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Micro-CT is a promising modality to determine breast tumour size in three dimensions in intact lumpectomy specimens. We compared the accuracy of tumour size measurements using specimen micro-CT with measurements using multimodality pre-operative imaging.A tabletop micro-CT was used to image breast lumpectomy specimens. The largest tumour dimension on three-dimensional reconstructed micro-CT images of the specimen was compared with the measurements determined by pre-operative mammography, ultrasound and MRI. The largest dimension of pathologic invasive cancer size was used as the gold standard reference to assess the accuracy of imaging assessments.50 invasive breast cancer specimens in 50 patients had micro-CT imaging. 42 were invasive ductal carcinoma, 6 were invasive lobular carcinoma and 2 were other invasive cancer. Median patient age was 63 years (range 33-82 years). When compared with the largest pathologic tumour dimension, micro-CT measurements had the best correlation coefficient (r = 0.82, p 0.001) followed by MRI (r = 0.78, p 0.001), ultrasound (r = 0.61, p 0.001) and mammography (r = 0.40, p 0.01). When compared with pre-operative modalities, micro-CT had the best correlation coefficient (r = 0.86, p 0.001) with MRI, followed by ultrasound (r = 0.60, p 0.001) and mammography (r = 0.54, p 0.001). Overall, mammography and ultrasound tended to underestimate the largest tumour dimension, while MRI and micro-CT overestimated the largest tumour dimension more frequently.Micro-CT is a potentially useful tool for accurate assessment of tumour dimensions within a lumpectomy specimen. Future studies need to be carried out to see if this technology could have a role in margin assessment.Micro-CT is a promising new technique which could potentially be used for rapid assessment of breast cancer dimensions in an intact lumpectomy specimen in order to guide surgical excision.

The 2014 guidelines endorsed by Society of Surgical Oncology, the American Society of Breast Surgeons, and the American Society for Radiation Oncology advocate “no ink on tumor” as the new margin requirement for breast-conserving therapy (BCT). We used our lumpectomy margins database from 2004 to 2006 to predict the effect of these new guidelines on BCT. Patients with neoadjuvant therapy, pure ductal carcinoma-in situ, or incomplete margin data were excluded. We applied new (“no ink on tumor”) and old (≥2 mm) margin guidelines and compared rates of positive margins, reexcision, and rates of residual disease found at reexcision. A total of 437 lumpectomy surgeries met the eligibility criteria. Eighty-six percent had invasive ductal carcinoma, 12 % invasive lobular carcinoma, and 2 % invasive ductal carcinoma and invasive lobular carcinoma. Using a ≥2 mm margin standard, 36 % of lumpectomies had positive margins compared to 18 % using new guidelines (p

An increasing number of women are candidates for nipple preservation with mastectomy. It is unclear how previous breast surgery impacts nipple-sparing mastectomy and immediate breast reconstruction.A single-institution retrospective review was performed between June of 2007 and June of 2013.Four hundred forty-four patients underwent 775 immediate breast reconstructions after nipple-sparing mastectomy. Of these, 160 patients and 187 reconstructions had previous breast surgery, including 154 lumpectomies, 27 breast augmentations, and six reduction mammaplasties. Two hundred eighty-four patients with 588 reconstructions without previous breast surgery served as the control group. The previous breast surgery patients were older (49.6 years versus 45.8 years; p0.001) but otherwise had similar demographics. Previous breast surgery reconstructions were more often unilateral, therapeutic, and associated with preoperative radiotherapy (p0.001 for each). Extension of breast scars was common with previous breast surgery, whereas the inframammary incision was most frequent if no scars were present (p0.001). Multivariate regression analysis showed that previous breast surgery was not a significant risk factor for ischemic complications or nipple loss. Subgroup analysis showed extension of prior irradiated incisions was predictive of skin flap necrosis (OR, 9.518; p = 0.05). A higher number of lumpectomy patients had preoperative radiotherapy (41 versus 11; p0.001), and patients with breast augmentation had more single-stage reconstructions (85.2 percent versus 62.9 percent; p = 0.02).Nipple-sparing mastectomy and immediate reconstruction can be performed in patients with prior breast surgery with no significant increase in nipple loss or ischemic complications.Therapeutic, III.

Few studies in the literature examine outcomes of immediate breast reconstruction after mastectomy with nipple preservation and radiation therapy.Retrospective analysis of multisurgeon consecutive implant-based reconstructions after nipple-sparing mastectomy from June of 2007 to December of 2012 was conducted at a single institution.Six hundred five immediate breast reconstructions were performed following nipple-sparing mastectomy, of which 88 were treated with radiation therapy. There was a trend toward more complications in patients with radiation (19.3 percent versus 12.8 percent; p = 0.099) associated with a higher rate of implant loss (6.8 percent versus 1.0 percent; p = 0.001). Preoperative radiotherapy had a higher risk of total complications (p = 0.04; OR, 2.225; 95 percent CI, 1.040 to 4.758) and postoperative radiotherapy had a higher risk of explantation (p = 0.015; OR, 5.634; 95 percent CI, 1.405 to 22.603). There were no significant differences in nipple removal secondary to malposition or positive oncologic margins in patients with radiation compared to those without radiation. Patients with radiation did have a higher incidence of secondary procedures for capsular contracture (12.5 percent versus 2.3 percent; p0.001) and fat grafting (13.6 percent versus 3.9 percent; p0.001). The total nipple retention rate in patients with radiation therapy was 90 percent (79 of 88), and the reconstruction failure rate was 8 percent.Nipple-sparing mastectomy and immediate reconstruction in patients who had or will receive radiation therapy is associated with a higher incidence of complications and operative revisions compared with patients without radiation. However, most patients have successful reconstructions with nipple retention and no recurrences.

The biotechnological task of controlling human aging will evidently be complex, given the failure of all simple strategies for accomplishing this task to date. In view of this complexity, a multi-step approach will be necessary. One precedent for a multi-step biotechnological success is the burgeoning control of human infectious diseases from 1840 to 2000. Here we break down progress toward the control of infectious disease into four key steps, each of which have analogs for the control of aging. (1) Agreement about the fundamental nature of the medical problem. (2) Public health measures to mitigate some of the factors that exacerbate the medical problem. (3) Early biotechnological interventions that ward off the more tractable disease etiologies. (4) Deep understanding of the underlying biology of the diseases involved, leading in turn to comprehensive control of the medical problems that they pose. Achievement of all four of these steps has allowed most people who live in Western countries to live largely free of imminent death due to infectious disease. Accomplishing the equivalent feat for aging over this century should lead to a similar outcome for aging-associated disease. Neither infection nor aging will ever be entirely abolished, but they can both be rendered minor causes of death and disability.

