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The anatomy of the nipple has become clinically relevant. Diagnostic techniques access the breast through nipple ducts and surgeons offer nipple-sparing mastectomy. There is variation in the number of ducts reported and little is known about the spatial location of ducts, their size, and their relationship to orifices on the surface. Nipple specimens were taken from 129 consecutive mastectomies. Each was sectioned coronally into 3 mm blocks and one section was prepared from each block. The number of ducts and cross-sectional areas of nipple and duct ‘bundle’ were recorded. Three nipples were sectioned at 50 μm intervals and digitally reconstructed in three dimensions. The median number of ducts was 23 (interquartile range 19–28). Reconstructions and summary data from 25 nipples show a central duct bundle narrowing to form a ‘waist’ as the ducts enter breast parenchyma. A three-dimensional reconstruction focusing on one nipple tip demonstrated 29 ducts arising from 15 orifices. Beneath the skin, most ducts are very narrow, gradually becoming larger deeper within the nipple. This work demonstrates that many ducts share a few common openings onto the surface of the nipple, explaining the observed discrepancy between number of ducts and of orifices. Neither duct diameter nor position predicts whether a duct system will terminate close to the nipple or pass deeper into the breast. These new insights into nipple anatomy will be of use in considering the reliability of a ductal approach to diagnosis and in planning nipple-sparing mastectomy.

To retrospectively determine the long-term risk of false-positive mammographic assessments and to evaluate the effect of screening regularity on the risk of false-positive events.Institutional review board approval was obtained, and informed consent was waived. Retrospective analysis was performed for the occurrence of false-positive assessments among 83,511 women who underwent 314,185 mammographic examinations from January 1, 1985, to February 19, 2002. Data were collected from a database that had been assembled prospectively. Two categories of false-positive events were examined: biopsies that did not reveal cancer and false-positive mammographic assessments. Rates of false-positive events were compared by using a chi2 analysis, and 95% confidence limits were calculated. Because comparisons of multiple pairs were considered, all P values that demonstrated statistical significance exceeded the requirement of the Bonferroni correction.While the overall rates of biopsies that did not reveal cancer and of false-positive mammographic assessments were similar to those found in other studies, most of the burden of false-positive events was borne by women who underwent intermittent screening. Long-term rates of false-positive events were lower among women who underwent regular screening than among those who underwent intermittent screening. In the 5-year group, 2.9% of women who underwent five mammographic examinations over the next 5 years had biopsy results that did not reveal cancer, whereas 4.6% of women who underwent three mammographic examinations over the next 5 years had biopsy results that did not reveal cancer. For women who underwent regular screening, the risk of undergoing biopsies that did not reveal cancer declined over time to 0.25% per year after several years of screening, a value that is lower than the risk of these events among women who did not undergo screening. The rate of false-positive mammographic assessments was also lower for women who underwent regular screening than for those who underwent intermittent screening.Prompt annual attendance for mammographic screening reduces the occurrence of false-positive mammographic results.

Purpose: We present our initial clinical experience with proton, three-dimensional, conformal, external beam, partial-breast irradiation (3D-CPBI). Methods and Materials: Twenty patients with Stage I breast cancer were treated with proton 3D-CPBI in a Phase I/II clinical trial. Patients were followed at 3 to 4 weeks, 6 to 8 weeks, 6 months, and every 6 months thereafter for recurrent disease, cosmetic outcome, toxicity, and patient satisfaction. Results: With a median follow-up of 12 months (range, 8–22 months), no recurrent disease has been detected. Global breast cosmesis was judged by physicians to be good or excellent in 89% and 100% of cases at 6 months and 12 months, respectively. Patients rated global breast cosmesis as good or excellent in 100% of cases at both 6 and 12 months. Proton 3D-CPBI produced significant acute skin toxicity with moderate to severe skin color changes in 79% of patients at 3 to 4 weeks and moderate to severe moist desquamation in 22% of patients at 6 to 8 weeks. Telangiectasia was noted in 3 patients. Three patients reported rib tenderness in the treated area, and one rib fracture was documented. At last follow-up, 95% of patients reported total satisfaction with proton 3D-CPBI. Conclusions: Based on our study results, proton 3D-CPBI offers good-to-excellent cosmetic outcomes in 89% to 100% of patients at 6-month and 12-month follow-up and nearly universal patient satisfaction. However, proton 3D-CPBI, as used in this study, does result in significant acute skin toxicity and may potentially be associated with late skin (telangiectasia) and rib toxicity. Because of the dosimetric advantages of proton 3D-CPBI, technique modifications are being explored to improve acute skin tolerance.

