A prospective investigation of fluorescence imaging to detect sentinel lymph nodes at robotic-assisted endometrial cancer staging.

Background: The accuracy of sentinel lymph node mapping has been shown in endometrial cancer, but studies to date have primarily focused on cohorts at low risk for nodal involvement. In our practice, we acknowledge the lack of benefit of lymphadenectomy in the low-risk subgroup and omit lymph node removal in these patients. Thus, our aim was to evaluate the feasibility and accuracy of sentinel node mapping in women at sufficient risk for nodal metastasis warranting lymphadenectomy and in whom the potential benefit of avoiding nodal procurement could be realized.

Outcome of unexpected adnexal neoplasia discovered during risk reduction salpingo-oophorectomy in women with germ-line BRCA1 or BRCA2 mutations.

Objective: This study computed the risk of clinically silent adnexal neoplasia in women with germ-line BRCA1 or BRCA2 mutations (BRCA(m+)) and determined recurrence risk.

Methods: We analyzed risk reduction salpingo-oophorectomies (RRSOs) from 349 BRCA(m+) women processed by the SEE-FIM protocol and addressed recurrence rates for 29 neoplasms from three institutions.

Results: Nineteen neoplasms (5.

Patterns of spread and recurrence of sex cord-stromal tumors of the ovary.

Objective: Sex cord-stromal tumors are an uncommon type of ovarian neoplasm and limited data are available in the literature to guide clinical management. Recent published series suggested a lack of lymph node involvement and recommended abandonment of the lymph node dissection as part of the primary surgical staging of these tumors. To confirm these findings, we evaluated pathologic findings in women undergoing surgical management of sex cord-stromal tumors in the Seattle metropolitan area.

FOXP3+ regulatory T-cells are abundant in vulvar Paget's disease and are associated with recurrence.

Objective: To characterize clinical features of vulvar Paget's disease, and examine the quantity of immunosuppressive regulatory T-cells in vulvar Paget's tissue.

Methods: Vulvar Paget's cases from 1992 to 2007 from two institutions were identified by pathology database search. Regulatory T-cells were identified with FOXP3 immunohistochemistry and quantified at the dermal-epidermal junction using image analysis software.

Candidate serous cancer precursors in fallopian tube epithelium of BRCA1/2 mutation carriers.

Occult invasive and intraepithelial carcinomas have been identified in the tubal fimbria of BRCA mutation carriers undergoing prophylactic surgery, and recently described lesions overexpressing p53 in the distal tubes of mutation carriers, and non-carriers, have been proposed as histological precursors of high-grade serous carcinoma. The aim of this study was to confirm these findings in a larger, independent case set, to further characterize the cancer precursor lesions, and to determine their frequency in BRCA mutation-positive (n=176) and control groups (n=64). For the purposes of this study, we excluded cases without documentation of a germline mutation of BRCA1/2, and without histological examination of the entire tube, and cases with a diagnosis of invasive carcinoma.

Evidence for a latent precursor (p53 signature) that may precede serous endometrial intraepithelial carcinoma.

Both serous intraepithelial carcinoma and endometrial glandular dysplasia are associated with uterine serous carcinoma. Recently a candidate serous cancer precursor containing p53 mutations (p53 signature) was described in the fallopian tube. We analyzed normal and neoplastic endometrium for a similar entity.

Clear cell adenocarcinoma of the vagina in a patient with vaginal endometriosis.

Background: Malignant transformation of endometriosis is an infrequent complication of endometriosis. Extragonadal disease is uncommon.

Case: 55-year-old female presented with postmenopausal bleeding.

Spontaneous regression of high-grade cervical dysplasia: effects of human papillomavirus type and HLA phenotype.

Purpose: Persistent infection with oncogenic human papillomaviruses (HPV) plays a central etiologic role in the development of squamous carcinomas of the cervix and their precursor lesions, cervical intraepithelial neoplasias (CIN). We carried out a prospective observational cohort study evaluating known, quantifiable prognostic variables of clinical behavior in women with high-grade cervical lesions.

Experimental Design: Our study cohort included healthy women with high-grade cervical lesions (CIN2/3) with residual visible lesions after colposcopically directed biopsy.

Anomalous expression of the HLA-DR alpha and beta chains in ovarian and other cancers.

Tumor formation in immunocompetent hosts is believed to be dependent on the ability of tumor cells to evade the immune system, as suggested by the alterations of expression of the major histocompatibility complex (MHC) and related molecules in a number of cancers. Our previous serial analysis of gene expression (SAGE) study revealed that HLA-DRA (encoding the alpha chain of HLA-DR) is one of the most highly overexpressed genes in ovarian cancer. This finding was unanticipated, as overexpression of MHC molecules would be expected to increase tumor immunogenicity, therefore compromising tumor growth.