We sought to determine the risk of lymphedema associated with immediate breast reconstruction compared to mastectomy alone.Immediate breast reconstruction is increasingly performed at the time of mastectomy. Few studies have examined whether breast reconstruction impacts development of lymphedema.A total of 616 patients with breast cancer who underwent 891 mastectomies between 2005 and 2013 were prospectively screened for lymphedema at our institution, with 22.2 months' median follow-up. Mastectomies were categorized as immediate implant, immediate autologous, or no reconstruction. Arm measurements were performed preoperatively and during postoperative follow-up using a Perometer. Lymphedema was defined as 10% or more arm volume increase compared to preoperative. Kaplan-Meier and Cox regression analyses were performed to determine lymphedema rates and risk factors.Of 891 mastectomies, 65% (580/891) had immediate implant, 11% (101/891) immediate autologous, and 24% (210/891) no reconstruction. The two-year cumulative incidence of lymphedema was as follows: 4.08% [95% confidence interval (CI): 2.59-6.41%] implant, 9.89% (95% CI: 4.98-19.1%) autologous, and 26.7% (95% CI: 20.4-34.4%) no reconstruction. By multivariate analysis, immediate implant [hazards ratio (HR): 0.352, P 0.0001] but not autologous (HR: 0.706, P = 0.2151) reconstruction was associated with a significantly reduced risk of lymphedema compared to no reconstruction. Axillary lymph node dissection (P 0.0001), higher body mass index (P 0.0001), and greater number of nodes dissected (P = 0.0324) were associated with increased lymphedema risk.This prospective study suggests that in patients for whom implant-based reconstruction is available, immediate implant reconstruction does not increase the risk of lymphedema compared to mastectomy alone.

We present our experience with sentinel lymph node (SLN) biopsy in men with breast cancer and review the literature published to date. Consecutive men with breast cancer undergoing SLN biopsy were identified in our prospectively maintained database. A PubMed search for “male breast cancer” and “sentinel node biopsy” was performed. Thirty patients underwent 31 SLN biopsy procedures between 1996 and 2006. Twenty-five patients presented with a palpable mass, and 13 underwent surgical biopsy for diagnosis. The sentinel lymph node was successfully identified in 90%; 61% of SLN biopsies were positive and, in 65% of this group, the sentinel node was the only positive node. Combined data from the literature from 110 procedures resulted in an identification rate of 96%, positive sentinel nodes in 45% and the sentinel node as the only positive node in 56%. Only 13 patients underwent completion axillary node dissection after a negative SLN biopsy; none were false negatives. This series extends previous knowledge about SLN biopsy in men with respect to diagnostic biopsy, type of mapping agent, lymphoscintigraphy, and location of injection site. The identification rate mirrors that of large randomized trials of women with breast cancer. The high rate of lymph node—positive disease, even in this series of patients with clinically node-negative disease, reflects the later presentation of breast cancer in men.

Womenor = 40 years account for 5% of new breast cancer diagnoses. Although there is increased awareness of genetic and other breast cancer risk factors, it is not clear whether this has resulted in earlier diagnosis in young women.A database review identified 8892 women treated for breast cancer from 1980 to 2002. We compared 925 women agedor = 40 years with 2362 women aged 50 to 60 years. The mean and median tumor size and lymph node status were determined for each group.There were significant differences in tumor size and lymph node status in younger versus older women. From 1980 to the mid 1990s, tumor size and nodal status did not differ. Since the mid 1990s, tumor size has decreased more rapidly for women aged 50 to 60 years than for thoseor = 40 years. In 1998 to 2002, the mean tumor size reached a plateau of 1.8 cm in women 50 to 60 years, compared with a plateau of 2.4 cm in womenor = 40 years (P.001). The median tumor size in 1998 to 2002 was 1.4 cm in women 50 to 60 years compared with 1.9 cm in womenor = 40 years (P.001). Lymph node status was also significantly different during 1998 to 2002: 23.9% positive in women 50 to 60 years versus 35.2% in womenor = 40 years (P.001).Since the 1980s, women aged 50 to 60 years have enjoyed a greater decrease in tumor size and percentage with positive nodes. These data could be the result of ineffective screening of younger women or of more aggressive tumor biology. Further study is required to determine whether more effective identification and screening of young, high-risk women can result in earlier detection.

The diagnosis of breast cancer in young women presents particular challenges in surgical decision making and treatment. These challenges arise from concurrent genetic or other risk factors, potentially more aggressive tumor biology, larger tumor size, and psychosocial factors unique to young women. Local recurrence and survival rates for breast-conserving surgery compared to mastectomy are reviewed and strategies for reducing local recurrence after breast conserving therapy are discussed. Options for incorporating genetic testing and counseling into surgical management are presented. Management of young women with BRCA gene mutations, with a positive family history without a risk gene mutation, and with a history of mantle irradiation for Hodgkin's disease is discussed.

Purpose It has been hypothesized that wide excision alone with margins ≥ 1 cm may be adequate treatment for small, grade 1 or 2 ductal carcinoma in situ (DCIS). To test this hypothesis, we conducted a prospective, single-arm trial. Methods Entry criteria included DCIS of predominant grade 1 or 2 with a mammographic extent of ≤ 2.5 cm treated with wide excision with final margins of ≥ 1 cm or a re-excision without residual DCIS. Tamoxifen was not permitted. The accrual goal was 200 patients. Results In July 2002, the study closed to accrual at 158 patients because the number of local recurrences met the predetermined stopping rules. The median age was 51 and the median follow-up time was 40 months. Thirteen patients developed local recurrence as the first site of treatment failure 7 to 63 months after study entry. The rate of ipsilateral local recurrence as first site of treatment failure was 2.4% per patient-year, corresponding to a 5-year rate of 12%. Nine patients (69%) experienced recurrence of DCIS and four (31%) experienced recurrence with invasive disease. Twelve recurrences were detected mammographically and one was palpable. Ten were in the same quadrant as the initial DCIS and three were elsewhere within the ipsilateral breast. No patient had positive axillary nodes at recurrence or subsequent metastatic disease. Conclusion Despite margins of ≥ 1 cm, the local recurrence rate is substantial when patients with small, grade 1 or 2 DCIS are treated with wide excision alone. This risk should be considered in assessing the possible use of radiation therapy with or without tamoxifen in these patients.