The favorable prognosis associated with tubular carcinoma of the breast has led some studies to propose less aggressive treatments for patients with this disease. This study aims to address the extent of therapy needed for tubular patients.A retrospective review identified 73 cases of tubular carcinoma treated at the Massachusetts General Hospital between 1980 and 2002. Primary treatment was conservative surgery (CS) plus radiation therapy (RT) in 67%, CS without RT in 18%, and mastectomy in 15%. Median follow-up time was 90.5 months. The published literature of 529 conservatively treated tubular carcinomas was reviewed along with the 62 conservative cases from this series. : No patients developed distant metastasis or died from this disease. Local failure occurred in three (4%) of the cases, after 13, 84 and 121 months. All three had initially been treated with CS + RT. Five cases were node-positive, three of which were associated with a primary tumor smaller than 1 cm. Thirteen women, with a median age of 74, were treated by CS without RT and none recurred. A literature review showed that adjuvant RT reduces local failure following CS for tubular carcinoma.Tubular carcinoma is associated with an excellent prognosis, but long-term follow-up is essential for detecting local failures and a small primary tumor size does not preclude nodal involvement. Adjuvant RT reduces the incidence of local failure following CS for tubular carcinoma, however, elderly women treated by CS may have a very low risk of local recurrence without adjuvant RT.

BACKGROUND Identifying BRCA1 and BRCA2 mutation carriers is increasingly important as new management options show promise in decreasing morbidity and mortality in these women. The authors sought to determine the prevalence of family histories suggestive of a hereditary breast carcinoma syndrome in a cohort of patients with a personal history of breast and/or ovarian carcinoma presenting for mammography. METHODS The authors reviewed the family histories of all women with a history of breast or ovarian carcinoma presenting for mammography over a 37-week period. Using the Myriad model, the authors evaluated the prevalence of family histories with a ≥ 10% risk of a BRCA1 or BRCA2 mutation. RESULTS During the period of the current study, 14,597 women completed a family history questionnaire. Of these women, 1764 had a personal history of breast or ovarian carcinoma, 86.6% had unilateral breast carcinoma, 4.6% had bilateral breast carcinoma, 8.2% had ovarian carcinoma, and 0.5% had both breast and ovarian carcinoma. Overall, 20.6% met the criteria for a ≥ 10% risk of mutation according to the Myriad model. This incidence was higher among Ashkenazi women (47.3%) and among patients with a personal history of ovarian carcinoma (35.9%). CONCLUSIONS Application of the Myriad model to women with a personal history of breast and ovarian carcinoma suggested that approximately 1 in 5 of these women (20.6%) will have family histories suspicious for a genetic mutation. This risk was higher for Ashkenazi women and for those with a personal history of ovarian carcinoma. This prevalence was considerably higher than the rate reported among women with no personal history of cancer, and has significant implications for their management, as well as for the capacity for risk assessment and testing. Cancer 2005. © 2005 American Cancer Society.

Surgical procedures performed for diagnosis and treatment of breast disease have become progressively less invasive. As an increasing proportion of breast surgery is performed on an outpatient basis, identification and management of postoperative problems have become a collaborative effort involving the surgeon, the patient, home care services and medical office staff. Although this shift to outpatient care has created a number of challenges, complication rates are no higher when breast procedures are performed on an outpatient or short-stay basis. Perioperative, short-term and long-term complications, including wound complications, injuries to adjacent structures, lymphedema, and pain syndromes are discussed.

This article presents the author's current approaches to the management of breast cancer in older women, with emphasis on clinical and surgical treatment of the disease in this population. There are controversies surrounding the management of breast cancer in this population regarding adjuvant therapy, radiation therapy and surgical options. We endeavor to address these issues in the article.

A topical 1% diclofenac liposomal cream proved to be safe, easy to use, and effective in reducing equine lameness caused by degenerative joint disease. Diclofenac liposomal cream was shown to reduce lameness as graded by owners and veterinarians, regardless of the severity or chronicity of the clinical condition. Topical application allowed for more convenient administration than oral or injectable agents, and no clinically relevant hematologic or serum biochemical changes were noted. The liposomal cream provided a delivery system for diclofenac, an NSAID, to achieve therapeutic levels locally with decreased risk for systemic toxicity and side effects and improved targeting of the painful area.

