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Introduction: To systematically review the accuracy of self-reported conflicts of interest (COIs) among transcarotid artery revascularization (TCAR) studies and evaluate factors associated with increased discrepancies., Materials and Methods: A literature search identified all TCAR-related studies with at least one American author published between January 2017 and December 2020. Industry payments from Silk Road Medical, Inc. were collected using the Centers for Medicare and Medicaid Open Payments database. COI discrepancies were identified by comparing author declaration statements with payments found for the year of publication and year prior (24-mo period). Risk factors for COI discrepancy were evaluated at both the study and author level., Results: A total of 79 studies (472 authors) were identified. Sixty four studies (81%) had at least one author who received payments from Silk Road Medical, Inc. Fifty eight (73%) studies had at least one author who received an undeclared payment. Consulting fees represented the majority of general payment subtype (60%). Authors who accurately disclosed payments received significantly higher median payments compared to authors who did not accurately disclose payments ($37,222 [interquartile range: $28,203-$132,589] versus $1748 [interquartile range $257-$35,041], P < 0.0001). Senior authors were significantly more likely to have a COI discrepancy compared to first authors (P = 0.0219)., Conclusions: The majority of TCAR-related studies did not accurately declare COI. A multivariate analysis demonstrated no effect of sponsorship on study recommendations or impact factor. This study highlights the need for increased efforts in accountability to improve the transparency of industry sponsorship, especially when consulting authors are reporting their results on patient outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: In the absence of lymph node involvement, tumor size is arguably the most important prognostic factor for women with breast cancer. Radiation therapy use in the T3 node-negative population is controversial. We investigated the use of postmastectomy radiation therapy (PMRT) in women with T3 node-negative breast cancer., Methods: A retrospective cohort study was conducted by identifying women with T3 node-negative breast cancer from the 1988-2009 Surveillance, Epidemiology and End Results database. Our primary outcome was breast cancer-specific survival. Survival curves were generated using the Kaplan-Meier method. Cox proportional hazard ratios (HRs) and propensity score analysis were used to evaluate the impact on survival., Results: We identified 2874 patients with T3 node-negative breast cancer and 961 (33%) received PMRT and 1913 (67%) did not. Statistically significant differences were seen in adjuvant radiation therapy use based on patient age, marital status, tumor grade, tumor size, and receptor status (P < 0.05 for all). Overall survival was lower in the PMRT group in unadjusted analysis (crude HR, 0.718; 95% confidence interval [CI], 0.614-0.840); however, adjusted HRs demonstrated no difference in overall survival (adjusted HR, 0.898; 95% CI, 0.765-1.054). Unadjusted analysis of breast cancer-specific survival demonstrated no difference between those who received PMRT and those who did not (crude HR, 0.834; 95% CI, 0.682-1.021). Propensity score analysis demonstrated no difference in breast cancer-specific survival based on PMRT use (adjusted HR, 0.939; 95% CI, 0.762-1.157)., Conclusions: Analysis of the Surveillance, Epidemiology and End Results database suggests that receipt of PMRT is not clinically beneficial in T3 node-negative breast cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: We sought to determine the incidence of postmastectomy bleeding, identify bleeding predictors, and evaluate the economic impact., Methods: Using the 2011 Healthcare Cost and Utilization Project-Nationwide Inpatient Sample, hospital discharges for a primary diagnosis of breast cancer were extracted using International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes 85.34-85.48 for mastectomy and diagnosis codes 174.0-174.9 for breast cancer. Discharges with postoperative bleeding were identified using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes 998.11 and 998.12. Discharges with male gender or a history of coagulation disorders were excluded. Bleeding complication rates and reoperation rates were assessed. Predictors and the impact of bleeding on length of stay and hospital costs were determined using regression analysis and projected to the national level., Results: A total of 7907 discharges met inclusion criteria; 201 had bleeding complications (2.54%), with 42 cases requiring reoperation. On univariate analysis, the presence of congestive heart failure (CHF), obesity, diabetes, chronic pulmonary disease, and the absence of concomitant reconstruction were associated with increased bleeding events. On multivariate analysis, only the presence of CHF remained as a significant predictor of bleeding complications (odds ratio [95% confidence interval], 2.45, [1.25-4.92], P = 0.009). On average, bleeding complications extended the length of stay by 1.3 d (P < 0.0001) while increasing hospital costs by $5495 per admission (P < 0.0001). Projected to a national level, bleeding complications accounted for an additional 1254 d of hospital care at a cost exceeding $5.3 million., Conclusions: