In nonfatty breasts, US and MR imaging were more sensitive than mammography for invasive cancer, but both MR imaging and US involved risk of overestimation of tumor extent. Combined mammography, clinical examination, and MR imaging were more sensitive than any other individual test or combination of tests.

Metabolic profiling of cancer cells has recently been established as a promising tool for the development of therapies and identification of cancer biomarkers.Here we characterized the metabolomic profile of human breast tumors and uncovered intrinsic metabolite signatures in these tumors using an untargeted discovery approach and validation of key metabolites. The oncometabolite 2-hydroxyglutarate (2HG) accumulated at high levels in a subset of tumors and human breast cancer cell lines. We discovered an association between increased 2HG levels and MYC pathway activation in breast cancer, and further corroborated this relationship using MYC overexpression and knockdown in human mammary epithelial and breast cancer cells. Further analyses revealed globally increased DNA methylation in 2HG-high tumors and identified a tumor subtype with high tissue 2HG and a distinct DNA methylation pattern that was associated with poor prognosis and occurred with higher frequency in African-American patients. Tumors of this subtype had a stem cell-like transcriptional signature and tended to overexpress glutaminase, suggestive of a functional relationship between glutamine and 2HG metabolism in breast cancer. Accordingly, 13C-labeled glutamine was incorporated into 2HG in cells with aberrant 2HG accumulation, whereas pharmacologic and siRNAmediated glutaminase inhibition reduced 2HG levels. Our findings implicate 2HG as a candidate breast cancer oncometabolite associated with MYC activation and poor prognosis.

Symptomatic complicated cysts generally warrant aspiration. All clustered microcysts were benign, but further study is required. Cystic lesions with thick indistinct walls and/or thick septations (> or =0.5 mm), intracystic masses, and predominantly solid masses with eccentric cystic foci should be examined at biopsy; 18 of 79 of such complex cystic lesions proved malignant in this series.

PURPOSE-After initial surgery, there has been no established consensus regarding adjunctive therapy for patients with uterine carcinosarcoma (CS). This study was designed to compare patient outcome following treatment with adjuvant whole abdominal irradiation (WAI) versus (vs) chemotherapy for patients with this rare group of female pelvic malignancies.PATIENTS AND METHODS-Eligible, consenting women with stage I-IV uterine CS, no more than 1 cm postsurgical residuum and/or no extra-abdominal spread had their treatments randomly assigned as either WAI or three cycles of cisplatin (C), ifosfamide (I), and mesna (M).RESULTS-232 patients were enrolled, of whom 206 (WAI=105; CIM=101) were deemed eligible. Patient demographics and characteristics were similar between arms. FIGO stage (both arms) was: I=64 (31%); II=26 (13%); III=92 (45%); IV=24 (12%). The estimated crude probability of recurring within 5 years was 58% (WAI) and 52% (CIM). Adjusting for stage and age, the recurrence rate was Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. CONCLUSION-We did not find a statistically significant advantage in recurrence rate or survival for adjuvant CIM over WAI in patients with uterine CS. However, the observed differences favor the use of combination chemotherapy in future trials. NIH Public Access

Metastatic cases of breast cancer pose the primary challenge in clinical management of this disease, demanding the identification of effective therapeutic strategies which remain wanting. In this study, we report that elevated levels of α-tubulin acetylation are a sufficient cause of metastatic potential in breast cancer. In suspended cell culture conditions, metastatic breast cancer cells exhibited high α-tubulin acetylation levels that extended along microtentacle protrusions. Mutation of the acetylation site on α-tubulin and enzymatic modulation of this post-translational modification exerted a significant impact on microtentacle frequency and the re-attachment of suspended tumor cells. Reducing α-tubulin acetylation significantly inhibited migration but did not affect proliferation. In an analysis of over 140 matched primary and metastatic tumors from patients, we found that acetylation was maintained and in many cases increased in lymph node metastases compared to primary tumors. Proteomic analysis of an independent cohort of over 390 patient specimens further documented the relationship between increased α-tubulin acetylation and the aggressive behaviors of basal-like breast cancers, with a trend toward increased risk of disease progression and death in patients with high intensity α-tubulin acetylation in primary tumors. Taken together, our results identify a tight correlation between acetylated α-tubulin levels and aggressive metastatic behavior in breast cancer, with potential implications for the definition of a simple prognostic biomarker in breast cancer patients.