BACKGROUND The American Cancer Society recommends yearly mammographic screening for women starting at the age of 40 years. The authors examined the age at which women began screening at a large tertiary care center. METHODS Utilization of mammography was assessed in a population of 72,417 women who received 254,818 screening mammograms at the Massachusetts General Hospital Avon Comprehensive Breast Center from January 1, 1985 to February 19, 2002, of which 940 received their first mammogram between January 16, 2000 and February 19, 2002. RESULTS The median age at first mammogram for women in the population as a whole was 40.4 years. Sixty percent of women had their first mammogram by the end of their 40th year, and almost 90% had begun screening by age 50 years. However, these reassuring findings were not seen in several specific subpopulations of women. Black women began screening at a median age of 41.0 years, 0.7 years later than white women. Hispanic women began screening at a median age of 41.4 years, 1.1 years later than non-Hispanic women. Obese women began screening at a median age of 41.2 years, 1.6 years later than thin women. Women without a primary care physician began screening at a median age of 42.1 years, 1.8 years later than women with a primary care physician. Women without private health insurance began screening at a median age of 46.6 years, 6.3 years later than women with private health coverage. Women who did not speak English began screening at a median age of 49.3 years, 9.0 years later than women for whom English was the primary language. Women who both lacked private health insurance and spoke a language other than English began screening at a median age of 55.3 years, 15.2 years later than women without these characteristics. CONCLUSIONS The analysis presented in the current study provided one of the most detailed descriptions of the age at screening initiation to be performed to date. Most women in the study population began screening by the end of their 40th year. This contrasted with the widespread failure of women to return promptly for subsequent annual examinations. However, specific subpopulations of women were at risk for not beginning screening on time, including women without private insurance, women without a primary care physician, and women who did not speak English. These findings suggest that there is little to be gained from populationwide efforts to encourage entry into the screening process, and that public health efforts should be focused on those subpopulations of women at highest risk for not using screening. These results also indicate that public health efforts to encourage women to start screening may be less critical than interventions to improve prompt return once they have entered the screening system. Cancer 2004. © 2004 American Cancer Society.

Golgin-160 is a member of the coiled-coil family of golgin proteins, which are proposed to regulate the structure of the Golgi complex. The C-terminal two-thirds of golgin-160 is predicted to form a coiled-coil domain and the N-terminal head domain contains several putative binding domains, regulatory motifs and phosphorylation sites. Recently, it has been demonstrated that caspase-dependent cleavage of the golgin-160 head domain occurs rapidly after induction of apoptosis. The role of golgin-160 phosphorylation and the functional implications for Golgi structure have not been defined. In this study, we investigated the kinase(s) responsible for phosphorylation of golgin-160. Signaling through the small G-protein Rac and mixed-lineage-kinase-3 (MLK3) resulted in increased phosphorylation of golgin-160. The intracellular distribution of MLK3 overlapped with that of golgin-160 and the two proteins could be co-immunoprecipitated. In vitro kinase assays demonstrated that MLK3 directly phosphorylates golgin-160 in the N-terminal head region between residues 96 and 259. Overexpression of MLK3 caused an enhanced caspase-dependent cleavage of golgin-160 at Asp139. Golgin-160 is the first non-kinase substrate of MLK3 identified, and phosphorylation by MLK3 might modulate cleavage of golgin-160 during apoptosis.

Using cryo-electron microscopy we have determined a projection map of the structure of the water selective pore aquaporin-1.

BACKGROUND It has long been known that both tumor size and the presence of malignant disease in the regional lymph nodes are indicators of outcome for patients with invasive breast carcinoma; however, the way in which these two characteristics could be integrated into an overall assessment of prognosis has not been obvious. METHODS Kaplan–Meier survival estimates (15 years) according to tumor size and lymph node status were obtained for women with invasive breast carcinoma who were observed at the University of Southern California/Van Nuys Breast Center (Van Nuys, California) or at Massachusetts General Hospital (Boston, Massachusetts). RESULTS To isolate the individual contributions to death made by tumor size and lymph node status, data were sorted according to both of these variables. For women with tumors of equivalent size, lethality increased with increasing number of positive lymph nodes, such that there was an extra ≈6% chance of death associated with each positive lymph node. For women with equivalent lymph node status, tumor size was associated with increased lethality, such that each millimeter of tumor diameter was associated with an additional ≈1% chance of death. The overall lethality was equal to the sum of the contribution from lymph node status and the contribution from tumor size, and this finding led to the creation of a new technique (the Size+Nodes method) for predicting outcome. CONCLUSIONS The Size+Nodes method was shown to be capable of accurately estimating the risk of death due to invasive breast carcinoma from information on the size of the primary tumor and the number of positive lymph nodes. In addition, this method was used to stratify women into groups according to breast carcinoma lethality. In contrast, classification of women according to lymph node positivity, T status, or disease stage created groups with wide and overlapping levels of lethality. Cancer 2003. © 2003 American Cancer Society.

