Breast cancer outcome in relation to bone mineral density and bisphosphonate use: a sub-study of the DATA trial.

PURPOSE: The phase III DATA study compared 6 and 3 years of adjuvant anastrozole following 2-3 years of tamoxifen in postmenopausal breast cancer patients. This pre-planned side-study assessed the relationship between a reduced bone mineral density (BMD) and distant recurrence-free survival (DRFS), and evaluated the effect of bisphosphonates on DRFS. METHODS: We selected all patients with a BMD measurement within 3 years after randomisation (landmark) without any DRFS events. Kaplan-Meier methods and Cox proportional hazards models were used for analyses. RESULTS: Of 1860 eligible patients, 1142 had a DEXA scan before the landmark. The BMD was normal in 436 (38.2%) and showed osteopenia in 565 (49.5%) and osteoporosis in 141 (12.3%) patients. After a median follow-up of 5.0 years from the landmark, neither osteopenia nor osteoporosis (compared with normal BMD) were associated with DRFS in both the 6-year [osteopenia HR 0.82 (95% CI 0.45-1.49), osteoporosis HR 1.10 (95% CI 0.26-4.67)] and the 3-year arm [osteopenia HR 0.75 (95% CI 0.40-1.42), osteoporosis HR 1.86 (95% CI 0.43-8.01)]. Moreover, bisphosphonate use did not impact DRFS. CONCLUSION: No association was observed between a reduced BMD and DRFS. Neither did we observe an impact of bisphosphonates on DRFS.

The trans-DATA study: aims and design of a translational breast cancer prognostic marker identification study.

BACKGROUND: The effect of extended adjuvant aromatase inhibition in hormone-positive breast cancer after sequential tamoxifen, aromatase inhibitor treatment of 5 years was recently investigated by the DATA study. This study found no statistically significant effect of prolonged aromatase therapy. However, subgroup analysis showed post hoc statistically significant benefits in certain sub-populations. The trans-DATA study is a translational sub-study aiming to identify DNA methylation markers prognostic of patient outcome. METHODS: Patients from the DATA study are included in the trans-DATA study. Primary breast tumour tissue will be collected, subtyped and used for DNA isolation. A genome-wide DNA methylation discovery assay will be performed on 60 patients that had a distant recurrence and 60 patients that did not have a distant recurrence using the Infinium Methylation EPIC Bead Chip platform. Differentially methylated regions of interest will be selected based on Akaike's Information Criterion, Gene Ontology Analysis and correlation between methylation and expression levels. Selected candidate genes will subsequently be validated in the remaining patients using qMSP. DISCUSSION: The trans-DATA study uses a cohort derived from a clinical randomised trial. This study was designed to avoid common pitfalls in marker discovery studies such as selection bias, confounding and lack of reproducibility. In addition to the usual clinical risk factors, the results of this study may identify predictors of high recurrence risk in hormone receptor-positive breast cancer patients treated with sequential tamoxifen and aromatase inhibitor therapy.

Assessment and management of bone health in women with early breast cancer receiving endocrine treatment in the DATA study.

The phase III DATA study investigates the efficacy of adjuvant anastrozole (6 vs. 3 year) in postmenopausal women with breast cancer previously treated with 2-3 years of tamoxifen. This planned side-study assessed patterns of care regarding detection and treatment of osteopenia/osteoporosis, and trends in bone mineral density (BMD) during and after therapy. We registered all BMD measurements and bisphosphonate-use. Time to osteopenia/osteoporosis was analysed by Kaplan Meier methodology. For the trend in T-scores we used linear mixed models with random patients effects. Of 1860 eligible DATA patients, 910 (48.9%) had a baseline BMD measurement. Among patients with a normal baseline BMD (n = 417), osteopenia was observed in 53.5% and 55.4% in the 6- and 3-year group respectively (p = 0.18), during follow-up. Only two patients (3-year group) developed osteoporosis. Of the patients with osteopenia at baseline (n = 408), 24.4% and 20.4% developed osteoporosis respectively (p = 0.89). Three years after randomisation 18.3% and 18.2% used bisphosphonates in the 6- and 3-year groups respectively and 6 years after randomisation this was 23.7% and 20.9% respectively (p = 0.90) of which the majority used oral bisphosphonates. The yearly mean BMD-change during anastrozole in the lumbar spine showed a T-score decline of 0.075. After bisphosphonate addition the decline became less prominent (0.047 (p < 0.001)) and after anastrozole cessation, while continuing bisphosphonates, the mean BMD yearly increased (0.047 (p < 0.001)). In conclusion, extended anastrozole therapy was not associated with a higher incidence of osteoporosis. Anastrozole-use was associated with a BMD decrease; however, the decline was modest and partially reversible after anastrozole cessation.