Purpose: Several accelerated partial-breast irradiation (APBI) techniques are being investigated in patients with early-stage breast cancer. We present our initial experience using three-dimensional conformal radiation therapy (3D-CRT). Methods and Materials: Sixty-one patients with tumors of 2 cm or less and negative axillary nodes were treated with 3D-CRT accelerated partial-breast irradiation (APBI) between August 2003 and March 2005. The prescribed radiation dose was 32 Gy in 4-Gy fractions given twice daily. Efforts were made to minimize the number of beams required to achieve adequate planning target volume (PTV) coverage. Results: A combination of photons and electrons was used in 85% of patients. A three-field technique that consisted of opposed, conformal tangential photons and enface electrons was employed in 43 patients (70%). Nine patients (15%) were treated with a four-field arrangement, which consisted of three photon fields and enface electrons. Mean PTV volumes that received 100%, 95%, and 90% of the prescribed dose were 93% ± 7%, 97% ± 4%, and 98% ± 2%, respectively. Dose inhomogeneity exceeded 10% in only 7 patients (11%). Mean doses to the ipsilateral lung and heart were 1.8 Gy and 0.8 Gy, respectively. Conclusions: Simple 3D-CRT techniques of APBI can achieve appropriate PTV coverage while offering significant normal-tissue sparing. Therefore, this noninvasive approach may increase the availability of APBI to patients with early-stage breast cancer.

There has been much uncertainty as to whether metastasis requires mutation at the time of spread. Here, we use clinical data to calculate the probability of the spread of melanoma and breast cancer cells. These calculations reveal that the probability of the spread of cancer cells is relatively high for small tumours (approximately 1 event of spread for every 500 cells for melanomas of 0.1 mm) and declines as tumours increase in size (approximately 1 event of spread for every 10(8) cells for melanomas of 12 mm). The probability of spread of breast cancer cells from the lymph nodes to the periphery is approximately 1 event of spread for every 10(8) cells in the nodal masses, which have a mean diameter of 5 mm, while the probability of spread of cancer cells from the breast to the periphery when the primary masses are 5 mm is also approximately 1 event of spread for every 10(8) cells. Thus, the occurrence of an event of spread from the breast to the lymph nodes appears not to increase the propensity of the progeny of those cells to spread from the lymph nodes to the periphery. These values indicate that the spread of human breast cancer and melanoma cells is unlikely to occur by a mechanism requiring mutation at the time of spread.

Background Because neoadjuvant chemotherapy is being used more frequently, the optimal timing of sentinel node biopsy (SNB) remains controversial. We previously evaluated the predictive value of SNB before neoadjuvant chemotherapy in clinically node-negative breast cancer. Our identification rate of the sentinel node among 52 patients before chemotherapy with a mean tumor size of 4 cm was 100%. In this study, we compared the identification rates of SNB before and after neoadjuvant chemotherapy and evaluated the false-negative rate of SNB after chemotherapy. Methods A retrospective institutional database review identified 36 women who underwent SNB after neoadjuvant chemotherapy for breast cancer from 1999 to 2004. The initial clinical tumor size and lymph node status, SNB pathology, axillary lymph node dissection pathology, and residual pathologic tumor size were reviewed. Results Sixteen of 36 patients had a clinically negative axilla before neoadjuvant therapy. SNB after neoadjuvant therapy was successful in 29 patients (80.6%), although 7 patients did not map (19.4%). Six of the 7 patients who failed to map had a clinically positive axilla initially. Axillary disease was found in 6 of 7 of these patients at dissection (85.7%). Of the 29 patients who mapped successfully, 13 (45%) were SNB negative, and 16 (55%) were SNB positive. Of the 13 SNB-negative patients, 2 had a positive axillary lymph node dissection, yielding a false-negative rate of 11%. Thirteen patients who mapped had a clinically positive axilla before therapy (45%). Of the 11 patients with true-negative SNBs, 7 (64%) were clinically node negative at presentation. The initial tumor sizes on examination ranged from 2 to 9 cm (mean, 5.0 cm), and residual pathologic tumor sizes ranged from 0 to 6 cm (mean, 1.8 cm). Failure to map correlated with a clinically positive axilla at presentation (100% vs 45%) but did not correlate with initial tumor size. Conclusions Sentinel node identification rates are significantly better when mapping is performed before neoadjuvant chemotherapy (100% vs 80.6%), with failure to map correlated with clinically positive nodal disease at presentation and residual disease at axillary lymph node dissection. Among patients who map successfully after chemotherapy, the false-negative rate is high (11%). Given these findings, we currently recommend SNB before neoadjuvant chemotherapy for clinically node-negative patients, and raise concerns about the use of SNB after neoadjuvant therapy in patients with an initially clinically positive axilla.

Purpose BRCA1 and BRCA2 mutations significantly increase a women's lifetime risk of breast and ovarian cancer. Because several management options have shown promise in decreasing morbidity and mortality for these women, identifying potential mutation carriers is increasingly important. We have developed a largescale method to collect family histories in a population of unaffected women presenting for mammography. We then applied current risk-assessment models to determine the prevalence of women at risk for hereditary breast and ovarian cancer. Materials and Methods We performed a retrospective review of family histories using data collected on all unaffected women presenting for mammography over a 14-week period. The Claus, Myriad II, and Hartmann models for hereditary risk assessment were applied to the survey results. RESULTS: The questionnaire was completed by 5736 women, 695 of whom were excluded because of a personal history of breast or ovarian cancer. Family histories of the remaining 5041 women were evaluated. Totals of 5.9%, 5.2%, and 3.3% of patients, respectively, met criteria for increased risk according to the Hartmann, Myriad II, and Claus models, corresponding to 3.5, 3.1, and 1.9 patients per day. Although 9.2% of patients met criteria for ≥ 1 model, only 1.4% met criteria for all 3. Conclusions Application of available models to a screening population classifies a larger than expected number of women at high risk for a BRCA1 or BRCA2 mutation. New approaches to risk assessment and counseling are needed to apply our knowledge of hereditary risk to a broad population in a practical manner.

A common feature of many advanced cancers is their enhanced capacity to metabolize glucose to lactic acid. In a challenging study designed to assess whether such cancers can be debilitated, we seeded hepatocellular carcinoma cells expressing the highly glycolytic phenotype into two different locations of young rats. Advanced cancers (2–3 cm) developed and were treated with the alkylating agent 3-bromopyruvate, a lactate/pyruvate analog shown here to selectively deplete ATP and induce cell death. In all 19 treated animals advanced cancers were eradicated without apparent toxicity or recurrence. These findings attest to the feasibility of completely destroying advanced, highly glycolytic cancers.