BACKGROUND While the question of whether the trials of breast cancer screening have resulted in a reduction in breast cancer death has been the subject of much scrutiny, there has been less attention to the reduction in tumor size achieved by screening. METHODS Size data for invasive breast tumors were assembled from a variety of sources. The health consequences that can be expected from finding tumors of various sizes were determined using a recently developed mathematical method for relating tumor size to death rate. RESULTS First, in both the Swedish two-country trial and at the MGH Breast Imaging Division, the sizes of the invasive breast cancers in the screening population (those masses seen at screening together with those found as palpable masses after screening examinations) were sufficiently smaller than the cancers found among women who had not used screening to have lead to considerable reductions in death. Second, the lack of reduction in death rates detected in both Canadian National Breast Screening Studies could be ascribed to the small reductions in tumor size achieved in these studies. Third, radiographic density had a small effect, whereas age had a negligible effect, on the capacity of mammographic screening to find breast carcinomas at smaller, and thus less lethal, sizes. CONCLUSIONS Prompt attendance at annual mammographic screening offers the potential to reduce tumor size and, presumably, breast carcinoma death, in women of all ages and density groups. Cancer 2003. © 2003 American Cancer Society.

Purpose To evaluate the toxicity of partial breast irradiation (RT) using escalating doses of low-dose-rate interstitial implant as the sole adjuvant local therapy for selected T1N0 breast cancer patients treated by wide local excision. The results of a European Organization for Research and Treatment of Cancer study have demonstrated a significant local control benefit using external beam RT to 65 Gy compared with 50 Gy. Thus, the tolerance of escalating doses of partial breast RT should be determined, because this approach may become a standard treatment for patients with early-stage breast cancer. Methods and materials Between 1997 and 2001, 48 patients with T1N0M0 breast cancer were enrolled into an institutional review board–approved Phase I/II protocol using low-dose-rate brachytherapy implants after wide local excision and lymph node staging surgery. Brachytherapy was started 3–4 days after surgery at a dose rate of 50 cGy/h, using 192 Ir sources evenly spaced to cover 3 cm around the resection margins. Typically, 2–3 planes were used, with a median of 14 catheters (range 10–16). The total dose was escalated in three groups: 50 Gy ( n = 19), 55 Gy ( n = 16), and 60 Gy ( n = 13). The implant volume was calculated and used to classify patients into quartiles: 76–127 cm 3 ( n = 12), 128–164 cm 3 ( n = 12), 165–204 cm 3 ( n = 12), and >204 cm 3 ( n = 12). Cosmesis, patient satisfaction, treatment-related complications, mammographic abnormalities, rebiopsies, and disease status were recorded at each scheduled patient visit. Results The median follow-up for all patients was 23.1 months (range 2–43). Very good to excellent cosmetic results were observed in 91.8% of patients. Ninety-two percent of patients were satisfied with their cosmetic outcome and said they would choose brachytherapy again over the standard course of external beam RT. Six perioperative complications occurred: two developed bleeding at the time of catheter removal, two had abscesses, one developed a hematoma, and one had a nonhealing sinus tract requiring surgical intervention. Significant fibrosis (moderate-to-severe scarring and thickening of the skin and breast) was noted in only 4 patients; 1 had received 55 Gy and 3 had received 60 Gy. Abnormal posttreatment mammograms were seen in 19 patients. Eight patients underwent rebiopsy for abnormalities found either by mammography or on physical examination; all proved to be fat necrosis or post-RT changes. The rebiopsy rates appeared to correlate with doses ≥55 Gy (6 [75%] of 8 compared with 29 [60%]of 48 overall) and implant volumes ≥128 cm 3 (7 [87.5%] of 8 compared with 36 [75%] of 48 overall). To date, no local, regional, or distant recurrences have been observed. Conclusion Low-dose-rate implants up to 60 Gy were well-tolerated overall. With an implant dose of 60 Gy, the incidence of posttreatment fibrosis (25%) appeared to be increased. Only the long-term follow-up of this and other implant studies will allow an understanding of the total radiation dose necessary for tumor control and the volume of breast that requires treatment.

570 Background: The OncotypeDX 21-gene assay Recurrence Score (RS) is widely used to risk-stratify ER+, node negative breast cancer to determine the 10 year risk of distant recurrence (RR) and the ...