Postmastectomy bleeding complications had an incidence of 2.54%, with CHF the only independent predictor identified. Such bleeding events, although infrequent, are associated with substantial economic costs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: We sought to identify clinicopathologic factors related to false negative axillary ultrasound (AUS) results., Methods: Patients with a clinically node-negative stage I-II breast cancer who also had a normal AUS were identified from our prospectively maintained database. All AUS studies were interpreted by dedicated breast radiologists as "normal" according to the absence of specific characteristics shown to be commonly associated with metastatic involvement. True- and false-negative AUS studies were compared statistically based on clinical, radiographic, and histologic parameters., Results: Of the 118 patients with a normal AUS, 25 (21%) were ultimately found to be node-positive on pathologic assessment after axillary surgery. On bivariate analysis, primary tumor size and lymphovascular invasion (LVI) were found to be significantly different between true- and false-negative AUS. The average tumor size was smaller in the true-negative group compared with that in the false-negative group (16 versus 21 mm [P < 0.01]). The presence of LVI was more likely in the false-negative group (44%) compared with that in the true-negative group (8%, P < 0.0001). No significant difference was noted between groups with regard to patient age, race, body mass index, tumor grade, histologic type, hormone receptor status, and time between AUS and axillary surgery. On multivariate analysis, only the presence of LVI achieved statistical significance (P = 0.0007)., Conclusions: AUS is a valuable tool that accurately predicted absence of axillary disease in 79% of patients with clinically node-negative breast cancer. AUS findings may be less accurate in the setting of LVI, and a negative AUS in patients with LVI should be interpreted cautiously., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: In breast conservation surgery (BCS) for breast cancer, the appropriate surgical margin is controversial. Margin index, a mathematical relationship between tumor size and closest margin, has been shown to be predictive of the probability of residual cancer after BCS for early stage breast cancer. We applied this tool to the same population of patients at our institution to evaluate its ability to predict residual disease after BCS., Methods: We retrospectively reviewed a prospectively maintained database of women undergoing BCS between 1980 and 2010 at the University of Pennsylvania. A total of 246 women underwent re-excision because of close margins. Average margin index between groups with and without residual disease in the re-excision specimen was compared using the Student t-test. A receiver operating curve was created using logistic regression to assess the overall diagnostic ability of the margin index on the presence or absence of residual disease., Results: Of patients who underwent re-excision, 29% of patients had residual disease. We analyzed several cutoff values for margin index, but none proved to be significant predictors of residual disease. Average margin index was significantly higher for patients without residual disease compared with patients with residual invasive cancer but not for patients with residual ductal carcinoma in situ., Conclusions: In women undergoing BCS for early stage breast cancer at our institution, margin index was not predictive of the presence of residual cancer on re-excision. We hypothesize that the predictive ability of a margin index is likely limited by several factors including the presence of ductal carcinoma in situ and the location and extent of the close margin., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Following reforms to the breast-cancer referral process for our city's health Safety Net (SN), we compared the experiences from first abnormality to definitive diagnosis of breast-cancer patients referred to Siteman Cancer Center from SN and non-SN (NSN) providers., Materials and Methods: SN-referred patients with any stage (0-IV) and NSN-referred patients with late-stage (IIB-IV) breast cancer were prospectively identified after diagnosis during cancer center consultations conducted between September 2008 and June 2010. Interviews were taped and transcribed verbatim; transcripts were independently coded by two raters using inductive methods to identify themes., Results: Of 82 eligible patients, 57 completed interviews (33/47 SN [70%] and 24/35 NSN [69%]). Eighteen SN-referred patients (52%) had late-stage disease at diagnosis, as did all NSN patients (by design). A higher proportion of late-stage SN patients (67%) than either early-stage SN (47%) or NSN (33%) patients reported feelings of fear and avoidance that deterred them from pursuing care for concerning breast findings. A higher proportion of SN late-stage patients than NSN patient reported behaviors concerning for poor health knowledge or behavior (33% versus 8%), but reported receipt of timely, consistent communication from health care providers once they received care (50% versus 17%). Half of late-stage SN patients reported improper clinical or administrative conduct by health care workers that delayed referral and/or diagnosis., Conclusions: Although SN patients reported receipt of compassionate care once connected with health services, they