Efficacy of anastrozole after tamoxifen in early breast cancer patients with chemotherapy-induced ovarian function failure.

The DATA study (NCT00301457) compared 6 and 3 years of anastrozole in postmenopausal women with hormone receptor-positive early breast cancer after 2-3 years of tamoxifen. Patients with chemotherapy-induced ovarian function failure (CIOFF) were also eligible, but could be at risk of ovarian function recovery (OFR). The current analysis compared the survival of women with CIOFF with definitely postmenopausal women and examined the influence of OFR on survival. Therefore, we selected patients from the DATA study aged 45-57 years at randomization who had received (neo)adjuvant chemotherapy. They were classified by reversibility of postmenopausal status: possibly reversible in case of CIOFF (n = 395) versus definitely postmenopausal (n = 261). The former were monitored by E2 measurements for OFR. The occurrence of OFR was incorporated as a time-dependent covariate in a Cox-regression model for calculating the hazard ratio (HR). We used the landmark method to calculate residual 5-year survival rates. When comparing CIOFF women with definitely postmenopausal women, the survival was not different. Among CIOFF women with available E2 follow-up values (n = 329), experiencing OFR (n = 39) had an unfavorable impact on distant recurrence-free survival (HR 2.27 [95% confidence interval [CI] 0.98-5.25; p = 0.05] and overall survival (HR 2.61 [95% CI 1.11-6.13; p = 0.03]). After adjusting for tumor features, the HRs became 2.11 (95% CI 0.89-5.02; p = 0.09) and 2.24 (95% CI 0.92-5.45; p = 0.07), respectively. The residual 5-year rate for distant recurrence-free survival was 76.9% for women with OFR and 92.1% for women without OFR, and for 5-year overall survival 80.8% and 94.4%, respectively. Women with CIOFF receiving anastrozole may be at increased risk of disease recurrence if experiencing OFR.

Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA): a randomised, phase 3 trial.

BACKGROUND: The effect of extended adjuvant aromatase inhibition in hormone receptor-positive breast cancer after sequential endocrine therapy of tamoxifen followed by an aromatase inhibitor for a 5-year treatment period still needs clarification. To address this issue, we began the DATA study to assess different durations of anastrozole therapy after tamoxifen. METHODS: DATA was a prospective, randomised, open-label, multicentre, phase 3 study done in 79 hospitals in the Netherlands. We randomly assigned postmenopausal women with hormone receptor-positive early breast cancer with no signs of disease recurrence after 2-3 years of adjuvant tamoxifen to either 3 or 6 years of anastrozole treatment (1 mg orally once a day) in a 1:1 ratio. We used TENALEA (Trans European Network for Clinical Trials Services) for the randomisation procedure. Stratification factors were nodal status, hormone receptor status, HER2 status, and tamoxifen treatment duration. The primary study endpoint of this analysis was disease-free survival starting beyond 3 years after randomisation (adapted disease-free survival). Here we report the final analysis from the DATA trial, which is registered with ClinicalTrials.gov, number NCT00301457. FINDINGS: Between June 28, 2006, and Aug 10, 2009, we screened 1912 patients of whom 955 were assigned to the 3-year group and 957 to the 6-year anastrozole treatment group. 1860 patients were eligible (931 in the 6-year group and 929 in the 3-year group) and 1660 were disease free 3 years after randomisation. The 5-year adapted disease-free survival was 83·1% (95% CI 80·0-86·3) in the 6-year group and 79·4% (76·1-82·8) in the 3-year group (hazard ratio [HR] 0·79 [95% CI 0·62-1·02]; p=0·066). Patients in the 6-year treatment group had more adverse events than those in the 3-year treatment group, including all-grade arthralgia or myalgia (478 [58%] of 827 in the 6-year treatment group vs 438 [53%] of 833 in the 3-year treatment group) and osteopenia or osteoporosis (173 [21%] vs 137 [16%]). INTERPRETATION: We cannot recommend the use of extended adjuvant aromatase inhibition after 5 years of sequential endocrine therapy in all postmenopausal women with hormone receptor-positive breast cancer. FUNDING: AstraZeneca.