PURPOSE: Mammograms and breast examinations are established methods for early breast cancer detection. Routine mammography screening reduces breast cancer mortality among women ages ≥ 50 years, but additional screening methods are needed. We and others have found high levels of carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA) in nipple aspirate fluids (NAFs), but the usefulness for these bio-markers for early breast cancer detection is unknown. PATIENTS AND METHODS: NAFs from one or both breasts of 388 women were analyzed for CEA, PSA, and albumin levels. The study included 44 women with newly diagnosed invasive breast cancers, 67 women with proliferative breast lesions (ductal and lobular carcinoma in situ and atypical ductal hyperplasia), and 277 controls without these breast lesions. Analyses were conducted using the log10-transformed CEA and PSA levels to normalize the distributions of these tumor markers. RESULTS: Nipple fluid CEAs are significantly higher for cancerous breasts than tumor-free breasts (median 1,830 and 1,400 ng/mL, respectively; P < .01). However, at 90% specificity of the assay (CEA = 11,750 ng/mL), the corresponding sensitivity for cancer detection is 32%. CEA levels are not significantly different for breasts with proliferative lesions compared with tumor-free breasts. Nipple fluid PSAs do not differ by tumor status. Analyses of NAF albumin-standardized CEAs and PSAs yield similar results. Nipple fluid CEA and PSA titers are correlated in the affected and unaffected breast of women with unilateral lesions. CONCLUSION: Nipple fluid CEAs are higher for breasts with untreated invasive cancers, but the test sensitivity is low. Nipple fluid PSA titers do not seem to be useful for breast cancer detection.

Background Experience with a novel method of notifying investigators about research subjects in a university-based emergency department (ED) is reported. Methods An automated paging system was linked to the electronic medical record to identify inclusion criteria and notify investigators at the time of ED triage. The rate of study enrolment 2 months before and after implementation of the automated system was compared and the time from triage completion to investigator notification was assessed. Results During the first 2-month period, 1/17 eligible patients were identified by staff. During the second 2-month period, 1/7 eligible patients were identified by staff while the automated paging system recognised 7/7 eligible patients, an absolute increase of 94.5%. The median time from completion of triage to automated notification of investigators was 0 min. Conclusion Automated paging using the electronic medical record has the potential to improve enrolment in clinical research studies by improving the speed and sensitivity of identifying eligible subjects.

Objective—To evaluate sevoflurane as an inhalation anesthetic for thoracotomy in horses. Animals—18 horses between 2 and 15 years old. Procedure—4 horses were used to develop surgical techniques and were euthanatized at the end of the procedure. The remaining 14 horses were selected, because they had an episode of bleeding from their lungs during strenuous exercise. General anesthesia was induced with xylazine (1.0 mg/kg of body weight, IV) followed by ketamine (2.0 mg/kg, IV). Anesthesia was maintained with sevoflurane in oxygen delivered via a circle anesthetic breathing circuit. Ventilation was controlled to maintain PaCO2 at approximately 45 mm Hg. Neuromuscular blocking drugs (succinylcholine or atracurium) were administered to eliminate spontaneous breathing efforts and to facilitate surgery. Cardiovascular performance was monitored and supported as indicated. Results—2 of the 14 horses not euthanatized died as a result of ventricular fibrillation. Mean (± SD) duration of anesthesia was 304.9 ± 64.1 minutes for horses that survived and 216.7 ± 85.5 minutes for horses that were euthanatized or died. Our subjective opinion was that sevoflurane afforded good control of anesthetic depth during induction, maintenance, and recovery. Conclusions and Clinical Relevance—Administration of sevoflurane together with neuromuscular blocking drugs provides stable and easily controllable anesthetic management of horses for elective thoracotomy and cardiac manipulation. (Am J Vet Res 2000;61:1430–1437)

Although health care organizational change is a constant phenomenon, little is understood as to how staff experience this change. Unsuccessful change efforts have suggested the possible important relationship between understanding staff's experience and improved results. The purpose of this phenomenological study was to describe what staff on a medical-surgical unit experience during the initial phase of the implementation of a nursing care coordinator position, a first step in a broad organizational change. A purposeful sample of 11 nursing and non-nursing staff, considered unit experts, were interviewed using broad, open-ended questions designed to solicit their experience. Additionally, observations and document abstraction were used to add depth and clarification to the interviews. Analysis of data was conducted using a combination of Giorgi's and Colaizzi's procedures. Contextual elements framing staff's experiences included introduction of a new role with no organizational history into an increasingly demanding environment that staff perceived as constantly changing. Major themes of "experiencing the effect" and "struggling to make sense" were revealed. These findings suggest that the introduction of a new role can create turmoil and job insecurity in the current health care environment. Recommendations to support staff's efforts to "make sense" are provided.