presented with higher-than-expected rates of late-stage disease. Psychological barriers, life stressors, and provider or clinic delays affected access to and navigation of the health care system and represent opportunities for intervention., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Management of occult primary breast cancer (OPBC), that is, breast cancer that first presents through regional nodal or distant disease without clinical or mammographic evidence of disease in the breast, has been controversial and inconsistent. Here, we review OPBC patients treated at our institution., Methods: We conducted a retrospective review of women diagnosed with a first primary breast cancer between March 1999 and September 2010 to identify patients who presented with isolated axillary lymphadenopathy proven to be histologically consistent with primary breast malignancy but had no evidence of a breast mass on physical examination, mammography, or ultrasound. Descriptions of treatments received, recurrence, morbidity, and mortality as of October 2012 are reported., Results: Of 5533 patients reviewed, seven (0.1%) patients were identified. The median age was 65 y old (range, 40-72), and the median length of follow-up was 86 mo (range, 42-124). Four patients underwent modified radical mastectomy, one patient had a lumpectomy and axillary lymph node dissection, and two patients had axillary lymph node dissection without breast surgery. Four patients received adjuvant radiation therapy. All seven patients received chemotherapy. Three patients received endocrine therapy, and two patients received anti-HER2 therapy. At the last follow-up, all seven patients were alive with no evidence of disease., Conclusions: Although there was some variation in the management of OPBC at our institution, our patients had excellent outcomes after multimodal treatment. Our results support a curative intent approach to the treatment of OPBC and illustrate the need for individualized treatment algorithms based on tumor biology and extent of the disease at diagnosis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: We sought to investigate whether the volume of ductal carcinoma in situ (DCIS) impacts margin status in patients undergoing lumpectomy for invasive breast cancer., Methods: We identified 358 patients with stages I-III invasive breast cancer and associated DCIS who were treated with breast-conserving therapy from 1999 to 2009. Data included patient and tumor characteristics, percentage of DCIS (<25%, 26%-50%, or >50%), and pathologic outcomes. Data were compared using chi-square and Fisher exact tests. A two-tailed P value of <0.05 was considered significant., Results: The 358 patients had a mean age of 58 ± 13 y; 260 (72%) patients were >50 y. The volume of DCIS in lumpectomy specimens was <25% in 296 (83%) patients, 26%-50% in 29 (8%) patients, and >50% in 33 (9%) patients. Tumors with decreasing DCIS volume were more likely to be estrogen receptor positive (239 [82%] with <25% DCIS, 21 [72%] with 26%-50% DCIS, 22 [67%] with >50% DCIS; P=0.026). DCIS volume was not significantly associated with patient age, tumor size, grade, and stage, nodal status, progesterone receptor status, or Her2 status (P>0.05). Overall, 137 (38%) patients had one or more positive margins, including 97 of 296 (33%) with <25% DCIS volume, 17 of 29 (59%) with 26%-50% DCIS volume, and 23 of 33 (70%) with >50% DCIS volume (P<0.0001)., Conclusions: The volume of DCIS associated with an invasive breast cancer in the final lumpectomy specimen is a strong predictor of positive surgical margins. Future analyses will focus on the ability of core pathology to provide this information for intraoperative surgical decision making., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Axillary ultrasound is used in the evaluation of breast cancer patients to identify subclinical node-positive disease. The study aim was to identify whether certain radiologic characteristics correlate with cytology and final pathology., Methods: We retrospectively reviewed ultrasound images of 110 women with clinically node-negative breast cancer and suspicious axillary ultrasound to identify specific anatomic characteristics previously shown to be more commonly associated with metastatic involvement. Results were compared with cytology and final pathology. We used descriptive statistics for data summary., Results: Of the 110 patients, cytology was positive in 71 (68%) and final pathology was positive in 80 (73%). The most common indication for biopsy was lymph node cortex characterized by thickening or eccentric contour (N = 40). Loss of the fatty hilum was described in 17 patients, and 9 patients had lymph nodes with both abnormal cortical and hilar features. Of 43 patients with "suspicious" disease without specific criteria, the most common indication for biopsy was disparity in size of one or more lymph nodes compared with others. Maximum cortical thickness was greater in patients with positive cytology compared with those with negative cytology (7.6 versus 6.2 mm; P = 0.047). Ultrasound characteristics such as lymph node size, cortical morphology, contour, and hilar fat were not individually predictive of final cytology and pathology., Conclusions: Axillary ultrasound is a valuable tool that accurately predicted malignant axillary disease in 73% of patients with clinically node-negative breast cancer. Elaboration of standard criteria for nodal evaluation will improve