Ovarian Function Recovery During Anastrozole in Breast Cancer Patients With Chemotherapy-Induced Ovarian Function Failure.

Background: Aromatase inhibitors (AIs) are given as adjuvant therapy for hormone receptor-positive breast cancer in postmenopausal women, also to those with chemotherapy-induced ovarian function failure. The current analysis reports on endocrine data of patients with chemotherapy-induced ovarian function failure who were included in the phase III DATA study assessing different durations of adjuvant anastrozole after tamoxifen. Methods: We identified all patients with chemotherapy-induced ovarian function failure. Women who underwent a bilateral ovariectomy or used luteinizing hormone-releasing hormone agonists before random assignment were excluded. Plasma estradiol and follicle-stimulating hormone levels were monitored until 30 months after random assignment at local laboratories. We aimed to determine the ovarian function recovery (OFR) rate during AI use by the cumulative incidence competing risk method and analyzed the trend of estradiol levels during AI use by a nested case-control approach in which a subset of control subjects were compared with the OFR patients excluding the value at OFR diagnosis. Results: The 329 eligible patients had a median age of 50.0 years (range = 45-57 years) at random assignment. Thirty-nine patients developed OFR, corresponding with a 30-month recovery rate of 12.4%. Of these, 11 (28.2%) were age 50 years or older at AI initiation. The estradiol level decreased statistically significantly by 37.8% (95% CI = 27.4% to 46.7%) over the initial 30 months of AI treatment in both groups. However, the estradiol levels in the women who experienced OFR remained statistically significantly higher (difference = 20.6%, 95% CI = 2.0% to 42.7%) prior to OFR diagnosis compared with those who did not experience OFR. Conclusions: The risk of OFR during AI treatment in breast cancer patients with chemotherapy-induced ovarian function failure is relevant, even beyond 45 years. Furthermore, women experiencing OFR had statistically significant higher estradiol levels during AI treatment (before OFR) than those without, with potential consequences regarding efficacy.

Impact of chemotherapy on the outcome of osteosarcoma of the head and neck in adults.

BACKGROUND: There is an ongoing debate about the value of (neo-)adjuvant chemotherapy in high- and intermediate-grade osteosarcoma of the head and neck. METHODS: All records of patients older than 16 years diagnosed with osteosarcoma of the head and neck in the Netherlands between 1993 and 2013 were reviewed. RESULTS: We identified a total of 77 patients with an osteosarcoma of the head and neck; the 5-year overall survival (OS) was 55%. In 50 patients with surgically resected high- or intermediate-grade osteosarcoma of the head and neck younger than 75 years, univariate and multivariable analysis, adjusting for age and resection margins, showed that patients who had not received chemotherapy had a significantly higher risk of local recurrence (hazard ratio [HR] = 3.78 and 3.66, respectively). CONCLUSION: In patients younger than 75 years of age with surgically resected high- and intermediate-grade osteosarcoma of the head and neck, treatment with (neo-)adjuvant chemotherapy resulted in a significantly smaller risk of local recurrence. Therefore, we suggest (neo-)adjuvant chemotherapy in patients amenable to chemotherapy. © 2016 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 39: 140-146, 2017.

Cardiotoxicity and Cardiac Monitoring During Adjuvant Trastuzumab in Daily Dutch Practice: A Study of the Southeast Netherlands Breast Cancer Consortium.

