Risk of ovarian cancer in BRCA1 and BRCA2 mutation-negative hereditary breast cancer families

Women from site-specific hereditary breast cancer families who carry a BRCA1 or BRCA2 mutation are at increased risk for ovarian cancer. It is less clear, however, whether individuals from hereditary breast cancer families who do not carry such a mutation are also at increased ovarian cancer risk. To determine whether women from BRCA mutation-negative hereditary breast cancer families are at increased risk for ovarian cancer, 199 probands from BRCA mutation-negative, site-specific breast cancer kindreds who consented to prospective follow-up at the time of genetic testing were identified. The incidence of new breast and ovarian cancers in probands and their families since receipt of their genetic test results was determined by questionnaire. The expected number of cancers and standardized incidence ratios (SIRs) were determined from age-specific cancer incidence rates from the Surveillance, Epidemiology, and End Results (SEER) program by using the method of Byar. All statistical tests were two-sided. During 2534 women-years of follow-up in 165 kindreds, 19 new cases of breast cancer were diagnosed, whereas only 6.07 were expected (SIR = 3.13, 95% confidence interval [CI] = 1.88 to 4.89; P < .001), and one case of ovarian cancer was diagnosed, whereas only 0.66 was expected (SIR = 1.52, 95% CI = 0.02 to 8.46; P = .48). These results suggest that women from BRCA mutation-negative, site-specific breast cancer families are not at increased risk for ovarian cancer.     

Assessing, mapping and validating site-specific ecotoxicological risk for pesticide mixtures: a case study for small scale hot spots in aquatic and terrestrial environments

Mixture toxicity is a real world problem and as such requires risk assessment solutions that can be applied within different geographic regions, across different spatial scales and in situations where the quantity of data available for the assessment varies. Moreover, the need for site specific procedures for assessing ecotoxicological risk for non-target species in non-target ecosystems also has to be recognised. The work presented in the paper addresses the real world effects of pesticide mixtures on natural communities. Initially, the location of risk hotspots is theoretically estimated through exposure modelling and the use of available toxicity data to predict potential community effects. The concept of Concentration Addition (CA) is applied to describe responses resulting from exposure of multiple pesticides The developed and refined exposure models are georeferenced (GIS-based) and include environmental and physico-chemical parameters, and site specific information on pesticide usage and land use. As a test of the risk assessment framework, the procedures have been applied on a suitable study areas, notably the River Meolo basin (Northern Italy), a catchment characterised by intensive agriculture, as well as comparative area for some assessments. Within the studied areas, the risks for individual chemicals and complex mixtures have been assessed on aquatic and terrestrial aboveground and belowground communities. Results from ecological surveys have been used to validate these risk assessment model predictions. Value and limitation of the approaches are described and the possibilities for larger scale applications in risk assessment are also discussed.     

Volume of resection in patients treated with breast conservation for ductal carcinoma in situ

Background: The optimal treatment of ductal carcinoma in situ (DCIS) is one of the most controversial issues in the management of breast cancer. Identification of factors that affect the risk of local recurrence is very important as the incidence of DCIS increases and the use of breast conservation becomes more widespread. Because the extent of resection may affect the relapse rate, we hypothesized that larger volumes of resection (VR) may account for the lower local recurrence rates we have previously found in elderly patients. Methods: Between 1978 and 1990, 173 cases of histologically confirmed DCIS were treated at MSKCC with breast conservation therapy. Of these, complete VR data were available for 126 cases. The VRs thus obtained were divided into two groups, <60 cm³ and 60 cm³, and were evaluated for correlating factors. The patients were divided into three groups by age at diagnosis: younger than 40 years, 40 to 69 years, and 70 years or older. Results: The eldest group had a significantly greater proportion of large VRs (30%) as compared to the middle group (11%) and the youngest group (9%) (P=.03, x²). Although not statistically significant, the large VR group had a lower 6-year actuarial local recurrence rate (5.6%) than did the small VR group (21.3%) (P=.16, log-rank test). This trend was observed even though adjuvant radiotherapy was used less often in patients who had large VRs. Conclusion: Breast conservation surgery for DCIS in elderly patients is more likely to employ a large VR. This may explain, at least in part, the observation that elderly patients have a lower local recurrence rate.Presented at the 50th Annual Cancer Symposium of The Society of Surgical Oncology, Chicago, Illinois, March 20–23, 1997.     