usefulness of this imaging modality in preoperative staging of the axilla., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: We investigated factors associated with positive margins following mastectomy and the impact on outcomes., Methods: We identified 240 patients with stage I-III invasive breast cancer who underwent mastectomy from 1999 to 2009. Data included patient and tumor characteristics, pathologic margin assessment, and outcomes. Margin positivity was defined as the presence of in situ or invasive malignancy at any margin. Descriptive statistics were used for data summary and were compared using χ(2)., Results: Of the 240 patients, 132 (55%) had a simple mastectomy with sentinel lymph node biopsy and 108 (45%) had a modified radical mastectomy. Overall, 21 patients (9%) had positive margins, including 12 (57%) with one positive margin, 3 (14%) with two positive margins, and 6 (29%) with three or more positive margins. The most commonly affected margin was the deep margin (48% of patients). Eight of the 21 patients (38%) received adjuvant chest wall irradiation. There were no differences between patients who had a positive margin and those who did not with respect to patient age, race, percentage of in situ component, tumor size, tumor grade, lymphovascular invasion, or immunostain profile (P > 0.05 for all). None of the patients with positive margins experienced a local recurrence., Conclusions: Positive margins following mastectomy occurred in nearly 10% of our patients. No specific patient or tumor characteristics predicted a risk for having a positive margin. Despite the finding that only approximately 40% of patients received adjuvant radiation in the setting of a positive margin, no local recurrences have been observed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Margin status is a significant risk factor for local recurrence. We sought to examine whether the method of tumor localization predicted the margin status and the need for re-excision for both nonpalpable and palpable breast cancer., Methods: We identified 358 consecutive breast cancer patients who were treated with breast-conserving therapy (BCT) from 1999 to 2006. Data included patient and tumor characteristics, method of localization (needle versus palpation), and pathologic outcomes. Descriptive statistics were used for data summary and data were compared using χ(2)., Results: Of 358 patients undergoing BCT, 234 (65%) underwent needle localization for a nonpalpable tumor and 124 (35%) underwent a palpation-guided procedure. Patients undergoing palpation-guided procedures were younger and had larger tumors at a more advanced pathologic stage of disease than those undergoing needle localization procedures (P < 0.05 for each). Patient race, tumor grade, presence of lymphovascular invasion, biomarker profile, and nodal status were not significantly different between the two groups (P > 0.05). Overall, 137 patients (38%) had one or more positive margins: 90 of 234 (38%) who had a needle localization procedure and 47 of 124 (38%) who had a palpation-guided procedure (P > 0.05). The number of margins affected did not differ significantly between the two groups., Conclusion: Although patients with palpable breast cancer had larger tumors than those with nonpalpable breast cancer, the incidence and number of positive margins was similar to those who had needle localization for nonpalpable tumors. Improved methods of localization are needed to reduce the rate of positive margins and the need for re-excision., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The development of an invasive breast cancer recurrence outside of the breast parenchyma following curative-intent therapy for ductal carcinoma in situ (DCIS) is rare. We describe the patient and tumor characteristics associated with such recurrences., Methods: A retrospective review was conducted of 621 patients who were treated for DCIS between 2004 and 2009. Patient, tumor, and treatment characteristics were collected. Descriptive statistics were utilized for data summary and data were compared using χ(2), where appropriate., Results: Of 621 patients who underwent curative-intent therapy for DCIS, 12 (1.9%) developed an invasive metastatic recurrence. Primary local therapy at the time of the initial DCIS diagnosis included 11 patients who underwent mastectomy and one who had lumpectomy and adjuvant radiotherapy. The metastatic recurrences were in chest wall and/or ipsilateral axillary lymph nodes only (n = 6) or distant sites with or without ipsilateral axillary or supraclavicular lymph nodes (n = 6). Of the 12 patients with invasive recurrence, eight had high grade DCIS with comedo necrosis at initial diagnosis. The biomarker profiles of the invasive recurrences included 55% estrogen receptor positivity, 45% progesterone receptor positivity, and 73% Her2/neu amplification. Patient age, tumor grade, presence of comedo necrosis, biomarker profile, and surgical treatment were not predictive of recurrence., Conclusion: Invasive metastatic recurrence following adequate local therapy for DCIS is uncommon and likely represents progression of unidentified invasive disease at the time of diagnosis. The majority of invasive recurrences were Her2/neu amplified. Further studies are necessary to determine if such a unique biomarker profile correlates with metastatic recurrence., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Because benign postoperative changes may