BACKGROUND In women 70 years of age or older who have early breast cancer, it is unclear whether lumpectomy plus tamoxifen is as effective as lumpectomy followed by tamoxifen plus radiation therapy. METHODS Between July 1994 and February 1999, we randomly assigned 636 women who were 70 years of age or older and who had clinical stage I (T1N0M0 according to the tumor-node-metastasis classification), estrogen-receptor-positive breast carcinoma treated by lumpectomy to receive tamoxifen plus radiation therapy (317 women) or tamoxifen alone (319 women). Primary end points were the time to local or regional recurrence, the frequency of mastectomy for recurrence, breast-cancer-specific survival, the time to distant metastasis, and overall survival. RESULTS The only significant difference between the two groups was in the rate of local or regional recurrence at five years (1 percent in the group given tamoxifen plus irradiation and 4 percent in the group given tamoxifen alone, P

BACKGROUND Although many studies support the life-saving potential of screening mammography, the actual utilization of screening and the impact of the actual pattern of screening use on the breast carcinoma death rate, remain incompletely understood. In the current report, the authors describe patterns of screening use among women who were examined at a large screening and diagnostic service and estimate the added mortality associated with missed screening mammograms. METHODS Mammography use was assessed in a population of 72,417 women who received a total of 254,818 screening mammograms at the Massachusetts General Hospital (MGH) Avon Comprehensive Breast Center (Boston, MA) between January 1, 1985, and February 19, 2002. A computer simulation of breast carcinoma growth, spread, and detection of breast carcinoma was used to estimate the likely health consequences of various types of screening use. RESULTS Both prompt return for annual screening and full use of screening over extended periods of time were rare, and comparison of the MGH population with other populations revealed that the low level of use observed in the MGH population was not atypical. Only 6% of women who received a mammogram in 1992 received all annual mammograms that were available over the next 10 years; the mean number of mammograms received during this period was 5.06, or 51% of the number recommended by the American Cancer Society. Computer simulation results indicate that this underutilization of screening should result in higher mortality levels. Women from traditionally underserved socioeconomic, racial, and ethnic groups, women without insurance, and women who did not speak English had lower levels of use compared with other women. Lower levels of use also were observed among women receiving their first mammogram or who in the past had not returned promptly. Women ages 55–65 years had higher levels of use than did younger or older women. Women who previously had breast carcinoma also had higher levels of screening use. Nonetheless, none of the subpopulations of women stratified by age, race, ethnicity, zip code, income,language, insurance, status, previous screening use, or medical history exhibited a widespread propensity to promptly return for annual screening over an extended period of time. CONCLUSIONS By many measures, the current analysis is one of the most detailed descriptions of screening use to date. The authors observed a level of screening use that was disappointingly low, with potentially negative health-related consequences, among women across categories defined by racial, ethnic, socioeconomic, and geographic characteristics; insurance status; language; age; medical history; and previous screening use. Improvements in the promptness with which women return to screening appear to have the potential to lead to considerable reductions in breast carcinoma death. Cancer 2004. © 2004 American Cancer Society.

Presentation of Case A 51-year-old, premenopausal woman came to this hospital with a newly diagnosed breast carcinoma and a strong family history of breast cancer. Three months earlier, on physical examination at another institution, a mass in the upper outer quadrant of the right breast had been found. Examination of a fine-needle aspirate showed atypical ductal cells. An excisional biopsy, also performed elsewhere, revealed a 0.2-cm invasive lobular carcinoma (stage T1a), with ductal carcinoma in situ and lobular carcinoma in situ (Figure 1). The patient came to this hospital for further treatment of her breast carcinoma. The results of routine . . .

Purpose: Using a 2 × 2 factorial design, we studied the adjuvant chemotherapy of women with axillary node–positive breast cancer to compare sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) with concurrent doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) for disease-free (DFS) and overall survival (OS); to determine whether the dose density of the agents improves DFS and OS; and to compare toxicities. Patients and Methods: A total of 2,005 female patients were randomly assigned to receive one of the following regimens: (I) sequential A × 4 (doses) → T × 4 → C × 4 with doses every 3 weeks, (II) sequential A × 4 → T × 4 → C × 4 every 2 weeks with filgrastim, (III) concurrent AC × 4 → T × 4 every 3 weeks, or (IV) concurrent AC × 4 → T × 4 every 2 weeks with filgrastim. Results: A protocol-specified analysis was performed at a median follow-up of 36 months: 315 patients had experienced relapse or died, compared with 515 expected treatment failures. Dose-dense treatment improved the primary end point, DFS (risk ratio [RR] = 0.74; P = .010), and OS (RR = 0.69; P = .013). Four-year DFS was 82% for the dose-dense regimens and 75% for the others. There was no difference in either DFS or OS between the concurrent and sequential schedules. There was no interaction between density and sequence. Severe neutropenia was less frequent in patients who received the dose-dense regimens. Conclusion: Dose density improves clinical outcomes significantly, despite the lower than expected number of events at this time. Sequential chemotherapy is as effective as concurrent chemotherapy.

Purpose: Trastuzumab combined with chemotherapy improves outcomes for women with human epidermal growth factor receptor 2 (HER2) overexpressing advanced breast cancer. We conducted a pilot study of preoperative trastuzumab and paclitaxel, followed by surgery and adjuvant doxorubicin and cyclophosphamide chemotherapy in earlier stage breast cancer. Patients and Methods: Patients with HER2-positive (2+ or 3+ by immunohistochemistry) stage II or III breast cancer received preoperative trastuzumab (4 mg/kg × 1, then 2 mg/kg/wk × 11) in combination with paclitaxel (175 mg/m2 every 3 weeks × 4). Patients received adjuvant doxorubicin and cyclophosphamide chemotherapy following definitive breast surgery. Clinical and pathologic response rates were determined after preoperative therapy. Left ventricular ejection fraction and circulating levels of HER2 extracellular domain were measured serially. Results: Preoperative trastuzumab and paclitaxel achieved clinical response in 75% and complete pathologic response in 18% of the 40 women on study. HER2 3+ tumors were more likely to respond than 2+ tumors (84% v 38%). No unexpected treatment-related noncardiac toxicity was encountered. Four patients developed grade 2 cardiotoxicity (asymptomatic declines in left ventricular ejection fraction). Baseline HER2 extracellular domain was elevated in 24% of patients and declined with preoperative therapy. Immunohistochemical analyses of posttherapy tumor specimens indicated varying patterns of HER2 expression following trastuzumab-based treatment. Conclusion: Preoperative trastuzumab and paclitaxel is active against HER2 overexpressing early-stage breast cancer and may be feasible as part of a sequential treatment program including anthracyclines. The observed changes in cardiac function merit further investigation. Correlative analyses of HER2 status may facilitate understanding of tumor response and resistance to targeted therapy.

The value of routine mammography screening for breast cancer has been the subject of heated debate for much of the last decade. Ten years ago, a baseline mammogram was recommended for women at age 35, and annual mammograms were recommended after age 40. These guidelines were based on the results of mammography trials in Europe and the United States in which a 30% reduction in breast cancer deaths was seen among women who underwent screening.