INTRODUCTION: We assessed the incidence and timing of first cardiac events, impact on trastuzumab prescription, and role of left ventricular ejection fraction (LVEF) monitoring in daily practice of trastuzumab-treated patients with human epidermal growth receptor 2 (HER2)-positive early breast cancer. METHODS: We included all patients with stage I-III breast cancer diagnosed in the early years (2005-2007) after the introduction of adjuvant trastuzumab in five hospitals in Southeast Netherlands. We studied the incidence and timing of cardiotoxicity in patients treated with adjuvant trastuzumab, using similar cardiac endpoints as in the Herceptin Adjuvant (HERA) trial. RESULTS: Of 2,684 included patients, 476 (17.7%) had a HER2-positive tumor. Of these, 269 (56.9%) were treated with adjuvant chemotherapy, and of these, 230 (85.5%) also received trastuzumab. Cardiotoxicity was observed in 29 of 230 patients (12.6%). Twenty of the 230 patients (8.7%) had symptomatic cardiotoxicity, defined as a drop in LVEF of at least 10 percentage points and to below 50%, accompanied by symptoms of congestive heart failure. Trastuzumab was definitely discontinued because of supposed cardiotoxicity in 36 patients (15.6%), of whom only 15 (6.5%) had a significant LVEF drop. Of the 36 patients who prematurely discontinued trastuzumab (including the 29 in whom cardiotoxicity was observed), 84.8% stopped in the first 6 months. No cardiac deaths were seen. CONCLUSION: In the first years after implementation of trastuzumab for treatment of early breast cancer, physicians frequently based their decision to discontinue treatment on patient symptoms apart from LVEF outcome. We suggest that focusing LVEF monitoring on the first 6 months might be more cost-effective without compromising patient safety. Nonetheless, further research is needed. IMPLICATIONS FOR PRACTICE: Knowledge of when cardiotoxicity occurs in daily practice will help shape the best follow-up method for cardiac monitoring in trastuzumab-treated patients with human epidermal growth receptor 2-positive early breast cancer. In the first years after implementation of trastuzumab for treatment of early breast cancer, physicians frequently based their decision to discontinue treatment on patient symptoms apart from left ventricular ejection fraction (LVEF) outcome. When cardiotoxicity was found in daily practice, it occurred mainly in the first 6 months after start of trastuzumab. This study suggests that focusing LVEF monitoring on the first 6 months might be more cost-effective without compromising patient safety. This insight stresses the relevance of performing real-world analyses.

Ultrasound is at least as good as magnetic resonance imaging in predicting tumour size post-neoadjuvant chemotherapy in breast cancer.

BACKGROUND: The aim of this study was to evaluate the accuracy of clinical imaging of the primary breast tumour post-neoadjuvant chemotherapy (NAC) related to the post-neoadjuvant histological tumour size (gold standard) and whether this varies with breast cancer subtype. In this study, results of both magnetic resonance imaging (MRI) and ultrasound (US) were reported. METHODS: Patients with invasive breast cancer were enrolled in the INTENS study between 2006 and 2009. We included 182 patients, of whom data were available for post-NAC MRI (n=155), US (n=123), and histopathological tumour size. RESULTS: MRI estimated residual tumour size with <10-mm discordance in 54% of patients, overestimated size in 28% and underestimated size in 18% of patients. With US, this was 63%, 20% and 17%, respectively. The negative predictive value in hormone receptor-positive tumours for both MRI and US was low, 26% and 33%, respectively. The median deviation in clinical tumour size as percentage of pathological tumour was 63% (P25=26, P75=100) and 49% (P25=22, P75=100) for MRI and US, respectively (P=0.06). CONCLUSIONS: In this study, US was at least as good as breast MRI in providing information on residual tumour size post-neoadjuvant chemotherapy. However, both modalities suffered from a substantial percentage of over- and underestimation of tumour size and in addition both showed a low negative predictive value of pathologic complete remission (Gov nr: NCT00314977).

Real-Life Use and Effectiveness of Adjuvant Trastuzumab in Early Breast Cancer Patients: A Study of the Southeast Netherlands Breast Cancer Consortium.