Although phyllodes tumors have minimal metastatic potential, we hypothesized that they have a proclivity for local recurrence and should be excised with a wide margin. We reviewed the clinical and radiological appearance of phyllodes tumors and analyzed the role of surgical treatment in their management.Medical records, imaging studies, pathology reports, and interventions were reviewed.A large tertiary care teaching hospital.Between 1980 and 1997, 40 patients with phyllodes tumors were identified through the tumor registry at the Massachusetts General Hospital, Boston.Surgical resection margins, rates of local recurrence, incidence of distant metastases, and survival.All 40 patients were female, with a mean age of 41 years. Each patient had a palpable mass or a mammographic finding that was indistinguishable from a fibroadenoma on examination. Tumor size ranged from 5 mm to 28 cm. Local recurrence correlated with excision margins (P.05), but not with tumor grade or size. Local recurrence occurred in 5 patients, each of whom had positive margins or margins less than 1 cm after excision. After reexcision with a 1-cm margin, these individuals remained free of recurrence. One patient developed metastatic disease after total mastectomy and died after chemotherapy.Phyllodes tumors mimic fibroadenomas and are often excised with close margins. Primary excision or reexcision with a 1-cm margin is recommended. Mastectomy is indicated for patients with large lesions. Lymph node metastases are unusual and occur secondary to necrotic tumor. Chemotherapy is based on guidelines for the treatment of sarcomas, not breast adenocarcinoma.

Merkel cell carcinoma is a rare dermal neuroendocrine carcinoma whose optimal treatment and prognostic factors are poorly defined. We hypothesize that high-risk patients with Merkel cell carcinoma are best treated with multimodality therapy.A retrospective review of all patients (N = 33) with Merkel cell carcinoma treated at the Massachusetts General Hospital from January 1, 1980, to August 24,1997. Median follow-up time was 37 months (range, 6-157 months).Adequate data for evaluation were available for 31 patients. Male to female distribution was 14 men and 17 women, with a median patient age of 68 years.Stage at presentation; factors associated with recurrence; and the effects of surgery, radiation therapy (XRT), and chemotherapy on recurrence, salvage, and survival rates.There were 12 extremity, 11 head and neck, and 8 truncal tumors. There were 22 isolated primary tumors, 8 with additional clinically positive lymph nodes, and 1 with distant disease. Therapy was local excision with or without XRT in 19 patients, local resection and lymphadenectomy with or without XRT in 8 patients, and XRT alone in 4 patients with head and neck tumors. Fifteen patients developed recurrences (7 local, 8 nodal, and 10 distant). Median time to recurrence was 8 months (range, 3-48 months). There were 7 tumor-related deaths, 6 of which were associated with truncal lesions (P.001). No locoregional recurrences occurred in patients with margins of resection of 2 cm or greater or adequate XRT. A multivariate analysis selected truncal location (P = .005) and nodal disease (P = .05) as predictors of mortality. Remission was possible in 5 patients with locoregional and 2 patients with distant recurrences.Merkel cell carcinoma is an aggressive dermal cancer with frequent nodal metastases; truncal tumors have the worst prognosis. Locoregional recurrence correlates with inadequate margins and lack of XRT, but remission is possible with multimodality therapy.

The Rh50 glycoprotein is suspected of being involved in Rh antigen expression. We prepared Rh50 cDNA from a human bone marrow library by polymerase chain reaction and then subcloned this cDNA into various vectors. The vector containing Rh50 cDNA produced a 30-kDa nonglycosylated form of Rh50 in a rabbit reticulocyte lysate system and produced partially glycosylated Rh50 (32 kDa) when microsomes were added to the system. COS-1 cells transiently transfected with the vector containing Rh50 cDNA produced partially glycosylated Rh50 (32 kDa) recognized by a Rh50-specific antibody. Surface expression of Rh50 in K562 cells was also detected by flow cytometry using mouse monoclonal antibody (2D10) specific to Rh50. Partially glycosylated Rh50 (32 kDa) was again isolated from the lysates of K562 cells metabolically labeled with [35S]-methionine or [3H]-mannose using anti-Rh50 antisera. These systems (K562 and COS-1 cells) should prove useful for studying the transport of Rh proteins within the cell and the necessary components needed for Rh antigenicity at the cell surface.

This article summarizes methods for the chemical synthesis and biophysical characterization of gramicidins with varying sequences and labels. The family of gramicidin channels has developed into a powerful model system for understanding fundamental properties, interactions, and dynamics of proteins and lipids generally, and ion channels specifically, in biological membranes.