BACKGROUND Women with an existing breast carcinoma diagnosis who are found to carry a BRCA1/2 mutation have a substantial risk of developing both a contralateral breast carcinoma and ovarian carcinoma. In a newly diagnosed breast carcinoma patient, this genetic information may influence the management of her disease. To assess the volume of patients who may need genetic services at the time of diagnosis, the authors determined the proportion of women with newly diagnosed breast carcinoma at the study institution who would be eligible for genetic testing. METHODS Fifty consecutive women with new breast carcinoma who were attending a multidisciplinary clinic were interviewed. Detailed, three-generation pedigrees were collected for each patient by a genetic counselor. Three commonly used probability models were used to calculate each woman's predicted risk of harboring a germline BRCA1/2 mutation. RESULTS Eleven of 50 patients (22% [95% confidence interval, 12–36%]) were calculated to have a ≥ 10% probability of carrying a BRCA1/2 mutation by at least one mathematic model and should have been offered genetic counseling that included the discussion of genetic testing. There were considerable discrepancies between probability calculations among the three mathematic models. One of the 11 patients who was eligible for genetic testing pursued genetic counseling within 12 months of diagnosis. CONCLUSIONS At a large academic medical center, a substantial proportion of unselected women attending a multidisciplinary clinic were found to have a ≥ 10% risk of carrying a BRCA1/2 mutation. The actual number of patients eligible to receive BRCA1/2 genetic testing outweighs the number of patients seen for genetic counseling at the study institution. Finally, limited correlation was found between current predictive models. Cancer 2002;94:305–13. © 2002 American Cancer Society.

This abstract was withdrawn by the authors.

9 Background: Optimal follow up care for the 3.1 million breast cancer (BC) survivors in the United States has not been definitively determined. ASCO and NCCN recommend that early stage BC patients have a history and physical by their oncology or primary care provider every 3 to 6 months in the first three years post treatment. Additional visits have not been shown to improve outcomes. However, many patients are seen more frequently, leading to increased healthcare costs. In this context, we developed and implemented a BC care redesign algorithm (BCCRA) to reduce redundant follow up. Methods: The BCCRA multidisciplinary team recommended BC survivors be seen by an oncology provider every 6 months for the first five years post treatment and annually thereafter. Retrospective chart review was conducted to evaluate BCCRA adherence from November 2014 to November of 2015. Patients were deemed ineligible if there was a medically necessary reason for visits outside of the BCCRA such as reconstruction, ongoing treatment or clinical trial participation. Eligible charts were analyzed for adherence. For survivors who did not adhere, charts were analyzed for outcome of additional visits. Results: 116 patient charts reviewed and 72 (62.1%) were deemed ineligible. Of the remaining 44 survivors, 26 (59.1 %) adhered and 18 (40.91%) did not adhere. Of the 18 survivors who did not adhere, six had visits due to clinical concern and 12 had visits due to patient or provider preference. Of the 6 patients who had visits for clinical concern, 4 resulted in a change in the patient’s medical management (CMM). Of the 12 patients who had visits due to patient/provider preference, 2 resulted in a CMM. Conclusions: Despite buy-in from a motivated multidisciplinary team, there were challenges to implementing the BCCRA. 62.1% of patients were ineligible and there was a significant proportion of patients/providers who chose more frequent visit schedules. However, the BCCRA had 59.1% adherence which could result in cost reduction and increased flexibility in oncologists’ schedules. Further evaluation of the model is needed to validate these claims.

Despite the growth of research in universities on point-of-care (POC) diagnostics for global health, most devices never leave the laboratory. The processes that move diagnostic technology from the laboratory to the field--the processes intended to evaluate operation and performance under realistic conditions--are more complicated than they might seem. Two case studies illustrate this process: the development of a paper-based device to measure liver function, and the development of a device to identify sickle cell disease based on aqueous multiphase systems (AMPS) and differences in the densities of normal and sickled cells. Details of developing these devices provide strategies for forming partnerships, prototyping devices, designing studies, and evaluating POC diagnostics. Technical and procedural lessons drawn from these experiences may be useful to those designing diagnostic tests for developing countries, and more generally, technologies for use in resource-limited environments.

The absence of real-time, detailed, 3D information on the composition of surgical specimens presents an enormous challenge in surgical oncology and pathology.

Methods of axillary evaluation in invasive breast cancer continue to evolve. The recent American College of Surgeons Oncology Group Z0011 Trial is a prospective, randomized, multicenter trial that compared the survival and locoregional recurrence rates after complete axillary lymph node dissection (ALND) versus sentinel node biopsy (SNB) alone in women with a positive sentinel node in an effort to avoid the complications associated with ALND. As the results of this trial are implemented clinically, affecting surgical management of axillary metastatic disease, radiologists may need to redefine their role in the preoperative assessment of the axilla. Before the Z0011 trial, breast imagers worked to identify axillary metastases preoperatively, allowing appropriate patients to proceed directly to ALND and avoiding the need for SNB. However, the Z0011 trial concluded that ALND may not be necessary in women with metastatic axillary disease who meet the trial criteria. In the Z0011 trial, after 6 years of median follow-up there was no difference in either locoregional recurrence or survival among the women who underwent SNB alone compared with those who underwent ALND, suggesting that ALND is unnecessary in a subset of women with a positive node at SNB. These results raise questions about how aggressively radiologists should pursue percutaneous sampling of axillary nodes, as some practitioners conclude that, in an otherwise eligible woman, positive results from imaging-guided percutaneous biopsy preclude a Z0011 trial-directed pathway. Debate about the best way to implement the results of the Z0011 trial into daily clinical practice exists. It is important for breast imagers to work closely with breast surgeons to provide the most appropriate treatment course for each patient.

AimsRadiation Therapy Oncology Group 98-04 sought to identify women with ‘good risk’ ductal carcinoma in situ (DCIS) who receive no significant benefit from radiation. Enrolment criteria excluded close or positive margins and grade 3 disease. To ensure reproducibility in identifying good risk pathology, an optional web based teaching tool was developed and a random sampling of 10% of submitted slides were reviewed by a central pathologist.MethodsSubmitting pathologists were asked to use the web based teaching tool and submit an assessment of the tool along with the pathology specimen form and DCIS H&E stained slide. Per protocol pathology was centrally reviewed for 10% of the cases.ResultsOf the 55 DCIS cases reviewed, three had close or positive margins and three were assessed to include grade 3 DCIS, therefore 95% of DCIS cases reviewed were correctly graded, and 89% reviewed were pathologically appropriate for enrolment. Regarding the teaching tool, 13% of DCIS cases included forms that indicated the website was used. One of these seven who used the website submitted DCIS of grade 3.ConclusionsCentral review demonstrates high pathological concordance with enrolment eligibility, particularly with regard to accurate grading. The teaching tool appeared to be underused.