BACKGROUND: The impact of drug prescriptions in real life as opposed to strict clinical trial prescription is only rarely assessed, although it is well recognized that incorrect use may harm patients and may have a significant impact on health care resources. We investigated the use and effectiveness of adjuvant trastuzumab in daily practice compared with the effectiveness in clinical trials. METHODS: We included all patients with stage I-III invasive breast cancer, irrespective of human epidermal growth factor receptor 2 (HER2) status, diagnosed in five hospitals in the southeast of The Netherlands in 2005-2007. We aimed to assess the actual use of adjuvant trastuzumab in early HER2-positive breast and its efficacy in daily practice. RESULTS: Of 2,684 patients included, 476 (17.7%) had a HER2-positive tumor. Of these, 251 (52.7%) patients had an indication for trastuzumab treatment of which 196 (78.1%) patients actually received it. Of the 225 patients without an indication, 34 (15.1%) received trastuzumab. Five-year disease-free survival was 80.7% for (n = 230) patients treated with versus 68.2% for (n = 246) patients not treated with trastuzumab (p = .0023), and 5-year overall survival rates were 90.7% and 77.4%, respectively (p = .0002). The hazard ratio for disease recurrence was 0.63 (95% confidence interval, 0.37-1.06) for trastuzumab when adjusting for potential confounders. CONCLUSION: This study shows that in real life, patients treated with trastuzumab in early-stage HER2-positive breast cancer had a 5-year disease-free and overall survival comparable to prior randomized trials. For informative decision making, real-life data are of additional value, providing insight on outcome of patients considered ineligible for treatment.

A Retrospective Cohort Study on the Influence of Comorbidity on Soft Tissue Reactions, Revision Surgery, and Implant Loss in Bone-anchored Hearing Implants.

OBJECTIVE: To identify risk factors for complications after bone-anchored hearing implant (BAHI) surgery. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: All adult patients who received titanium bone-anchored hearing implants at our clinic between September 1, 1988 and December 31, 2007 were approached to fill out a questionnaire on comorbidity factors. A total of 581 patients with 669 implants were included in the analysis. MAIN OUTCOME MEASURES: Implant loss, soft tissue reactions, and revision surgery after BAHI implantation. RESULTS: Skin disease and profound learning difficulties were risk factors for time to first soft tissue reaction, hazard rate ratio of 3.41 (95% CI 1.45-8.01) and 3.42 (1.03-11.39), respectively. Female gender showed a trend toward a negative risk for time to first soft tissue reaction, hazard rate ratio 0.60 (0.35-1.03). In multivariable analysis, skin disease and female gender were observed as independent associative factors, adjusted hazard ratio 3.08 (1.32-7.16) and 0.56 (0.33-0.94). For revision surgery, female gender and cardiovascular disease were identified as negative risk factors in univariable analysis, and smoking showed a trend toward a negative risk, with hazard ratios of 0.15 (0.07-0.32), 0.07 (0.03-0.20), and 0.51 (0.24-1.07), respectively. In multivariable analysis, smoking and female gender were observed as independent associative factors, adjusted hazard ratio 0.45 (0.22-0.95) and 0.14 (0.06-0.30). Smoking could be identified as a risk factor for implant loss with a hazard ratio of 3.32 (1.36-8.09). CONCLUSION: Retrospective analysis of comorbidity factors and clinical outcomes revealed risk factors for postoperative complications after BAHI surgery.

Annexin A5 haplotypes in familial hypercholesterolemia: lack of association with carotid intima-media thickness and cardiovascular disease risk.

OBJECTIVE: Annexin A5 (ANXA5) has been suggested to possess antiatherogenic properties. We investigated whether ANXA5 genetic variations and plasma ANXA5 levels were associated with carotid atherosclerosis and contributed to cardiovascular disease (CVD) risk in patients with familial hypercholesterolemia (FH). METHODS: We sequenced the promoter region and exon 2 of ANXA5 in 284 FH patients from the ASAP (Atorvastatin versus Simvastatin on Atherosclerosis Progression) trial. Common haplotypes (H) were constructed based on seven single nucleotide polymorphisms (SNPs). We studied whether plasma ANXA5 levels or ANXA5 haplotypes were associated with the extent of atherosclerosis (evaluated by carotid intima-media thickness (IMT). The association between ANXA5 haplotypes and the risk for CVD events was investigated in 1730 FH patients from the GIRaFH (Genetic Identification of Risk factors in Familial Hypercholesterolemia) study. RESULTS: In ASAP, individuals carrying the ANXA5 haplotype H2 exhibited lower plasma ANXA5 levels, whereas H4 carriers had increased levels of circulating ANXA5 compared to non-carriers. Plasma ANXA5 levels were not associated with carotid IMT. None of the four ANXA5 haplotypes correlated with the age-related IMT progression (ASAP study) or contributed to CVD risk (GIRaFH cohort). CONCLUSIONS: Both ANXA5 haplotypes and plasma ANXA5 levels were not associated with carotid IMT progression or CVD risk in FH patients.