Role of the RNA-binding protein HuR in colon carcinogenesis.

Immunohistochemical analysis of paired tumor and normal tissue specimens revealed that the expression and cytoplasmic abundance of the RNA-binding protein HuR increased with malignancy, particularly in colon carcinomas. Interventions to modulate HuR expression in human RKO colon cancer cells altered gene expression profiles and identified beta-catenin mRNA as a novel HuR target. Subcutaneous injection of HuR-overexpressing RKO cells into nude mice produced significantly larger tumors than those arising from control populations; conversely, RKO cells expressing reduced HuR through small interference RNA- or antisense HuR-based approaches developed significantly more slowly.

Tight junction proteins claudin-3 and claudin-4 are frequently overexpressed in ovarian cancer but not in ovarian cystadenomas.

Purpose: Claudin proteins represent a large family of integral membrane proteins crucial for tight junction (TJ) formation and function. Claudins have been shown to be up-regulated in various cancers and have been suggested as possible biomarkers and targets for cancer therapy. Because claudin-3 and claudin-4 have been proposed to be expressed in epithelial ovarian cancer, we have performed a detailed analysis of CLDN3 and CLDN4 expression in a panel of ovarian tumors of various subtypes and cell lines.

Remodeling of the extracellular matrix through overexpression of collagen VI contributes to cisplatin resistance in ovarian cancer cells.

The mechanisms of drug resistance in cancer are poorly understood. Serial analysis of gene expression (SAGE) profiling of cisplatin-resistant and sensitive cells revealed many differentially expressed genes. Remarkably, many ECM genes were elevated in cisplatin-resistant cells.

Immunohistochemical expression and prognostic significance of FAS and GLUT1 in bladder carcinoma.

Background: Fatty Acid Synthase (FAS) and Human Erythrocyte Glucose Transporter 1 (GLUT1) are new markers involved in the biological activities of cancer cells. FAS is a multifunctional enzyme that synthesizes palmitate from acetyl-CoA and malonyl-CoA. GLUT1 is a transmembrane protein normally expressed in perineurium and erythrocytes.

Regulation of fatty acid synthase expression in breast cancer by sterol regulatory element binding protein-1c.

Activation of fatty acid synthase (FAS) expression and fatty acid synthesis is a common event in human breast cancer. Sterol regulatory element binding proteins (SREBPs) are a family of transcription factors that regulate genes involved in lipid metabolism, including FAS. SREBP-1c expression is induced in liver and adipose tissue by insulin and by fasting/refeeding and is critical for nutritional regulation of lipogenic gene expression.

Activation of fatty acid synthesis during neoplastic transformation: role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase.

Activation of fatty acid synthase (FAS) expression and fatty acid synthesis is a common event in tumor cells from a variety of human cancers and is closely linked to malignant transformation and to tumor virulence in population studies of human cancer. We now show that, in contrast to nutritional regulation of lipogenesis in liver or adipose tissue, changes in fatty acid metabolism during in vitro transformation of the human mammary epithelial cell line MCF-10a are driven by increases in epidermal growth factor signaling, acting in major part through the mitogen-activated protein (MAP) kinase and phosphatidylinositol (PI) 3-kinase signaling cascades. H-ras transformation of MCF-10a cells resulted in upregulation of MAP kinase and PI 3-kinase signals, upregulation of sterol regulatory element binding protein 1 (SREBP-1) transcription factor levels, and upregulation of FAS expression and FA synthesis.

Immunohistochemical expression of human erythrocyte glucose transporter and fatty acid synthase in infiltrating breast carcinomas and adjacent typical/atypical hyperplastic or normal breast tissue.

To evaluate the immunohistochemical expression of GLUT1, human erythrocyte glucose transporter 1, and fatty acid synthase (FAS), 66 human breast carcinomas and adjacent peritumoral tissue were studied. GLUT1 and FAS were expressed in 53 and 61 carcinomas, in 17 and 14 typical/atypical hyperplastic tissues, and in 16 and 13 tissues adjacent to tumor normal breast tissue, respectively. Statistical analysis revealed association between invasive carcinomas, invasive carcinomas with in situ component and GLUT1 immunostaining.

Increased fatty acid synthase as a therapeutic target in androgen-independent prostate cancer progression.