We evaluated management of positive sub-areolar/nipple duct margins in nipple-sparing mastectomies (NSM) at our institution. Retrospective chart review of all NSM from January 2007 to April 2012 was performed and patient, tumor, and treatment information was collected. Sub-areolar/nipple duct margins included ductal tissue from within the nipple. Of 438 NSM, 22 (5%) had positive sub-areolar/nipple duct margins; 21 of 220 cancer-bearing breasts (10%) and 1 of 218 prophylactic mastectomies (0.5%). Positive margins included four with invasive lobular carcinoma and 18 with ductal carcinoma in situ (DCIS). Management included removal of eight nipples and nine nipple areola complexes (NAC). Four of 17 nipple/NAC specimens had evidence of residual DCIS and none had residual invasive cancer. The majority of nipple/NAC specimens excised for a positive margin had no residual malignancy. Future studies are needed to determine the extent of NAC tissue removal required for positive margins.

To compare the outcome of patients with invasive breast cancer, who had isolated tumor cells (ITC) in sentinel lymph nodes, pN0(i+), to patients with histologically negative nodes, pN0. We retrospectively studied 1,273 patients diagnosed with T1-T3 breast cancer from 1999 to 2009. Patients were divided into 2 populations: 807 patients treated with breast-conserving surgery (BCS) and radiotherapy (RT), 85(10.5 %) with pN0(i+) and 722(89.5 %) with pN0. And the other population had 466 patients treated with mastectomy without post-mastectomy radiation therapy (PMRT), 80(17.2 %) with pN0(i+),and 386(82.8 %)with pN0. All patients underwent sentinel node biopsy, and the presence of ITC was determined. Patients with axillary dissection only or neoadjuvant chemotherapy were excluded. Among the 1,273 patients studied; 87.3 % received adjuvant systemic therapy. Kaplan-Meier, Cox regression, and log-rank statistical tests were used. Median patient age was 55.7 years. Median follow-up was 69.5 months. The 5- and 10-year cumulative incidence of Loco-regional recurrence (LRR) for patients treated with BCS and RT was 1.6 and 3.5 % for 85 pN0(i+) patients, and 2.4 and 5 % for 722 pN0 patients, respectively. For patients treated with mastectomy without PMRT, 5- and 10-year LRR rates were 2.8 and 2.8 % for 80 pN0(i+) patients, and 1.8 and 3 % for 386 pN0 patients, respectively. There were no statistically significant differences in LRR (p = 0.9), distant recurrence (p = 0.3) ,and overall survival (p = 0.5) among all groups. On multivariate analysis, ITC were not associated with increased risk of LRR, distant recurrence and overall survival. Grade (p = 0.003) and systemic therapy (p = 0.02) were statistically significantly associated with risk of LRR. Sentinel node ITC have no significant impact on LRR, distant recurrence and overall survival in breast cancer patients. Additional treatments such as axillary dissection, chemotherapy, or regional radiation should not be given solely based on the presence of sentinel node ITC.

Aquaporin-1 (AQP1) is the prototype integral membrane protein water channel. Although the three-dimensional structure and water transport function of the molecule have been described, the physical interactions between AQP1 and other membrane components have not been characterized. Using fluorescein isothiocyanate-anti-Co3 (FITC-anti-Co3), a reagent specific for an extracellular epitope on AQP1, the fluorescence photobleaching recovery (FPR) and fluorescence imaged microdeformation (FIMD) techniques were performed on intact human red cells. By FPR, the fractional mobility of fluorescently labeled AQP1 (F-alphaAQP1) in the undeformed red cell membrane is 66 +/- 10% and the average lateral diffusion coefficient is (3.1 +/- 0.5) x 10(-11) cm2/s. F-alphaAQP1 fractional mobility is not significantly affected by antibody-induced immobilization of the major integral proteins band 3 or glycophorin A, indicating that AQP1 does not exist as a complex with these proteins. FIMD uses pipette aspiration of individual red cells to create a constant but reversible skeletal density gradient. F-alphaAQP1 distribution, like that of lipid-anchored proteins, is not at equilibrium after microdeformation. Over time, approximately 50% of the aspirated F-alphaAQP1 molecules migrate toward the membrane portion that had been maximally dilated, the aspirated cap. Based on the kinetics of migration, the F-alphaAQP1 lateral diffusion coefficient in the membrane projection is estimated to be 6 x 10(-10) cm2/s. These results suggest that AQP1 lateral mobility is regulated in the unperturbed membrane by passive steric hindrance imposed by the spectrin-based membrane skeleton and/or by skeleton-linked membrane components, and that release of these constraints by dilatation of the skeleton allows AQP1 to diffuse much more rapidly in the plane of the membrane.

While gynecomastia is common in adolescents, male breast cancer in the pediatric population is exceedingly rare. Occasional reports describe malignant and pre-malignant lesions in mastectomy specimens for gynecomastia in young adults. We present a 16-year-old male with unilateral gynecomastia discovered to have ductal carcinoma in situ (DCIS), treated by mastectomy with 4 year follow-up.

Poster Presentation Objective To compare the maternal mortality rate (MMR) in the Mississippi Delta region of the United States with that of the non‐Delta region states. Design Retrospective data analysis. Setting Mississippi Delta region of the United States. Sample Data from national birth certificates and death certificates from 1999 to 2007. Methods Data were aggregated for analysis by region, counties of the Delta Regional Authority, non‐Delta regions of the eight Delta states, and the 42 non‐Delta states. The MMR was calculated using birth data as the denominator and maternal mortality data as the numerator. Results Between 1999 and 2007 the national maternal mortality rate was 13.5/100,000 live births. The MMR for that same time period in the non‐Delta counties of Delta states was 13.1/100,000 live births, and for non‐Delta states, the MMR was 13.6/100,000 live births. The MMR for that same time period for the Delta counties was 18.5/100,000 live births. Even after adjusting for maternal race/ethnicity, age, marital status, and education, the MMR in the Delta compared with non‐Delta counties and non‐Delta states increased by 16%. Conclusion/Implications for Nursing Practice Overall maternal mortality is significantly greater in the Delta region of the United States than in the non‐Delta region. After controlling for maternal race/ethnicity, age, marital status, and education, the risk of maternal death remains 16% higher in the Delta region. This study provides a statistical representation of a long‐held belief that the risk of maternal mortality in a medically underserved area of low socioeconomic status within the United States is significantly higher than in other areas of the country. Health disparities and socioeconomic differences likely play important roles in this difference. Implications for nursing practice include efforts to provide more current and effective health care to these women and patient education regarding high risk health conditions and preventing unintended pregnancies.