A simple risk score to predict the presence of non-sentinel lymph node metastases in breast cancer patients with a positive sentinel node.

BACKGROUND: Historically, completion axillary lymph node dissection (cALND) is recommended in sentinel lymph node (SLN)-positive patients. However, the high rate of negative non-sentinel nodes (NSNs) in cALND and the reported low axillary recurrence rates have led to a more conservative approach. A risk score was developed to identify a patient's individual risk for NSN metastases. METHODS: Data of 182 SLN-positive patients who underwent cALND were used for risk score development. The risk score, consisting of pathological tumor size (≤ 20/>20 mm), lymphovascular invasion (no/yes), extracapsular extension (no/yes), size of metastases (≤ 2/>2 mm), and number of positive SLNs (1/>1), was subsequently validated on an external population (n = 180). RESULTS: The area under the receiver operating characteristic curve was 0.78 (95 % CI 0.71-0.85) in the original population and 0.78 (95 % CI 0.70-0.85) in the validation population. Based on the predicted risk for positive NSNs, three groups were defined: low risk (≤ 20 %), intermediate risk (21-50 %), and high risk (>50 %). In total, 88 patients met the Z0011 inclusion criteria and none of them had a high predicted risk. Of the 199 non-Z0011 patients, 67 (33.7 %) had low risk, 96 (48.2 %) had intermediate risk, and 36 (18.1 %) had high risk. CONCLUSION: A simple risk score, integrating just five clinicopathological variables, was developed that may assist in individual decision making regarding ALND in SLN-positive patients outside of the Z0011 trial.

Comparison of nodal risk formula and MR lymphography for predicting lymph node involvement in prostate cancer.

PURPOSE: To compare the nodal risk formula (NRF) as a predictor for lymph node (LN) metastasis in patients with prostate cancer with magnetic resonance lymphography (MRL) using Ultrasmall Super-Paramagnetic particles of Iron Oxide (USPIO) and with histology as gold standard. METHODS AND MATERIALS: Logistic regression analysis was performed with the results of histopathological evaluation of the LN as dependent variable and the nodal risk according to the NRF and the result of MRL as independent input variables. Receiver operating characteristic (ROC) analysis was performed to assess the performance of the models. RESULTS: The analysis included 375 patients. In the single-predictor regression models, the NRF and MRL results were both significantly (p<0.001) predictive of the presence of LN metastasis. In the models with both predictors included, NRF was nonsignificant (p=0.126), but MRL remained significant (p<0.001). For NRF, sensitivity was 0.79 and specificity was 0.38; for MRL, sensitivity was 0.82 and specificity was 0.93. After a negative MRL result, the probability of LN metastasis is 4% regardless of the NRF result. After a positive MRL, the probability of having LN metastasis is 68%. CONCLUSIONS: MRL is a better predictor of the presence of LN metastasis than NRF. Using only the NRF can lead to a significant overtreatment on the pelvic LN by radiation therapy. When the MRL result is available, the NRF is no longer of added value.

Determination of exposure to benzene, toluene and xylenes in Turkish primary school children by analysis of breath and by environmental passive sampling.