overlap those of malignancy, the utility of breast MRI following an excisional biopsy is unclear. We sought to investigate the ability of MRI to predict residual disease following an excisional biopsy for breast cancer., Materials and Methods: We reviewed 93 patients who underwent surgical treatment for stage 0-III breast cancer at our institution from January 2005 to May 2008. All patients had previously undergone excisional biopsy with subsequent MRI. Patient, tumor, and treatment characteristics were collected. Descriptive statistics were utilized for data summary and data were compared using Fisher's exact or χ(2) tests., Results: The mean age of the 84 patients who had additional surgery following MRI was 51 ± 7 y. Thirteen (15%) patients had only postoperative changes on MRI; six had residual disease on final pathology. Of 71 patients with MRI findings suspicious for residual disease, 54 (76%) had pathologic confirmation, while 17 (24%) had only benign pathology. The sensitivity and specificity of MRI following excisional biopsy were 90% and 29%, respectively. Overall, 49 (58%) of the 84 patients underwent mastectomy, including 11 of 24 (46%) with negative final pathology. Patient age, tumor size, tumor grade, biomarker profile, nodal status, and MRI findings were not predictive of surgical treatment type (P > 0.05)., Conclusion: Although excisional biopsy decreases the specificity of breast MRI, its sensitivity remains high. Nearly 50% of patients with a suspicious MRI and negative final pathology underwent mastectomy, suggesting that additional biopsy of all suspicious MRI findings is necessary to avoid surgical overtreatment., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The study aim was to investigate factors that predict the use of neoadjuvant versus adjuvant chemotherapy in patients with triple negative breast cancer (TNBC) and the overall survival in each group., Methods: We identified 493 patients with Stage I-III TNBC between 1998 and 2008. Patients were divided according to receipt of neoadjuvant, adjuvant, or none/unknown chemotherapy. Data were compared using chi(2) and Fisher's exact test. For more than two group comparisons and analyzing multiple dependent variables, MANOVA was used. Kaplan-Meier curves were generated., Results: Of 493 patients with TNBC, 154 (31%) received neoadjuvant chemotherapy, 251 (51%) received adjuvant chemotherapy, and 88 (18%) had no or unknown chemotherapy. Patients undergoing neoadjuvant chemotherapy were younger (mean 50, range 20-83) compared with those undergoing adjuvant chemotherapy (mean 53, range 25-83) or none/unknown chemotherapy (mean 62, range 29-86) (P < 0.0001). The three groups did not differ significantly by patient race, tumor histology, or tumor grade. Increased tumor size, nodal positivity, and advanced stage were more likely to be associated with use of neoadjuvant chemotherapy (all comparisons P < 0.0001). After controlling for covariates associated with survival in unadjusted tests, patients undergoing adjuvant therapy were less likely to die compared with patients undergoing neoadjuvant therapy or none/unknown therapy (overall aHR 0.476, 95% CI 0.295-0.770)., Conclusions: Women with TNBC who underwent adjuvant chemotherapy were 52% less likely to die overall compared with those who received neoadjuvant chemotherapy or none/unknown chemotherapy in this institutional series. Prospective studies are necessary to determine if this finding is durable., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: We sought to determine factors that predict the use of breast magnetic resonance imaging (MRI) surveillance in women previously treated for breast cancer and the incidence of in-breast recurrences and/or new cancers identified by MRI., Methods: We reviewed 141 patients who were treated between 2005 and 2008 who also underwent surveillance breast MRI following their treatment. Patient, tumor, treatment characteristics, and MRI findings were collected. Gail scores were calculated based on the patient's personal and family history prior to the breast cancer diagnosis. Data were compared using chi(2) and Fisher's exact test., Results: The average age of the study population was 51 (range 24-73). One hundred forty-one women underwent 202 surveillance breast MRIs during the study period. Sixteen of 141 (11%) required second look imaging, and six of 141 (4%) required biopsy of suspicious lesions. Two of the six were invasive breast cancers, while four were benign. Overall, the rate of new cancer detection on surveillance MRI during the study period was 0.9% (two of 202 imaging studies). Of the 71 women with evaluable Gail scores, the average lifetime risk score was 16.7%. Eight patients had BRCA mutations and three previously underwent irradiation for Hodgkin's lymphoma. Patient age, Gail score, tumor stage, grade, histology, receptor status, and surgical treatment were not predictive of MRI surveillance use., Conclusion: Prospective studies are needed to determine which patients may potentially benefit from breast MRI surveillance following curative-intent treatment. The lack of standardized guidelines may result in excessive or inappropriate use, unnecessary follow-up procedures, and a concomitant low yield., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: We investigated characteristics associated with axillary lymph node (LN) status in patients with T3 breast cancers and hypothesized that LN status is an independent predictor