Intradermal Radiocolloid and Intraparenchymal Blue Dye Injection Optimize Sentinel Node Identification in Breast Cancer Patients

Background: Radiotracer and blue dye mapping of sentinel lymph nodes (SLN) have been advocated as accurate methods to stage the clinically negative axilla in breast cancer patients. The technical aspects of SLN biopsy are not fully characterized. In this study we compare the results of intraparenchymal (IP) and intradermal (ID) injection of Tc-99m sulfur colloid, to establish an optimal method for SLN localization.Methods: 200 consecutive patients had SLN biopsy performed by a single surgeon. Of these, 100 (Group I) had IP injection and 100 (Group II) had ID injection of Tc-99m sulfur colloid. All patients had IP injection of blue dye as well. Endpoints included (1) successful SLN localization by lymphoscintigraphy, (2) successful SLN localization at surgery, and (3) blue dye–isotope concordance (uptake of dye and isotope by the same SLN).Results: Isotope SLN localization was successful in 78% of Group I and 97% of group II patients (P < .001). When isotope was combined with blue dye, SLN were found in 92% of group I and 100% of Group II (P < .01). In cases where both dye and isotope were found in the axilla, dye mapped the same SLN as radiotracer in 97% of Group I and 95% of Group II patients.Conclusions: The dermal and parenchymal lymphatics of the breast drain to the same SLN in most patients. Because ID injection is easier to perform and more effective, this technique may simplify and optimize SLN localization.     

Sentinel lymph node biopsy after percutaneous diagnosis of nonpalpable breast cancer.

PURPOSE: To determine the technical success rate of sentinel lymph node biopsy in women with nonpalpable infiltrating breast cancer diagnosed by using percutaneous core biopsy and to determine the frequency with which sentinel lymph node biopsy obviated axillary dissection. MATERIALS AND METHODS: Retrospective review revealed 33 women who underwent sentinel node biopsy after percutaneous core biopsy diagnosis of nonpalpable infiltrating breast cancer. Sentinel nodes were identified with radioisotope and blue dye; the procedure was technically successful if sentinel nodes were found at surgery. All sentinel nodes were excised. Axillary dissection was performed if tumor was present in sentinel nodes. RESULTS: Sentinel nodes were found at surgery in 30 women (91%). Sentinel nodes were identified with both radioisotope and blue dye in 22 (73%) of these women, with only radioisotope in six (20%), and with only blue dye in two (7%). Sentinel nodes were found in 12 (80%) of 15 women in the first half of the study versus all 18 (100%) women in the second half (P = .08). Sentinel nodes were free of tumor in 23 (77%) of 30 women. In six (86%) of seven women with tumor in sentinel nodes, the sentinel nodes were the only nodes with tumor. CONCLUSION: Sentinel node biopsy was successful in 30 women (91%) with nonpalpable infiltrating carcinoma diagnosed with percutaneous core biopsy and obviated axillary dissection in 23 women (70%). Using both radioisotope and blue dye may increase the success rate. A learning curve exists, and success improves with experience.     

Salvage mastectomy for local and regional recurrence after breast-conserving operation and radiation therapy.

Forty-six patients initially treated for carcinoma of the breast by tumor excision and radiation therapy who had local and regional recurrence with no evidence of distant disease and who underwent salvage mastectomy at Memorial Sloan-Kettering Cancer Center between 1970 and 1990 were reviewed retrospectively. These patients represent a recent series of patients treated with breast-conserving surgery, radiation therapy and subsequent salvage mastectomy with a median follow-up period of five years (range of one to 20 years). The mean age at initial diagnosis was 52 years (range of 31 to 75 years). All patients had excision of the primary tumor; 27 underwent local excision with axillary dissection. The median radiation therapy dose to the breast was 48 Gy. The distribution of stage of disease at the time of breast conserving treatment was stage 0 in seven patients, stage I in 13 patients, stage II in 14 and stage III in one patient. Twenty-seven patients received conservation treatment at other institutions and were referred to our institution for salvage operation. Local and regional relapse occurred at a median of 28 months (range of five months to seven years) after initial treatment. Relapses occurred only in the breast in 35 patients, in the axilla in one patient and in both sites in ten patients. Salvage operation consisted of total mastectomy in 50 per cent, modified radical mastectomy in 33 per cent and radical mastectomy in 17 per cent. Follow-up evaluation after salvage mastectomy (median 28 months, range of one month to 18 years) yielded an actuarial proportion free of disease at five years of 55 per cent (+/- 11 per cent) and an over-all five year survival rate of 76 per cent (+/- 10 per cent). The median time to relapse was 97 months (+/- eight months) and the median survival time was 103 months (+/- seven months). The local recurrence rate after salvage mastectomy was 15 per cent. These data suggest that salvage mastectomy provides local control of recurrent carcinoma of the breast and relapse-free survival time may be improved by postsalvage systemic therapy.     