Benzene, toluene, m/p-xylene and o-xylene (BTX) are toxic volatile organic compounds and ubiquitous air pollutants. Smoking and consumer products are indoor sources of BTX, whereas traffic and industrial activities are primary sources contributing to outdoor levels of BTX. The aim of this study was to characterize exposure of children to BTX by personal air sampling using diffusive samplers and by analysis of end-exhaled air. For this study, 101 children of 10-11 years of age were recruited from four primary schools in Southern Turkey during the warm season (May 2008). Two schools were situated in a residential area near primary and secondary iron and steel works (Payas) and two schools were located in a non-industrialized city (Iskenderun). The children and their parents were visited at home for an interview and to identify possible sources of BTX in the residence. Median concentrations of benzene determined by diffusive samplers were higher in Payas (4.1 microg/m(3)) than in Iskenderun (2.7 microg/m(3), p<0.001). For toluene, no differences were observed, whereas for xylene isomers air concentrations tended to be lower for children living in Payas. The median end-exhaled air concentrations were 8.2, 29, 3.8, and 5.7 pmol/L for benzene, toluene, m/p-xylene and o-xylene, respectively (Payas), and 6.9, 25, 4.9, and 6.0 pmol/L, respectively (Iskenderun). Concentrations of toluene in end-exhaled air were 50% higher in children living with household members who smoked indoors (p<0.05) and benzene in end-exhaled air was more than 3-fold higher for those children who were exposed to tobacco smoke inside a vehicle (p<0.001). End-exhaled concentrations of benzene were also higher in children living in a residence with an attached garage (p<0.05). These exposure modifying factors were not identified when using the results obtained with diffusive samplers.

More tumor-affected lymph nodes because of the sentinel lymph node procedure but no stage migration, because the 2002 TNM classifies small tumor deposits as pathologic N0 breast cancer.

BACKGROUND: Intensified examination of the sentinel lymph node (SN) may result in increased detection of tumor-affected lymph nodes. The authors of this report hypothesized that the introduction of the SN procedure has led to stage migration because of the intensified workup of SNs by pathologists. METHODS: After the introduction of the SN procedure, 360 patients with operable breast cancer were included prospectively from 2 large hospitals (Hospital A and Hospital B). The prospectively included patients (the "SN era" group) were compared with 88 historic controls from the year 1994 who were diagnosed with primary breast cancer before introduction of the SN procedure. RESULTS: After correcting for classic clinical and pathologic prognostic factors in a multiple logistic regression analysis, the detection frequency of lymph node involvement was significantly higher in the SN era group compared with historic controls (P = .04). However, when using the 2002 TNM classification, in which isolated tumor cells (

Risk factors for non-sentinel lymph node metastases in patients with breast cancer. The outcome of a multi-institutional study.

BACKGROUND: In this multi-institutional prospective study, we evaluated whether we could identify risk factors predictive for non-sentinel lymph node (non-SN) metastases in breast cancer patients with a positive sentinel lymph node (SN). METHODS: In this multi-institutional study, 541 eligible breast cancer patients were included prospectively. RESULTS: The occurrence of non-SN metastases was related to the size of the SN metastasis (P = .02), primary tumor size (P = .001), and lymphovascular invasion (P = .07). The adjusted odds ratio was 3.1 for SN micro-metastasis compared with SN isolated tumor cells, 4.0 for SN macro-metastasis versus SN isolated tumor cells, 3.1 for tumor size (>3.0 cm compared with 3.0 cm, and with vessel invasion. CONCLUSION: We identified three predictive factors for non-SN metastases in breast cancer patients with a positive SN: size of the SN metastasis; primary tumor size; and vessel invasion. We were not able to identify a specific group of patients with a positive SN in whom the risk for non-SN metastases was less than 5%.

Differences in sentinel lymph node pathology protocols lead to differences in surgical strategy in breast cancer patients.

BACKGROUND: Internationally, there is no consensus on the pathology protocol to be used to examine the sentinel lymph node (SN). At present, therefore, various hospitals use different SN pathology protocols of which the effect has not been fully elucidated. We hypothesized that differences between hospitals in SN pathology protocols affect subsequent surgical treatment strategies. METHODS: Patients from four hospitals (A-D) were prospectively registered when they underwent an SN biopsy. In hospitals A, B, and C, three levels of the SN were examined pathologically, whereas in hospital D, at least seven additional levels were examined. In the absence of apparent metastases with hematoxylin and eosin examination, immunohistochemical examination was performed in all four hospitals. RESULTS: In total, 541 eligible patients were included. In hospital D, more patients were diagnosed with a positive SN (P < .001) as compared with hospitals A, B, and C, mainly because of increased detection of isolated tumor cells. This led to more completion axillary lymph node dissections in hospital D (66.3% of patients (P < .0001), compared with 29.0% in hospitals A, B, and C combined). Positive non-SNs were detected in 13.9% of patients in hospital D, compared with 9.7% in hospitals A, B, and C (P = .70). That is, in 52.4% of patients in hospital D, a negative completion axillary lymph node dissection was performed, compared with 19.3% of patients in hospitals A, B, and C combined. CONCLUSIONS: Differences in SN pathology protocols between hospitals do have a substantial effect on SN findings and subsequent surgical treatment strategies. Whether ultrastaging and, thus, additional surgery can offer better survival remains to be determined.