Water transport during peritoneal dialysis (PD) requires ultrasmall pores in the capillary endothelium of the peritoneum and is impaired in the case of peritoneal inflammation. The water channel aquaporin (AQP)-1 has been proposed to be the ultrasmall pore in animal models. To substantiate the role of AQP-1 in the human peritoneum, we investigated the expression of AQP-1, AQP-2, and endothelial nitric oxide synthase (eNOS) in 19 peritoneal samples from normal subjects ( n = 5), uremic patients treated by hemodialysis ( n = 7) or PD ( n = 4), and nonuremic patients ( n = 3), using Western blotting and immunostaining. AQP-1 is very specifically located in capillary and venule endothelium but not in small-size arteries. In contrast, eNOS is located in all types of endothelia. Immunoblot for AQP-1 in human peritoneum reveals a 28-kDa band (unglycosylated AQP-1) and diffuse bands of 35–50 kDa (glycosylated AQP-1). Although AQP-1 expression is remarkably stable in all samples whatever their origin, eNOS (135 kDa) is upregulated in the three patients with ascites and/or peritonitis (1 PD and 2 nonuremic patients). AQP-2, regulated by vasopressin, is not expressed at the protein level in human peritoneum. This study 1) supports AQP-1 as the molecular counterpart of the ultrasmall pore in the human peritoneum and 2) demonstrates that AQP-1 and eNOS are regulated independently of each other in clinical conditions characterized by peritoneal inflammation.

To correlate quantitative echo-planar magnetic resonance (MR) imaging measures of gadopentetate dimeglumine tumor uptake with histologic diagnoses and microvessel density (MVD) and to compare dynamic echo-planar imaging of breast lesions with conventional dynamic MR imaging techniques.The study group comprised 63 patients (aged 13-70 years) with 71 breast lesions who underwent conventional and echo-planar MR imaging. The T1 values, change in gadopentetate dimeglumine concentration, and extraction-flow products were calculated with the echo-planar imaging data and were correlated with histologic findings and MVD estimates. Extraction-flow product data normalized to pectoral muscle gadopentetate dimeglumine concentration in invasive cancers was also correlated with MVD.On average, cancer T1 values were shorter than benign values, but there was substantial overlap between the two groups. Cancers had higher extraction-flow products than benign lesions (P.001). Sensitivity, specificity, positive predictive value, and negative predictive value were 83%, 79%, 67%, and 90%, respectively. Receiver operating characteristic analysis showed improved performance with extraction-flow products than with percentages of signal intensity change. Among the invasive cancers, there was no significant correlation between extraction-flow product and MVD.The T1 value remains important in more precise quantitative estimation of gadopentetate dimeglumine uptake in breast tumors, which helps improve the specificity of dynamic imaging. Tumor MVD affects the contrast medium enhancement of breast lesions, but other factors contribute.

OBJECTIVE: The authors assessed the impact of axillary dissection on adjuvant systemic therapy recommendations in patients with breast cancer. SUMMARY BACKGROUND DATA: With increasing use of systemic therapy in node-negative women and the desire to reduce treatment morbidity and cost, the need for axillary dissection in clinically node-negative patients with breast cancer has been challenged. METHODS: Two hundred eighty-two women with clinically negative axillae were analyzed using a model treatment algorithm. Systemic therapy was assigned with and without data from axillary dissection. Treatment shifts based on axillary dissection data were scored. RESULTS: Twenty-seven percent of clinically node-negative women had pathologically positive nodes. Eight percent of T1a and 10% of T1b tumors had positive nodes and would have been undertreated without axillary dissection. Seven percent of premenopausal women with tumors < 1 cm and 13% with tumors > or = 1 cm had treatment changed by axillary dissection. For women 50 to 60 years of age, 10% with tumors < 1 cm, 17% with tumors 1 to 2 cm with positive prognostic features, and 4% with poor prognostic features had significant treatment shifts after axillary dissection. For clinically node-negative women older than 60 years of age not eligible for chemotherapy, only 3% of those with tumors < 1 cm and none of those with tumors > or = 1 cm had their treatment changed by findings at axillary dissection. Treatment shifts based on axillary dissection were larger if the treatment algorithm allowed for more varied or more aggressive treatment options. CONCLUSIONS: Data obtained from axillary dissection will alter adjuvant systemic therapy regimen in a significant number of clinically node-negative women younger than 60 years of age and for older women eligible to receive chemotherapy.

Aquaporin-4 is a mammalian water channel protein that is predominately expressed in brain, where it is believed to mediate water homeostasis. Here we report the isolation and characterization of the cDNA for mouse Aqp4 and map the gene to the proximal region of mouse chromosome 18. This region contains the neurological mutation ataxia, but further analysis reveals that Aqp4 is not responsible for the ataxia phenotype.

To investigate the influence of increased respiratory frequency on respiratory mechanics in the horse, measurements were made in two groups of seven tracheostomised horses before and after the administration of doxapram. The horses in group I had normal base line values for respiratory mechanics, whereas the horses in group II had significantly lower values of dynamic compliance (Cdyn), higher respiratory resistance (R), and a higher total change in pleural pressure (ΔP). The administration of 0·3 mg kg −1 doxapram intravenously resulted in a significant increase in respiratory frequency (f R ), R, ΔP, tidal volume (V T ), and peak to peak respiratory flow (V), and a decrease in Cdyn in both groups of horses. The group II horses had significantly greater increases in R and ΔP than the horses in group I.

