Background: Some oxysterols are identified in atheromatous plaques and in plasma of atherosclerotic patients. We asked whether they might modulate cytokine secretion on human monocytic cells. In healthy and atherosclerotic subjects, we also investigated the relationships between circulating levels of C‐reactive protein (CRP), conventional markers of hyperlipidemia, some oxysterols (7β‐hydroxycholesterol, 7‐ketocholesterol, and 25‐hydroxycholesterol), and various cytokines. Methods: Different flow cytometric bead‐based assays were used to quantify some cytokines (IL‐1β, IL‐2, IL‐4, IL‐5, IL‐6, IL‐7, IL‐8, IL‐10, IL‐12, IL‐13, IL‐17, G‐CSF, GM‐CSF, IFN‐γ, MCP‐1, MIP‐1β, or TNF‐α) in the culture media of oxysterol‐treated U937 and THP‐1 cells, and in the sera of healthy and atherosclerotic subjects. CRP and markers of hyperlipidemia were determined with routine analytical methods. Oxysterols were quantified by gas chromatography/mass spectrometry. Flow cytometric and biochemical methods were used to measure IL‐8 mRNA levels, intracellular IL‐8 content, and protein phosphorylation in the mitogenic extracellular kinase/extracellular signal‐regulated kinase1/2 (MEK/ERK1/2) signaling pathway. Results: All oxysterols investigated are potent in vitro inducers of MCP‐1, MIP‐1β, TNF‐α, and/or IL‐8 secretion, the latter involving the MEK/ERK1/2 cell signaling pathway. In healthy and atherosclerotic subjects, no relationships were found between cytokines (IL‐8, IL‐1β, IL‐6, IL‐10, TNF‐α, IL‐12, and MCP‐1), CRP, conventional markers of hyperlipidemia, and oxysterols. However, in patients with arterial disorders of the lower limbs, small but statistically significant differences in the circulating levels of CRP, TNF‐α, and IL‐10 were observed comparatively to healthy subjects and according to the atherosclerotic stage considered. Conclusions: Flow cytometric bead‐based assays are well adapted to measure variations of cytokine secretion in the culture media of oxysterol‐treated cells and in the sera of healthy and atherosclerotic subjects. They underline the in vitro proinflammatory properties of oxysterols and may permit to distinguish healthy and atherosclerotic subjects, as well as various atherosclerotic stages. © 2006 International Society for Analytical Cytology

BACKGROUND. To date, the impact of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 trial reported in 1999 on the use of tamoxifen after surgery for ductal carcinoma in situ (DCIS) is unknown. The current study was designed to evaluate the impact of NSABP B-24 on current practices at a comprehensive cancer center. METHODS. The records of 350 consecutive patients with DCIS who were treated at the authors' institution between July 1999 and June 2002 were obtained from a prospective database and analyzed. Whether patients were offered tamoxifen, whether patients accepted tamoxifen, and the associated reasons were recorded along with tamoxifen-related side effects and patient compliance with therapy. Clinical and pathologic factors were evaluated for their impact on recommendations regarding tamoxifen. Differences were assessed by chi-square analysis. RESULTS. Of the 350 patients, 73 were excluded because of evidence of invasive carcinoma on final pathology review. Of the remaining 277 patients, 166 patients (60%) were offered tamoxifen, and 90 patients (54%) chose to take tamoxifen. Of 111 patients who were not offered tamoxifen, 39 patients (35%) had documented explanations, which included bilateral mastectomy (n ϭ 25 patients), medical reasons (n ϭ 10 patients), and already received tamoxifen for other reasons at the time of diagnosis (n ϭ 4 patients). Of 94 patients who received tamoxifen, 20 patients (21%) discontinued use because of side effects or complications. Tamoxifen was more likely to be recommended for women who underwent segmental resection compared with women who underwent total mastectomy (P ϭ 0.002) and for women with smaller pathologic DCIS tumors (P ϭ 0.001). In addition, these two factors were interrelated. CONCLUSIONS. Physicians and patients remain cautious regarding the use of tamoxifen after local treatment for DCIS. The current findings have implications for current trials evaluating aromatase inhibitors and other chemopreventive agents for this disease. Cancer 2004;100:942-9.