PURPOSE The severity of endometrial hyperplasia (EH)-simple (SH), complex (CH), or atypical (AH)-influences clinical management, but valid estimates of absolute risk of clinical progression to carcinoma are lacking. Materials and METHODS We conducted a case-control study nested in a cohort of 7,947 women diagnosed with EH (1970-2002) at one prepaid health plan who remained at risk for at least 1 year. Patient cases (N = 138) were diagnosed with carcinoma, on average, 6 years later (range, 1 to 24 years). Patient controls (N = 241) were matched to patient cases on age at EH, date of EH, and duration of follow-up, and they were counter-matched to patient cases on EH severity. After we independently reviewed original slides and medical records of patient controls and patient cases, we combined progression relative risks (AH v SH, CH, or disordered proliferative endometrium [ie, equivocal EH]) from the case-control analysis with clinical censoring information (ie, hysterectomy, death, or left the health plan) on all cohort members to estimate interval-specific (ie, 1 to 4, 5 to 9, and 10 to 19 years) and cumulative (ie, through 4, 9, and 19 years) progression risks. Results For nonatypical EH, cumulative progression risk increased from 1.2% (95% CI, 0.6% to 1.9%) through 4 years to 1.9% (95% CI, 1.2% to 2.6%) through 9 years to 4.6% (95% CI, 3.3% to 5.8%) through 19 years after EH diagnosis. For AH, cumulative risk increased from 8.2% (95% CI, 1.3% to 14.6%) through 4 years to 12.4% (95% CI, 3.0% to 20.8%) through 9 years to 27.5% (95% CI, 8.6% to 42.5%) through 19 years after AH. CONCLUSION Cumulative 20-year progression risk among women who remain at risk for at least 1 year is less than 5% for nonatypical EH but is 28% for AH.

Epithelial-to-mesenchymal transition (EMT) is associated with increased breast tumor metastasis, but the specific mechanisms by which EMT promotes metastasis remain somewhat unclear. Despite the importance of cytoskeletal dynamics during both EMT and metastasis, very few current studies examine the cytoskeleton of detached and circulating tumor cells. Specific post-translational α-tubulin modifications are critical for adherent cell motility and implicated in numerous pathologies, but also remain understudied in detached cells. We report here that EMT induced through ectopic expression of Twist or Snail promotes α-tubulin detyrosination and the formation of tubulin-based microtentacles in detached human mammary epithelial cells. Mechanistically, EMT downregulates tubulin tyrosine ligase enzyme resulting in an accumulation of detyrosinated α-tubulin (Glu-tubulin), and increases microtentacles that penetrate endothelial layers to facillitate tumor cell reattachment. Confocal microscopy demonstrates that microtentacles are capable of penetrating the junctions between endothelial cells. Suppression of endogenous Twist in metastatic human breast tumor cells is capable of reducing both tubulin detyrosination and microtentacles. Clinical breast tumor samples display high concordance between Glu-tubulin and Twist expression levels, emphasizing the coupling between EMT and tubulin detyrosination in vivo. Coordinated elevation of Twist and Glu-tubulin at invasive tumor fronts, particularly within ductal carcinoma in situ samples, establishes that EMT-induced tubulin detyrosination occurs at the earliest stages of tumor invasion. These data support a novel model where the EMT that occurs during tumor invasion downregulates tubulin tyrosine ligase, increasing α-tubulin detyrosination and promoting microtentacles which could enhance the reattachment of circulating tumor cells to the vascular endothelium during metastasis.

Although endometrial carcinoma (EC) is generally considered to have a good prognosis, over 20% of women with EC die of their disease, with a projected increase in both incidence and mortality over the next few decades. The aim of accurate prognostication is to ensure that patients receive optimal treatment and are neither overtreated nor undertreated, thereby improving patient outcomes overall. Patients with EC can be categorized into prognostic risk groups based on clinicopathologic findings. Other than tumor type and grade, groupings and recommended management algorithms may take into account age, body mass index, stage, and presence of lymphovascular space invasion. The molecular classification of EC that has emerged from the Cancer Genome Atlas (TCGA) study provides additional, potentially superior, prognostic information to traditional histologic typing and grading. This classifier does not, however, replace clinicopathologic risk assessment based on parameters other than histotype and grade. It is envisaged that molecular and clinicopathologic prognostic grouping systems will work better together than either alone. Thus, while tumor typing and grading may be superseded by a classification based on underlying genomic abnormalities, accurate assessment of other pathologic parameters will continue to be key to patient management. These include those factors related to staging, such as depth of myometrial invasion, cervical, vaginal, serosal surface, adnexal and parametrial invasion, and those independent of stage such as lymphovascular space invasion. Other prognostic parameters will also be discussed. These recommendations were developed from the International Society of Gynecological Pathologists Endometrial Carcinoma project.