The entry and exit of water from cells is a fundamental process of life. Recognition of the high water permeability of red blood cells led to the proposal that specialized water pores exist in the plasma membrane. Expression in Xenopus oocytes and functional studies of an erythrocyte integral membrane protein of relative molecular mass 28,000, identified it as the mercury-sensitive water channel, aquaporin-1 (AQP1). Many related proteins, all belonging to the major intrinsic protein (MIP) family, are found throughout nature. AQP1 is a homotetramer containing four independent aqueous channels. When reconstituted into lipid bilayers, the protein forms two-dimensional lattices with a unit cell containing two tetramers in opposite orientation. Here we present the three-dimensional structure of AQP1 determined at 6A resolution by cryo-electron microscopy. Each AQP1 monomer has six tilted, bilayer-spanning alpha-helices which form a right-handed bundle surrounding a central density. These results, together with functional studies, provide a model that identifies the aqueous pore in the AQP1 molecule and indicates the organization of the tetrameric complex in the membrane.

Whether wide excision with margins ≥1 cm is sufficient treatment for small low- or intermediate-grade ductal carcinoma in situ (DCIS) is unclear. This is an updated analysis of a phase II, single-arm, prospective trial testing this hypothesis. A total of 158 patients with low- or intermediate-grade DCIS who underwent wide excision alone (without radiation or tamoxifen) were entered onto the trial from 1995 to 2002. Entry criteria included mammographic extent ≤2.5 cm, predominantly low or intermediate nuclear grade, and excision with final microscopic margins ≥1 cm. Eight-year minimum potential follow-up was required for inclusion in the analysis; the final population comprised 143 patients. Cumulative incidence curves were generated to assess rates of local recurrence (LR) or other events. Median follow-up time was 11 years. Nineteen patients (13 %) had LR as a first event within 8 years. Thirteen LR (68 %) were DCIS only and six (32 %) were invasive. Fourteen (74 %) occurred in the original quadrant. The 10-year estimated cumulative incidence of LR was 15.6 %. The estimated annual percentage rate of LR was 1.9 % per patient-year. With longer follow-up, there remains a substantial and ongoing risk of LR in patients with favorable DCIS treated with wide excision margins without radiation. This information should be useful as patients and clinicians weigh the options of wide excision with and without radiation.

The purpose of this study is to evaluate arm volume measurements and clinico-pathologic characteristics of breast cancer patients to define a threshold for intervention in breast cancer-related lymphedema. We prospectively performed arm volume measurements on breast cancer patients using a Perometer. Arm measurements were performed pre- and post-operatively, and change in arm volume was quantified using a relative volume change (RVC) equation. Patient and treatment risk factors were evaluated. Cox proportional hazards models with time-dependent covariates for RVC were used to evaluate whether RVC elevations of ≥3 to5 % or ≥5 to10 % occurring ≤3 months or3 months after surgery were associated with progression to ≥10 % RVC. 1,173 patients met eligibility criteria with a median of 27 months post-operative follow-up. The cumulative incidence of ≥10 % RVC at 24 months was 5.26 % (95 % CI 4.01-6.88 %). By multivariable analysis, a measurement of ≥5 to10 % RVC occurring3 months after surgery was significantly associated with an increased risk of progression to ≥10 % RVC (HR 2.97, p 0.0001), but a measurement of ≥3 to5 % RVC during the same time period was not statistically significantly associated (HR 1.55, p = 0.10). Other significant risk factors included a measurement ≤3 months after surgery with RVC of ≥3 to5 % (p = 0.007), ≥5 to10 % (p 0.0001), or ≥10 % (p = 0.023), axillary lymph node dissection (ALND) (p 0.0001), and higher BMI at diagnosis (p = 0.0028). Type of breast surgery, age, number of positive or number of lymph nodes removed, nodal radiation, chemotherapy, and hormonal therapy were not significant (p 0.05). Breast cancer patients who experience a relative arm volume increase of ≥3 to5 % occurring3 months after surgery do not have a statistically significant increase in risk of progression to ≥10 %, a common lymphedema criterion. Our data support utilization of a ≥5 to10 % threshold for close monitoring or intervention, warranting further assessment. Additional risk factors for progression to ≥10 % include ALND, higher BMI, and post-operative arm volume elevation.

Microscopically clear lumpectomy margins are essential in breast conservation, as involved margins increase local recurrence. Currently, 18-50% of lumpectomies have close or positive margins that require re-excision. We assessed the ability of micro-computed tomography (micro-CT) to evaluate lumpectomy shaved cavity margins (SCM) intraoperatively to determine if this technology could rapidly identify margin involvement by tumor and reduce re-excision rates. Twenty-five SCM from six lumpectomies were evaluated with a Skyscan 1173 table top micro-CT scanner (Skyscan, Belgium). Micro-CT results were compared to histopathological results. We scanned three SCM at once with a 7-minute scanning protocol, and studied a total of 25 SCM from six lumpectomies. Images of the SCM were evaluated for radiographic signs of breast cancer including clustered microcalcifications and spiculated masses. SCM were negative by micro-CT in 19/25 (76%) and negative (≥2 mm) by histopathology in 19/25 (76%). Margin status by micro-CT was concordant with histopathology in 23/25 (92%). Micro-CT overestimated margin involvement in 1/25 and underestimated margin involvement in 1/25. Micro-CT had an 83.3% positive predictive value, a 94.7% negative predictive value, 83.3% sensitivity, and 94.7% specificity for evaluation of SCM. Evaluation of SCM by micro-CT is an accurate and promising method of intraoperative margin assessment in breast cancer patients. The scanning time required is short enough to permit real-time feedback to the operating surgeon, allowing immediate directed re-excision.

Purpose To determine whether there is a benefit to adjuvant radiation therapy after breast-conserving surgery and tamoxifen in women age ≥ 70 years with early-stage breast cancer. Patients and Methods Between July 1994 and February 1999, 636 women (age ≥ 70 years) who had clinical stage I (T1N0M0 according to TNM classification) estrogen receptor (ER) –positive breast carcinoma treated by lumpectomy were randomly assigned to receive tamoxifen plus radiation therapy (TamRT; 317 women) or tamoxifen alone (Tam; 319 women). Primary end points were time to local or regional recurrence, frequency of mastectomy, breast cancer–specific survival, time to distant metastasis, and overall survival (OS). Results Median follow-up for treated patients is now 12.6 years. At 10 years, 98% of patients receiving TamRT (95% CI, 96% to 99%) compared with 90% of those receiving Tam (95% CI, 85% to 93%) were free from local and regional recurrences. There were no significant differences in time to mastectomy, time to distant metastasis, breast cancer–specific survival, or OS between the two groups. Ten-year OS was 67% (95% CI, 62% to 72%) and 66% (95% CI, 61% to 71%) in the TamRT and Tam groups, respectively. Conclusion With long-term follow-up, the previously observed small improvement in locoregional recurrence with the addition of radiation therapy remains. However, this does not translate into an advantage in OS, distant disease-free survival, or breast preservation. Depending on the value placed on local recurrence, Tam remains a reasonable option for women age ≥ 70 years with ER-positive early-stage breast cancer.