BACKGROUNDIn three prospective, single‐arm studies, the authors previously showed an improved outcome for anthracycline‐naïve patients with isolated sites of recurrent breast carcinoma (BC) who were treated with doxorubicin‐based chemotherapy after local therapy (surgery and/or radiotherapy). In the current report, the initial results are presented from a Phase II trial of docetaxel (100 mg/m2 every 21 days for 6 cycles) given after local therapy for recurrent BC (Stage IV BC with no evidence of clinically measurable disease) in patients who received prior adjuvant anthracycline‐based chemotherapy, and the authors provide an update of the 3 previous studies. An analysis of prognostic factors for these patients also is presented.METHODSEligibility criteria for all studies included histologic proof of recurrent BC that had been resected and/or irradiated with curative intent. Survival was calculated using the Kaplan–Meier method. Univariate survival analyses were performed to test for associations between patient characteristics and outcome (log‐rank test). Cox proportional hazards models were used to determine the multivariable correlations between patient characteristics and outcome.RESULTSThe median follow‐up for the docetaxel‐based trial (n = 26 patients) was 45 months. Early outcomes for this study are promising. The median disease‐free survival (DFS) was 44 months, and the 3‐year DFS and overall survival (OS) rates were 58% and 87%, respectively. In the 3 doxorubicin‐based studies, the median follow‐up was 121.5 months for all living patients, and the estimated 20‐year DFS and OS rates were both 26%. On multivariable analysis of patients from all 4 studies, the only significant prognostic factor for DFS and OS (P = 0.0006) was the number of involved axillary lymph nodes at initial diagnosis.CONCLUSIONSA proportion of patients with isolated BC recurrences achieved prolonged DFS with combined‐modality treatment. Patients who receive anthracycline‐based chemotherapy at primary diagnosis may benefit from local treatment followed by docetaxel‐based chemotherapy for isolated recurrences. The only significant independent prognostic factor was the number of involved axillary lymph nodes at initial diagnosis. Cancer 2005. © 2005 American Cancer Society.

BACKGROUNDThe majority of patients with breast carcinoma with ≥ 10 metastatic axillary lymph nodes (ALNs) develop recurrent disease within 5 years from diagnosis. The purpose of the current study, performed retrospectively, was to characterize the natural history of this subset of patients, both before and after the advent of adjuvant anthracycline‐based chemotherapy and tamoxifen.METHODSRetrospectively, patients with primary breast carcinoma (N = 882) with ≥ 10 metastatic ALNs, treated between 1954 and 1998, were selected from 3 institutions: The University of Texas M. D. Anderson Cancer Center (Houston, TX); the Institut Gustave Roussy (Villejuif, France); and Hospital Clinico Universitario (Valencia, Spain). All patient data had been registered prospectively in clinical databases. One group consisted of 314 patients treated with locoregional therapy alone (no adjuvant therapy) from 1954 to 1983. The second group included 568 patients who received adjuvant anthracycline‐based chemotherapy between 1974 and 1998 with or without adjuvant tamoxifen.RESULTSThe median follow‐up time was 140 months. Disease‐free survival rates at 15 and 20 years for the no adjuvant therapy and adjuvant therapy groups were 17% and 16% versus 26% and 24%, respectively. The overall survival rates at 20 years for the no adjuvant therapy and the adjuvant therapy groups were 9% and 21%, respectively. By multivariate analysis, the independent factors associated with survival in the adjuvant therapy group were tumor size and the number of metastatic lymph nodes.CONCLUSIONSThe retrospective analysis suggested that adjuvant anthracycline‐based chemotherapy and hormonal therapy have altered the natural history in this high‐risk group of patients. However, despite such improvements, survival rates remained low, and innovative therapeutic approaches are, therefore, needed to improve clinical outcomes. Cancer 2005. © 2005 American Cancer Society.

Comparative studies of the structural organization of the brain are fundamental to our understanding of human brain function. However, whereas brains of experimental animals are fixed by perfusion of a fixative through the vasculature, human or ape brains are fixed by immersion after varying postmortem intervals. Although differential treatments might affect the fundamental characteristics of the tissue, this question has not been evaluated empirically in primate brains. Monkey brains were either perfused or acquired after varying postmortem intervals before immersion‐fixation in 4% paraformaldehyde. We found that the fixation method affected the neuroanatomical characteristics of the monkey hippocampal formation. Soma size was smaller in Nissl‐stained, immersion‐fixed tissue, although overall brain volume was larger as compared to perfusion‐fixed tissue. Nonphosphorylated high‐molecular‐weight neurofilament immunoreactivity was lower in CA3 pyramidal neurons, dentate mossy cells, and the entorhinal cortex, whereas it was higher in the mossy fiber pathway in immersion‐fixed tissue. Serotonin‐immunoreactive fibers were well stained in perfused tissue but were undetectable in immersion‐fixed tissue. Although regional immunoreactivity patterns for calcium‐binding proteins were not affected, intracellular staining degraded with increasing postmortem intervals. Somatostatin‐immunoreactive clusters of large axonal varicosities, previously reported only in humans, were observed in immersion‐fixed monkey tissue. In addition, calretinin‐immunoreactive multipolar neurons, previously observed only in rodents, were found in the rostral dentate gyrus in both perfused and immersion‐fixed brains. In conclusion, comparative studies of the brain must evaluate the effects of fixation on the staining pattern of each marker in every structure of interest before drawing conclusions about species differences. J. Comp. Neurol. 512:27–51, 2009. © 2008 Wiley‐Liss, Inc.