147 Background: Dual neoadjuvant HER2 directed therapy is offered only in a clinical trial setting and is not standard of care, but emerging data suggests targeting multiple mechanisms may be more effective. We conducted a comprehensive systematic review and meta-analysis to evaluate the impact of neoadjuvant dual and single agent HER2 blockade on breast conserving surgery (BCS), and on pathological complete response (pCR) for estrogen receptor (ER)+ and ER- tumors, as well as the impact of pCR on disease-free survival (DFS) and overall survival (OS) for HER2+ breast cancer. Methods: MEDLINE, EMBASE, and Cochrane Controlled Clinical Trials Register databases were queried to identify eligible trials. Inclusion criteria were prospective, neoadjuvant trials that had at least one arm with HER2 directed therapy, and reported pCR. Pooled relative risk ratios (RRs) and p values were estimated for endpoints using the random effects statistical model. Results: We identified 36 trials (N = 4130). High pCR rates (> 40%) were seen with anthracycline-based chemotherapy and trastuzumab alone, and non-anthracycline based dual HER2 blockade. The addition of trastuzumab to chemotherapy did not improve BCS rate (RR 1.40, p = 0.15), but significantly increased rates of pCR (RR 1.91, p = 0.0001). Similarly, dual HER2 blockade compared to trastuzumab alone did not improve BCS rate (RR 1.03, p = 0.84), but significantly increased rates of pCR overall (RR 1.39, p < 0.00001), in both ER+ (RR 1.72, p = 0.01) and ER- subsets (RR 1.91, p = 0.0001), with no increase in grade 3/4 toxicity (RR:1.13, p = 0.16). Dual HER-2 blockade without chemotherapy was associated with pCR in a subset (11.2% - 27%) with minimal toxicity (incidence of grade 3/4 toxicity:1-5%). Higher pCR was associated with improved DFS (RR 2.29, p = 0.006) and OS (RR 4.61, p = 0.009). Conclusions: Neither the addition of trastuzumab to chemotherapy, nor the dual-HER2 blockade compared to trastuzumab, improves rates of BCS. However,both significantly improve rates of pCR, which is associated with improved DFS and OS. Dual HER2 blockade,with endocrine therapy for ER+, could potentially lessen or even obviate the use of chemotherapy.

647 Background: While the addition of trastuzumab to neoadjuvant chemotherapy (CTX) is well established for HER2+ BC, the use of dual agent HER2 blockade in the preoperative setting is not considered standard of care. We conducted a comprehensive systematic review and meta-analysis to evaluate the impact of neoadjuvant dual and single agent HER2 blockade on breast conserving surgery (BCS), pathological complete response (pCR) for estrogen receptor (ER)+ and ER- tumors, and impact of pCR on disease-free survival (DFS) and overall survival (OS) for HER2+ BC. Methods: Based on QUORUM guidelines, MEDLINE and Cochrane Controlled Clinical Trials Register databases were queried to identify eligible trials. Inclusion criteria were prospective, neoadjuvant trials that had at least one arm with HER2 directed therapy, and reported pCR. Pooled relative risk ratios (RRs) and 95% confidence intervals (CIs) were estimated for endpoints using the random effects model. Results: We identified 34 trials (N = 4064). High pCR rates (> 40%) were seen with anthracycline-based CTX and trastuzumab, as well as taxane based CTX alone with dual HER2 blockade. The addition of trastuzumab to CTX did not improve BCS rate (RR 1.40, CI: 0.89-2.22, p=.15), but significantly increased rates of pCR (RR 1.91, CI: 1.38-2.64, p=.0001). Similarly, dual HER2 blockade compared to trastuzumab alone did not improve BCS rate (RR 1.03, CI: 0.77-1.38, p=.84), but significantly increased rates of pCR overall (RR 1.38, CI: 1.24-1.53, p

1100 Background: Neoadjuvant therapy is commonly used in operable breast cancer. We prospectively evaluated the surgical complications in a cohort of patients who underwent mastectomy following neoadjuvant doxorubucin hydrochloride/cyclophosphamide/paclitaxel (AC/T) plus bevacizumab and compared the rate of complications to a matched cohort of neoadjuvant AC/T without bevacizumab. Methods: One hundred patients with HER2-negative breast cancer enrolled in a single-arm trial of neoadjuvant AC/T plus bevacizumab (cohort 1), 60 of these patients underwent mastectomy and were matched with 59 patients who received standard neoadjuvant AC/T (cohort 2) over a similar time period in the same healthcare system. All patients underwent mastectomy with or without reconstruction. Fisher’s exact tests were used to compare complication rates, with a p