitive to apoptosis-inducing chemotherapeutic drugs. EXPERIMENTAL DESIGN: We investigated the association between primary tumor expression levels of TIMP-1 protein and objective response to first-line chemotherapy in 173 patients with metastatic breast cancer. RESULTS: When analyzed as a continuous log-transformed variable, increasing TIMP-1 levels were significantly associated with lack of response to cyclophosphamide/methotrexate/5-fluorouracil and anthracycline-based chemotherapy (P = 0.01; odds ratio, 2.0; 95% confidence interval, 1.1-3.3). In a multivariate model, including lymph node status, steroid hormone receptor status, menopausal status, dominant metastases site, type of chemotherapy, and disease-free interval, TIMP-1 was significantly associated with resistance to treatment (P = 0.03; odds ratio, 1.7; 95% confidence interval, 1.1-3.3). CONCLUSIONS: In the present exploratory study, we showed that elevated tumor tissue TIMP-1 levels were significantly associated with a poor response to chemotherapy. By using TIMP-1, we identified a group of patients with metastatic breast cancer, which hardly respond to the most frequently used chemotherapy regimes (i.e., cyclophosphamide/methotrexate/5-fluorouracil and anthracyclines).

Tissue inhibitor of metalloproteinases-1 in the postoperative monitoring of colorectal cancer.

The aim of this study was to investigate whether the pre- and postoperative plasma levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) were associated with outcome in colorectal cancer (CRC). Pre- and postoperative plasma TIMP-1 from 280 curatively resected CRC patients and carcinoembryonic antigen (CEA) in corresponding serum samples were measured and correlated with patient outcome (death, local recurrence (LR) and distant metastases (DM)). The results showed that the course of plasma TIMP-1 from pre- to postoperative levels correlated with patient outcome (P=0.005). However, postoperative plasma TIMP-1 alone was strongly associated with patient outcome, high TIMP-1 predicting short survival (P=0.002). Combining postoperative TIMP-1 and CEA demonstrated that high TIMP-1 and CEA levels predicted poor outcome (P<0.0001); multivariate analysis identifying both parameters as strong prognostic factors for survival, LR and DM (P<0.0001). In conclusion, postoperative plasma TIMP-1 predicts patient outcome both alone and in combination with CEA. Postoperative TIMP-1 may be a marker of residual disease after primary surgery for CRC.

Localization of tissue inhibitor of metalloproteinases 1 (TIMP-1) in human colorectal adenoma and adenocarcinoma.

Tissue inhibitor of matrix metalloproteases 1 (TIMP-1) inhibits the proteolytic activity of matrix metalloproteases and hereby prevents cancer invasion. However, TIMP-1 also possesses other functions such as inhibition of apoptosis, induction of malignant transformation and stimulation of cell-growth. We have previously demonstrated that TIMP-1 is elevated in blood from colorectal cancer patients and that high TIMP-1 levels predict poor prognosis. To clarify the role of TIMP-1 in colorectal tumorigenesis, the expression pattern of TIMP-1 in benign and malignant colorectal tumors was studied. In all of 24 cases of colorectal adenocarcinoma TIMP-1 mRNA was detected by in situ hybridization. In all cases TIMP-1 expression was found in fibroblast-like cells located at the invasive front but was seen only sporadically in normal mucosa. No TIMP-1 mRNA was seen in any of the cases in benign or malignant epithelial cells, in vascular cells or smooth muscle cells. Comparison of sections processed for TIMP-1 in situ hybridization with sections immunohistochemically stained with antibodies against TIMP-1 showed good correlation between TIMP-1 mRNA and immunoreactivity. Combining TIMP-1 in situ hybridization with immunohistochemical staining for alpha-smooth muscle actin or CD68 showed TIMP-1 mRNA in myofibroblasts but not in macrophages. TIMP-1 mRNA was detected in 2 of 7 adenomatous polyps in the adenoma area: in both cases associated with focal stromal inflammation at the epithelial-stromal interface. In conclusion, TIMP-1 expression is a rare event in benign human colon tissue but is highly expressed by myofibroblasts in association with invading colon cancer cells.

Plasma TIMP-1 in patients with colorectal adenomas: a prospective study.

Colorectal cancer patients have increased plasma levels of tissue inhibitor of metalloproteinases-1 (TIMP-1). However, it remains unresolved whether colorectal adenomas are associated with increased plasma TIMP-1. Plasma TIMP-1 levels were determined using an immunoassay in 121 patients prospectively enrolled from surveillance colonoscopy programmes. TIMP-1 levels were correlated to various clinicopathological parameters. No significant associations were found between plasma TIMP-1 and size, macro- or microscopic morphology or grade of dysplasia of the adenomas. No significant differences in TIMP-1 levels were found between patients with adenomas (n = 36), hyperplastic polyps (n = 12) or no pathology (n = 68) of the large intestine. However, patients with colonic (n = 3) or rectal (n = 2) adenocarcinomas had significantly increased TIMP-1 levels (P = 0.02). The present study demonstrates that measurement of plasma TIMP-1 cannot be used for the identification of adenomatous or hyperplastic polyps of the large intestine.