Intraoperative radiographic examination of breast specimens is commonly performed to confirm excision of image-detected breast lesions, but it is not reliable for assessing margin status. A more accurate method of intraoperative breast specimen imaging is needed. Micro-CT provides quantitative imaging parameters, image rotation, and virtual "slicing" of intact breast specimens. We explored the use of micro-CT for assessment of a variety of clinical breast specimens. Specimens were evaluated with a table top micro-CT scanner, Skyscan 1173 (Skyscan, Belgium), with a 40-130 kV, 8 W X-ray source. Skyscan software for 3D image analysis (Dataviewer and CTVox) was employed to review 3D graphics of specimens. Scanning for 7 min and another 7 min for image reconstruction provided the desired resolution for breast specimens. Breast lumpectomy specimens, shaved cavity margins, mastectomy specimens, and axillary lymph nodes were imaged by micro-CT. The micro-CT images could be rotated in all directions and cross sections of internal portions of specimens could be visualized from any angle. This provided information about spatial orientation of masses and calcifications relative to margins in intact lumpectomy specimens. Micro-CT is a potentially useful tool for assessment of breast cancer specimens, allowing real-time analysis of tumor location in breast lumpectomy specimens or shaved cavity margins. Micro-CT may also be useful for assessing sentinel lymph nodes and mastectomy specimens.

Increased bilateral mastectomy for breast cancer treatment has generated an increased demand for bilateral breast reconstruction. This study examines changing patterns of reconstruction over the last decade to accommodate increased case volume and decreased morbidity associated with reconstruction. A single institution series of 3171 consecutive breast reconstruction cases of more than 10 years was divided into 2 periods, that is, 1999 to 2004 and 2005 to 2010. Bilateral breast reconstruction case volume increased 260% from 1999 to 2004 (n = 237) to 2005 to 2010 (n = 634). Mean patient age at diagnosis decreased by 7 years (P < 0.001). In 2005 to 2010, autologous reconstruction decreased from 60% to 26%, implant-based reconstruction increased from 40% to 74%. There was a noted increase in single-stage implant reconstruction and selective application of perforator flaps for bilateral autologous reconstruction (P < 0.001). Two-staged tissue expander reconstruction accounted for the greatest share of total cost (45%) in the later period. A younger patient demographic and increased case volume were accommodated through increased single-staged and prosthesis-based procedures.

Mortality reduction from mammographic screening is controversial. Individual randomized trials and meta-analyses demonstrate statistically significant mortality reductions in all age groups invited to screening. In women actually screened, mortality reductions are greater. Individual trials and meta-analyses show varying rates of mortality reduction, leading to questions about screening's value and whether treatment advances have diminished the importance of early detection. This study hypothesized that breast cancer deaths predominantly occurred in unscreened women.Invasive breast cancers diagnosed between 1990 and 1999 were followed through 2007. Data included demographics, mammography use, surgical and pathology reports, and recurrence and death dates. Mammograms were categorized as screening or diagnostic based on absence or presence of breast signs or symptoms, and were substantiated by medical records. Breast cancer deaths were defined after documentation of prior distant metastases. Absence of recurrent cancer and lethal other diseases defined death from other causes.Invasive breast cancer failure analysis defined 7301 patients between 1990 and 1999, with 1705 documented deaths from breast cancer (n = 609) or other causes (n = 905). Among 609 confirmed breast cancer deaths, 29% were among women who had been screened (19% screen-detected and 10% interval cancers), whereas 71% were among unscreened women, including 2 years since last mammogram (6%), or never screened (65%). Overall, 29% of cancer deaths were screened, whereas 71% were unscreened. Median age at diagnosis of fatal cancers was 49 years; in deaths not from breast cancer, median age at diagnosis was 72 years.Most deaths from breast cancer occur in unscreened women. To maximize mortality reduction and life-years gained, initiation of regular screening before age 50 years should be encouraged.

Aquaporin-1 (AQP1) is an abundant protein in human erythrocyte membranes which functions as a specific and constitutively active water conducting pore. Solubilized and isolated as tetramer, it forms well-ordered two-dimensional (2D) crystals when reconstituted in the presence of lipids. Several high resolution projection maps of AQP1 have been determined, but information on its three-dimensional (3D) mass distribution is sparse. Here, we present surface reliefs at 0.9 nm resolution that were calculated from freeze-dried unidirectionally metal-shadowed AQP1 crystals as well as surface topographs recorded with the atomic force microscope of native crystals in buffer solution. Our results confirm the 3D map of negatively stained AQP1 crystals, which exhibited tetramers with four major protrusions on one side and a large central cavity on the other side of the membrane. Digestion of AQP1 crystals with carboxypeptidase Y, which cleaves off a 5 kDa intracellular C-terminal fragment, led to a reduction of the major protrusions, suggesting that the central cavity of the tetramer faces the outside of the cell. To interpret the results, sequence based structure predictions served as a guide.

Background. A great deal of information about breast cancer risk is available to the public. The accuracy of impressions formed from this information is unknown. Methods. A total of 750 women attending a breast center and 112 women attending a primary care office completed written surveys of their perceptions of average population risk, personal lifetime risk, and personal 10-year risk of getting breast cancer. Data sufficient to apply the Gail model were obtained, and a calculated estimate of risk was generated. Ratios of perceived to calculated risk were correlated with the respondent's age, family history of breast cancer, and location in a breast center or primary care office. Results. Women in both practice settings overestimated population risk by more than twofold. Eighty percent overestimated personal lifetime risk by more than 50% and 35% by more than fivefold. Only 7% significantly underestimated risk. Ten-year risk estimates were even more inaccurate, with 69% overestimating risk by more than fivefold, 46% by more than 10-fold, and 17% by more than 20-fold. Results from a primary care population were nearly identical. Women at the extremes of age were most inaccurate in estimating risk. It was surprising that family history had little impact on perception of personal risk. Conclusions. Women in both breast center and primary care settings have a falsely high perception of both short-term and long-term breast cancer risk. Health care providers should recognize these misconceptions and be aware that many women may benefit from risk counseling.