Low maternal dietary intakes of iron, magnesium, and niacin are associated with spina bifida in the offspring.

Evidence about the preventive effects of nutrients other than folate on the occurrence of spina bifida is scarce. Therefore, the aim of this work was to investigate the role of maternal nutritional intake and the risk of spina bifida in the offspring. In 106 cases and 181 controls, the mothers' nutrient intakes were obtained by an FFQ approximately 24 mo after conception of the index pregnancy. Energy-adjusted mean nutrient intakes were compared, and odds ratios (OR) and 95% CI were calculated. Although mean nutrient intakes were comparable to the Dutch food consumption survey data, fat, cholesterol, iron, and folate intakes were below the 1998 Dutch Recommended Daily Allowances. Case mothers had significantly lower intakes of plant proteins (7%), polysaccharides (4%), fiber (7%), iron (6%), magnesium (6%), and niacin (4%) than control mothers. Mono- and disaccharide intakes were significantly higher (6%) in the case mothers than in control mothers. The adjusted OR (95% CI) in the lowest quartiles for plant proteins was 5.4 (2.3-12.4), for fiber 3.1 (1.5-6.8), for iron 3.5 (1.4-8.3), for magnesium 1.9 (0.9-4.1), and for niacin 2.5 (1.2-5.2). Mono- and disaccharide and polysaccharide intakes in the highest quartile had ORs (95% CI) of 2.9 (1.4-6.3) and 0.5 (0.3-1.0), respectively. The nutritional intake of Dutch women from food groups containing iron and folate seems to be compromised. Low preconceptional intakes of plant proteins, iron, magnesium, and niacin are associated with a 2- to 5-fold increased risk of spina bifida.

Estimating life expectancy and related probabilities in screen-detected breast cancer patients with restricted follow-up information.

Issues such as life expectancy after diagnosis, the number of life years gained by early diagnosis through screening, the probability of dying from breast cancer or of dying from other causes during the lead time period or thereafter can be derived from information on complete survival after diagnosis. A method is presented to estimate complete survival and relevant outcomes after diagnosis of screen-detected cancer when the follow-up period is substantially shorter than the maximum follow-up possible. Survival after diagnosis until death from breast cancer is modelled as the sum of the lead time (LT) and the post-lead time (PLT), where both time periods follow exponential distributions and are assumed to be independent. The survival period after diagnosis until death from causes other than breast cancer (X) is assumed to follow a Gompertz distribution. The survival period after diagnosis until death from any cause (Z) is modelled as the minimum of LT+PLT and X. Maximum likelihood methods were then used to estimate all parameters of Z. This procedure for obtaining maximum likelihood estimates of Z does not need the cause of death (breast cancer or other), which is an advantage over most other methods. Especially in older patients, it may be difficult or even impossible to ascertain the true cause of death. The model was applied to data from the long-term breast cancer screening programme in Nijmegen, the Netherlands. Complete survival was estimated on the basis of survival data on 528 screen-detected breast cancer patients, diagnosed in 1975-1997 and with a mean follow-up of 8.9 years. Estimated life expectancy ranged between 22.3 and 9.0 years for patients diagnosed at the age of 50 and 79 years, respectively, that is, 6.1 and 0.7 life years gained by screening. Through early diagnosis and treatment, screen-detected patients diagnosed at the age of 50 years may have reduced their lifetime risk of dying from breast cancer from 79 per cent to 56 per cent; at the age of 79 the reduction of risk is reduced from 23 per cent to 13 per cent.