State-of-the-art approaches to sentinel node biopsy for breast cancer: study design, patient selection, technique, and quality control at Memorial Sloan-Kettering Cancer Center

Sentinel lymph node (SLN) biopsy has the potential to become a standard operation for most patients with operable breast cancer, but raises a number of issues for the surgeon and institution wishing to start a SLN program. We began to perform SLN biopsy for breast cancer at Memorial Sloan-Kettering Cancer Center in September of 1996. Based on a pilot study of 60 patients, detailed analyses of our first 500 and 1000 cases, and a cumulative experience of 1500 procedures, we report the lessons learned in starting a SLN program, emphasizing study design, case selection, technique and quality control. All patients had clinical T1-2N0 breast cancers and isotope plus blue dye mapping. The combination of blue dye and isotope localization was superior to either method alone, unfiltered technetium sulfur colloid was superior to filtered, and optimum isotope localization was achieved with a low-volume, low-dose intradermal injection. In our first 1000 cases, 14% of SLN were found by isotope alone, and 8% by dye alone. 10% of positive SLN were found by isotope alone, and 11% by dye alone. Failed and false-negative SLN procedures were less frequent as experience increased.     

Shift in imaging modalities of the spine through 25 years and its impact on patient ionizing radiation doses

STUDY DESIGN: Retrospective. OBJECTIVE: To explore the shift in modalities when diagnosing the spine in the years 1979-2003. To see how this shift, together with a radiation protective policy, have influenced on the ionizing radiation doses. SUMMARY OF BACKGROUND DATA: The shift from CT/myelography to MR when diagnosing the spine is well known. To what extent this has changed the radiation doses has to our knowledge not yet been published. METHODS: Activity reports from a department of radiology have been reviewed. Relevant radiation doses estimates have been obtained from the Norwegian Radiation Protection Authority. RESULTS: MRI was introduced in 1992 and has been used increasingly since then. Conventional X-ray to the spine has been practically unchanged. Myelography and CT decreased markedly after the introduction of MRI. The total number of examinations of the spine has increased, but the radiation doses given have decreased since 1993. CONCLUSIONS: The introduction of MRI together with a radiation protective policy have reduced the ionizing radiation doses given to this population, in spite of an increase in the total number of examinations of the spine.     

Quantifying the potential for dose reduction with visual grading regression

Objectives

To propose a method to study the effect of exposure settings on image quality and to estimate the potential for dose reduction when introducing dose-reducing measures.

Methods

Using the framework of visual grading regression (VGR), a log(mAs) term is included in the ordinal logistic regression equation, so that the effect of reducing the dose can be quantitatively related to the effect of adding post-processing. In the ordinal logistic regression, patient and observer identity are treated as random effects using generalised linear latent and mixed models. The potential dose reduction is then estimated from the regression coefficients. The method was applied in a single-image study of coronary CT angiography (CTA) to evaluate two-dimensional (2D) adaptive filters, and in an image-pair study of abdominal CT to evaluate 2D and three-dimensional (3D) adaptive filters.

Results

For five image quality criteria in coronary CTA, dose reductions of 16–26% were predicted when adding 2D filtering. Using five image quality criteria for abdominal CT, it was estimated that 2D filtering permits doses were reduced by 32–41%, and 3D filtering by 42–51%.