of survival., Methods: Characteristics associated with axillary LN metastasis among women with T3 breast cancers were identified from the 1988-2003 Surveillance, Epidemiology, and End Results (SEER) database. The primary outcome was breast cancer-specific mortality. Cox models were used to calculate adjusted hazard ratios (aHR) and 95% confidence intervals (CI)., Results: A total of 12,778 patients with T3 breast cancers were analyzed (8201 LN+, 3695 LN-, 882 unknown). LN+ patients were more likely to be <50 y, married, and have ER+/PR+, grade 3 invasive ductal cancers (P<0.01 for each). Most patients underwent mastectomy (87.4%). Post-mastectomy radiation was more commonly used in LN+ patients (P<0.01). LN+ patients had higher breast cancer-specific mortality (36.2% versus 16.4%, P<0.01) and were more likely to die during the follow-up period (aHR = 2.87, 95% CI: 2.62-3.15) compared with LN- patients., Conclusions: Analysis of the SEER database indicated that several patient and tumor characteristics predict a higher likelihood of axillary LN involvement in patients with T3 breast cancers. LN status was an independent predictor of survival in women with T3 breast cancers., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: Black women often present with advanced-stage breast cancer compared with White women, which may result in the observed higher mortality among Black women. Age-related factors (e.g., comorbidity) also affect mortality. Whether racial disparities in mortality are evident within age and/or stage groups has not been reported, and risk factors for greater mortality among Black women are not well defined., Methods: Using the 1988-2003 Surveillance, Epidemiology, and End Results Program data, we conducted a retrospective, population-based cohort study to compare overall and stage-specific breast-cancer mortality between Black and White women within each age (<40, 40-49, 50-64, and 65+) and stage (stage 0-IV and unstaged) group at diagnosis. Cox regression models calculated unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CI), the latter controlling for potential confounders of the relationship between race and survival., Results: In the 1988-2003 Surveillance, Epidemiology, and End Results data, 20,424 Black and 204,506 White women were diagnosed with first primary breast cancer. In unadjusted models, Black women were more likely than White women to die from breast cancer (HR: 1.90; 95% CI: 1.83-1.96) and from all causes (HR: 1.52; 95% CI: 1.48-1.55) during follow-up. In models stratified by age and stage, Black women were at increased risk of breast-cancer-specific mortality within each stage group among women <65 y., Conclusion: Racial disparities in breast-cancer-specific mortality were predominantly observed within each stage at diagnosis among women <65 y old. This greater mortality risk for Black women was largely not observed among women >or=65 y of age.

Background: 2C mice bearing the cytotoxic TCR for class I L(d) on a C57BL/6 (B6) background have a preponderance of 1B2+CD8+ T cells directed against L(d). These naive CD8+ T cells are not directly cytotoxic without prior in vivo or in vitro activation. However, after in vitro sensitization, they become highly cytotoxic and will acutely and specifically reject a tolerant L(d+) BALB/c heart graft. Anti-lymphocyte serum (ALS) treatment eliminates CD4+ and CD8+ cells and a large double negative (CD4-CD8-) 1B2+ non-cytotoxic transgenic cell population remains. The immunological function of this unique peripheral population of T cells is investigated in the 2C transgenic mouse., Materials and Methods: To determine the activation characteristics of the 2C CD4-CD8- T cells, 2C peripheral T cells were analyzed for 1B2+, CD8+, and CD4+ marker by FACS before and 48-h after 0.5 cc ALS i.p. Similarly, in vitro, the response of these 2C CD4-CD8- T cells remaining after deletion of mature CD4+ and CD8+ T cells with ALS plus complement were evaluated by mixed lymphocyte culture and cytotoxic T lymphocyte after 7 days culture with BALB/c, IL-2, or BALB/c + IL-2. Parallel experiments were performed with control non-transgenic B6 mice. Following in vitro culture with BALB/c + IL-2, 2C CD4-CD8- T cells were injected into B6 mice with a tolerant BALB/c heart (tolerization via anti-CD4 mAb and intrathymic BALB/c) to determine their immunogenicity., Results: While peripheral T cells in control B6 mice have <5% CD4-CD8- cells, transgenic 2C mice have a significantly increased percentage at 29 to 35% (P < 0.01). After the deletion of CD4+ and CD8+ T cells with either in vivo or in vitro ALS, 2C CD4-CD8- T cells increased to 96 to 99%. After 7-day culture, the 2C CD4-CD8- T cells decreased again to 33 to 38%. Simultaneously, 2C CD8+ T cells decreased from 56 to 62% to 0.1 to 3% after ALS treatment, but again increased to 61 to 70% after in vitro culture. Untreated 2C cells responded to IL-2 or BALB/c antigen equally well. However, after ALS treatment, CD4-CD8- T cells responded to IL-2 and IL-2 plus antigen, but not BALB/c antigen alone. Finally, CD4-CD8- T cells cultured for 7 days with BALB/c + IL-2 rejected the tolerant BALB/c heart in 5.3 +/- 0.3 days., Conclusion: In the periphery of transgenic 2C mice is a unique CD4-CD8- population of T cells bearing the transgenic specific marker 1B2. These non-cytotoxic cells can be optimally stimulated to develop marked specific L(d) cytotoxicity in parallel with the expression of the CD8+ epitope.