Background: Fatty acid synthase (FAS) performs the anabolic conversion of dietary carbohydrate or protein to fat. FAS expression is low in most normal tissues, but is elevated in many human cancers, including androgen-sensitive and androgen-independent prostate cancer.

Methods: Immunohistochemical evaluation of FAS expression was performed in human prostate cancer specimens under various states of androgen ablation.

Fatty acid synthase (FAS) expression in human breast cancer cell culture supernatants and in breast cancer patients.

Fatty acid synthase (FAS) is selectively expressed in certain human cancers, including carcinoma of the breast, prostate, colon, ovary, and endometrium, compared to normal human tissues and therefore is a putative tumor marker. In this study, we found FAS concentrations were elevated in cell culture supernatants during cell growth in two human breast cancer cell lines but not other cancer cell lines. A quantitative enzyme-linked immunosorbent assay and Western blot analysis were employed in this study.

Pharmacological inhibition of fatty acid synthase activity produces both cytostatic and cytotoxic effects modulated by p53.

Fatty acid synthetic metabolism is abnormally elevated in tumor cells, and pharmacological inhibitors of the anabolic enzyme fatty acid synthase (FAS), including the natural product cerulenin and the novel synthetic compound c75, are selective inhibitors of tumor cell growth. We have recently reported that these two FAS inhibitors both produce rapid, potent inhibition of DNA replication and S-phase progression in human cancer cells, as well as apoptotic death. Here we report an additional characterization of the cellular response to FAS inhibition.

Large-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancer.

Difficulties in the detection, diagnosis, and treatment of ovarian cancer result in an overall low survival rate of women with this disease. A better understanding of the pathways involved in ovarian tumorigenesis will likely provide new targets for early and effective intervention. Here, we have used serial analysis of gene expression (SAGE) to generate global gene expression profiles from various ovarian cell lines and tissues, including primary cancers, ovarian surface epithelia cells, and cystadenoma cells.

Sterol regulatory element-binding protein-1 participates in the regulation of fatty acid synthase expression in colorectal neoplasia.

Endogenous fatty acid synthesis has been observed in certain rapidly proliferating normal and neoplastic tissues. Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate the expression of lipogenic genes including fatty acid synthase (FAS), the major biosynthetic enzyme for fatty acid synthesis. We have previously shown that SREBP-1, FAS, and Ki-67, a proliferation marker, colocalized in the crypts of the fetal gastrointestinal tract epithelium.

A frequent deletion polymorphism on chromosome 22q13 identified by representational difference analysis of ovarian cancer.

Sizable homozygous deletions (>100 bp) of genomic DNA in cancer cells are typically interpreted as an indication of the location of a tumor suppressor gene. In an effort to identify novel ovarian growth-suppressing genes, we performed representational difference analysis (RDA) of ovarian cancer cells. One of the RDA probes identified a 276-bp region of chromosome 22q deleted in 47% of the ovarian cancer cell lines examined.

Lipogenic enzymes fatty acid synthase and acetyl-coenzyme A carboxylase are coexpressed with sterol regulatory element binding protein and Ki-67 in fetal tissues.

Endogenous fatty acid synthesis has been observed in some rapidly proliferating cells and tissues, both normal and neoplastic, and probably supports membrane synthesis. Sterol regulatory element binding proteins (SREBPs) are transcription factors that regulate the expression of genes for both cholesterol and fatty acid synthesis. The inactive precursor form resides in cytoplasmic membranes.

A binary architectural grading system for uterine endometrial endometrioid carcinoma has superior reproducibility compared with FIGO grading and identifies subsets of advance-stage tumors with favorable and unfavorable prognosis.

The International Federation of Gynecology and Obstetrics (FIGO) grading of uterine endometrial endometrioid carcinoma requires evaluation of histologic features that can be difficult to assess, including recognition of small amounts of solid growth, distinction of squamous from nonsquamous solid growth, and assessment of degree of nuclear atypia. The authors describe a novel, binary architectural grading system that uses low-magnification assessment of amount of solid growth, pattern of invasion, and presence of necrosis to divide endometrioid carcinomas into low- and high-grade tumors. The authors analyzed its performance for predicting prognosis and with respect to intra- and interobserver reproducibility.

Vascular embolization of benign granulosa cells.

Objective(s): Most conditions involving sex cord-stromal cells can be diagnosed on morphologic criteria alone. We describe a case of vascular embolization of benign granulosa cells in which immunohistochemistry was of value as a diagnostic tool.

Methods: We reviewed the clinical history and gross pathologic findings from a 48-year-old patient who presented with abdominal pain and fullness.