Conclusions

VGR including a log(mAs) term can be used for predictions of potential dose reduction that may be useful for guiding researchers in designing subsequent studies evaluating diagnostic value. With appropriate statistical analysis, it is possible to obtain direct numerical estimates of the dose-reducing potential of novel acquisition, reconstruction or post-processing techniques.The ultimate diagnostic value of an imaging procedure can be assessed only in relation to an accepted reference standard, using concepts such as sensitivity, specificity or receiver operating characteristic (ROC). Such studies require considerable resources in terms of image material and competent reviewers, and are typically performed at a late stage in the development of new procedures. However, in the earlier phases, when protocols are being formulated, evaluated and compared, there is often a need to perform repeated evaluations of protocols that differ only slightly (e.g. to optimise the diagnostic value in relation to ionising radiation dose in CT or examination time in MRI). In these situations, an attractive alternative is visual grading experiments (i.e. experiments in which diagnosticians are asked to assess some aspect of the quality of an image on an ordinal scale, or to compare a pair of images using a similar scale) [1]. The image quality criteria often relate to the visibility of certain anatomical structures, as is the case with the European Union criteria for CT image quality [2].In particular, several methods have been proposed to reduce the dose of ionising radiation in CT. As the obvious price of a reduced dose is an increase in image noise, most of these have aimed at suppressing the amount of noise in the images, in order to preserve diagnostic image quality while reducing the dose. Of particular interest is the use of alternative reconstruction techniques (iterative—algebraic or statistical—algorithms rather than filtered back projection), which have a long history [3-5] but have only recently become commercially available [6,7], as well as the application of post-processing in the form of non-linear filters [8]. For evaluating these methods, visual grading experiments may be useful.The basic design of visual grading studies is rather straightforward, comprising either evaluation of one image (or stack) at a time or comparison of two images (stacks) simultaneously [1]. However, when it comes to the statistical analysis of the rating data, there is less consensus on the choice of methods. The use of parametric statistical methods based on least-square approximation, such as analysis of variance, may be tempting, but is not statistically appropriate, as the data to be analysed are defined on an ordinal scale. To solve this problem, Båth and Månsson [9] have proposed the non-parametric visual grading characteristic (VGC) method. In simple situations where two imaging protocols are to be compared, this approach appears to work well. The same is true of an alternative non-parametric method introduced by Svensson [10], which has also been applied to the evaluation of image quality [11]. For more complex situations, however, the visual grading regression (VGR) method [12] is easier to apply if one wants to separately evaluate the effects of acquisition settings, reconstruction algorithms and post-processing.With the traditional design of visual grading studies evaluating dose reduction measures, images with and without the intervention studied, and acquired at a limited number of different dose levels, are compared with each other, either directly in image-pair experiments or indirectly by studying the grading scores in single-image experiments. It thus seems possible to draw conclusions only on actually tested doses.An alternative approach to the evaluation of dose-reducing techniques is to try and quantify separately the effects of the intervention and of variations in the dose, and then relate these effects to each other. The goal of the analysis would then be to obtain direct numerical estimates of the potential for dose reduction brought about by the intervention.The aim of this article is to demonstrate how a parametric statistical model can be used to obtain quantitative estimates of the potential for dose reduction when using post-processing such as adaptive filtering.     

Identifying microRNAs regulating B7-H3 in breast cancer: the clinical impact of microRNA-29c

Background:

B7-H3, an immunoregulatory protein, is overexpressed in several cancers and is often associated with metastasis and poor prognosis. Here, our aim was to identify microRNAs (miRNAs) regulating B7-H3 and assess their potential prognostic implications in breast cancer.

Methods:

MicroRNAs targeting B7-H3 were identified by transfecting two breast cancer cell lines with a library of 810 miRNA mimics and quantifying changes of B7-H3 protein levels using protein lysate microarrays. For validations we used western immunoblotting and 3′-UTR luciferase assays. Clinical significance of the miRNAs was assayed by analysing whether their expression levels correlated with outcome in two cohorts of breast cancer patients (142 and 81 patients).

Results:

We identified nearly 50 miRNAs that downregulated B7-H3 protein levels. Western immunoblotting validated the impact of the 20 most effective miRNAs. Thirteen miRNAs (miR-214, miR-363*, miR-326, miR-940, miR-29c, miR-665, miR-34b*, miR-708, miR-601, miR-124a, miR-380-5p, miR-885-3p, and miR-593) targeted B7-H3 directly by binding to its 3′-UTR region. Finally, high expression of miR-29c was associated with a significant reduced risk of dying from breast cancer in both cohorts.

Conclusions:

We identified miRNAs efficiently downregulating B7-H3 expression. The expression of miR-29c correlated with survival in breast cancer patients, suggesting a tumour suppressive role for this miRNA.