Background: The role of the proinflammatory cytokine interferon-gamma (IFN-gamma) in the development of oral or portal venous tolerance is poorly defined. By using knockout mice for IFN-gamma (GKO mice), we investigated the effect of both oral and portal venous administration of alloantigen on the systemic delayed type hypersensitivity (DTH) response to alloantigen rechallenge., Materials and Methods: C57BL/6 (B6) control and GKO mice (also on a B6 background) were given either saline or BALB/c spleen cells (25 million) by oral gavage (PO) or by injection into the portal vein (PV) on day 0. The injection of 10 million BALB/c spleen cells subcutaneously into the dorsal flanks was performed after 7 days followed by footpad injection of 10 million BALB/c spleen cells on day 14. Specific footpad swelling was measured 24 h later using a micrometer. Splenocyte responsiveness was measured by in vitro mixed lymphocyte culture and cytotoxic T lymphocyte assay. Cytokine production of interleukin (IL)-2, IL-4, IL-10, and IFN-gamma was measured by enzyme-linked immunosorbent assay., Results: Although B6 mice given PO or PV saline demonstrated a DTH response of 0.47 +/- 0.04 mm and 0.49 +/- 0.05 mm, respectively, in GKO mice, a greater DTH response of 0.72 +/- 0.08 mm and 0.75 +/- 0.05 mm was measured after either PO or PV saline (P < 0.05, P < 0.05, respectively). In vitro MLC and CTL confirmed the heightened DTH response to BALB/c observed in GKO versus B6. Despite this heightened response in control GKO mice, the DTH response was completely suppressed in both GKO and B6 mice, after both PO and PV BALB/c feedings (P < 0.001, P < 0.001, respectively, in both GKO and B6 mice). The unchanged brisk response to third-party C3H/HeJ demonstrated antigenic specificity., Conclusions: Although DTH responsiveness to alloantigen is increased in the absence of IFN-gamma, both oral and portal venous alloantigen-specific tolerance can still be established in GKO mice similar to that in control B6 mice. The achievement of a tolerogenic immune response by both oral and portal venous routes indicates that lack of IFN-gamma does not preclude the induction of tolerance in this murine model.

Background: Prior administration of the Gram-positive bacteria Propionibacterium acnes (PA) results in hypersensitivity and hepatocyte necrosis to a subsequent low dose of lipopolysaccharide (LPS). Endotoxin tolerance has been shown to prevent lethality after ischemia/reperfusion injuries, sepsis, and endotoxic shock. We investigated whether prior induction of LPS tolerance could prevent subsequent PA-priming and LPS-induced death. The levels of known effector cytokines possibly responsible for these changes were measured., Methods: C57BL/6 (B6) mice were given heat-killed PA (0.5 mg/mouse) followed 7 days later by LPS (20 microg/mouse). In parallel experiments, B6 mice were pretreated with a single 20 microg/mouse dose of LPS (lethal dose = 800 microg/mouse) 7 days prior to PA priming. Animal survival, liver and spleen weights, and histology were examined. Cytokine levels of the inflammatory cytokines interferon-alpha, tumor necrosis factor-gamma, interleukin (IL)-6, and IL-12 and the anti-inflammatory cytokines IL-4 and IL-10 were measured by enzyme-linked immunosorbent assay and by reverse-transcription polymerase chain reaction., Results: Hepatomegaly, splenomegaly, and hepatocyte necrosis with death developed in all PA-primed B6 mice challenged with LPS. However, 83% of B6 mice given a tolerizing dose of LPS prior to PA survived (P < 0.01) without any increase in liver or spleen weights and without histological evidence of necrosis. Markedly decreased in vivo and in vitro inflammatory (interferon-alpha, tumor necrosis factor-gamma, IL-6, and IL-12) cytokine levels corresponded with survival in the LPS-tolerant mice. Endotoxin tolerance and subsequent survival were also associated with an increase in anti-inflammatory (IL-4 and IL-10) mRNA expression., Conclusions: Lethal PA-primed LPS-induced hepatic injury can be prevented by administering a tolerizing dose of LPS prior to PA-priming. LPS protects the liver by preventing hepatic mononuclear cellular infiltration, reducing the production of the toxic proinflammatory cytokines, and inducing the production of endogenous anti-inflammatory cytokines.

Background: Local antigen presentation via either the oral (PO) or the portal venous (PV) routes results in suppression of systemic delayed-type hypersensitivity (DTH). The responsible cell populations are not well defined. Because NK1.1(+) T cells express the Fas ligand and produce high levels of the immunosuppressive cytokine, IL-4, they may play a role in both activated T-cell apoptosis and a Th1 to Th2 immune shift, thus promoting tolerance induction., Methods: C57BL/6 mice were tolerized to BALB/c alloantigen by PV or PO spleen cells (25 x 10(6)) on Day 0. Subcutaneous (SQ) challenge with 10 x 10(6) BALB/c cells on Day 7 was followed by footpad injection of 10 x 10(6) BALB/c cells on Day 14. Footpad swelling was measured 24 h later. A single injection of the NK1.1(+) cell-depleting antibody, PK-136, was given IP (10 mg/kg) 2 days prior to PV or PO antigen. Flow cytometry evaluated NK1.1(+) cell depletion. CD1 knockout (KO) mice, lacking NK1.1(+) T cells, were also challenged with PV and PO Balb/c in parallel experiments., Results: The DTH to BALB/c antigen was markedly suppressed in C57BL/6 mice when this alloantigen was given by either PO or PV routes (P < 0.001, P < 0.001). The maintenance of an unaltered response to third-party C3H/HeJ demonstrated alloantigenic specificity. Administration of the anti-NK1.1 T cell monoclonal antibody, PK-136, resulted in complete restoration of in vivo DTH responsiveness in PO tolerance (P < 0.01), and partial restoration in PV tolerance (P < 0.05) in C57BL/6 mice. FACS confirmed virtually complete depletion of liver, splenic, Peyer's patch, and mesenteric lymph node NK1.1(+) lymphocytes. Development of both PO and PV tolerance was prevented in CD1 KO mice., Conclusion: NK1.1(+) T cells play an essential role in antigen-specific suppression of the DTH response mediated by both oral and portal venous tolerance.

Background: CD4+ T cells play an essential role in allograft rejection. Monoclonal anti-rat CD4 antibody, RIB 5/2, has been shown to modulate the CD4 glycoprotein without eliminating recipient T cells. A single dose of monoclonal anti-rat CD4 antibody RIB 5/2 plus donor splenocytes results in donor-specific unresponsiveness to heart and kidney allografts, but not skin allografts. This study examined whether tolerance to the more resistant skin graft could also be achieved with RIB 5/2., Methods: Buffalo (RT1(b)) recipients were given a single dose (20 mg/kg) of monoclonal antibody RIB 5/2 IP plus IV Lewis (RT1(l)) splenocytes (25 x 10(6)) 21 days before Lewis heart, kidney, or skin grafts. In addition, Lewis skin was grafted either simultaneously with or after long- term Lewis heart or kidney allograft acceptance (>50 days)., Results: While IV alloantigen plus RIB 5/2 results in long-term acceptance of both heart and kidney, skin allografts are rejected when transplanted alone. Simultaneous transplantation with a Lewis kidney, but not with a Lewis heart, resulted in long-term Lewis skin graft acceptance. However, recipients tolerant to Lewis kidney or heart alone will not accept subsequent Lewis skin grafts, while recipients of simultaneous Lewis skin and kidney grafts subsequently accept a second Lewis, but not third-party Brown Norway (RT1(n)), skin graft., Conclusion: RIB 5/2 plus Lewis donor splenocytes tolerize for donor-specific heart and kidney but not skin grafts. However, Lewis skin grafted simultaneously with a Lewis kidney, but not Lewis heart, is accepted and protects a subsequent donor-specific Lewis skin graft., (Copyright 2001 Academic Press.)