Proceedings of the consensus conference on breast conservation, Milan, Italy, April 28-May 1, 2005.
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Journal Article↗
Biomedical subjects
Juan P Palazzo
Publications and source records attributed to Juan P Palazzo.
Proceedings of the Consensus Conference on Breast Conservation, April 28 to May 1, 2005, Milan, Italy.
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Breast↗
The molecular portraits of breast tumors are conserved across microarray platforms.
BACKGROUND: Validation of a novel gene expression signature in independent data sets is a critical step in the development of a clinically useful test for cancer patient risk-stratification. However, validation is often unconvincing because the size of the test set is typically small. To overcome this problem we used publicly available breast cancer gene expression data sets and a novel approach to data fusion, in order to validate a new breast tumor intrinsic list. RESULTS: A 105-tumor training set containing 26 sample pairs was used to derive a new breast tumor intrinsic gene list. This intrinsic list contained 1300 genes and a proliferation signature that was not present in previous breast intrinsic gene sets. We tested this list as a survival predictor on a data set of 311 tumors compiled from three independent microarray studies that were fused into a single data set using Distance Weighted Discrimination. When the new intrinsic gene set was used to hierarchically cluster this combined test set, tumors were grouped into LumA, LumB, Basal-like, HER2+/ER-, and Normal Breast-like tumor subtypes that we demonstrated in previous datasets. These subtypes were associated with significant differences in Relapse-Free and Overall Survival. Multivariate Cox analysis of the combined test set showed that the intrinsic subtype classifications added significant prognostic information that was independent of standard clinical predictors. From the combined test set, we developed an objective and unchanging classifier based upon five intrinsic subtype mean expression profiles (i.e. centroids), which is designed for single sample predictions (SSP). The SSP approach was applied to two additional independent data sets and consistently predicted survival in both systemically treated and untreated patient groups. CONCLUSION: This study validates the "breast tumor intrinsic" subtype classification as an objective means of tumor classification that should be translated into a clinical assay for further retrospective and prospective validation. In addition, our method of combining existing data sets can be used to robustly validate the potential clinical value of any new gene expression profile.
Breast Neoplasms↗
Classification and risk stratification of invasive breast carcinomas using a real-time quantitative RT-PCR assay.
INTRODUCTION: Predicting the clinical course of breast cancer is often difficult because it is a diverse disease comprised of many biological subtypes. Gene expression profiling by microarray analysis has identified breast cancer signatures that are important for prognosis and treatment. In the current article, we use microarray analysis and a real-time quantitative reverse-transcription (qRT)-PCR assay to risk-stratify breast cancers based on biological 'intrinsic' subtypes and proliferation. METHODS: Gene sets were selected from microarray data to assess proliferation and to classify breast cancers into four different molecular subtypes, designated Luminal, Normal-like, HER2+/ER-, and Basal-like. One-hundred and twenty-three breast samples (117 invasive carcinomas, one fibroadenoma and five normal tissues) and three breast cancer cell lines were prospectively analyzed using a microarray (Agilent) and a qRT-PCR assay comprised of 53 genes. Biological subtypes were assigned from the microarray and qRT-PCR data by hierarchical clustering. A proliferation signature was used as a single meta-gene (log2 average of 14 genes) to predict outcome within the context of estrogen receptor status and biological 'intrinsic' subtype. RESULTS: We found that the qRT-PCR assay could determine the intrinsic subtype (93% concordance with microarray-based assignments) and that the intrinsic subtypes were predictive of outcome. The proliferation meta-gene provided additional prognostic information for patients with the Luminal subtype (P = 0.0012), and for patients with estrogen receptor-positive tumors (P = 3.4 x 10-6). High proliferation in the Luminal subtype conferred a 19-fold relative risk of relapse (confidence interval = 95%) compared with Luminal tumors with low proliferation. CONCLUSION: A real-time qRT-PCR assay can recapitulate microarray classifications of breast cancer and can risk-stratify patients using the intrinsic subtype and proliferation. The proliferation meta-gene offers an objective and quantitative measurement for grade and adds significant prognostic information to the biological subtypes.
Breast Neoplasms↗
Consensus conference on breast conservation.
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Breast Neoplasms↗
Bile acids induce ectopic expression of intestinal guanylyl cyclase C Through nuclear factor-kappaB and Cdx2 in human esophageal cells.
BACKGROUND & AIMS: Although progression to adenocarcinoma at the gastroesophageal junction reflects exposure to acid and bile acids associated with reflux, mechanisms mediating this transformation remain undefined. Guanylyl cyclase C (GC-C), an intestine-specific tumor suppressor, may represent a mechanism-based marker and target of transformation at the gastroesophageal junction. The present studies examine the expression of GC-C in normal tissues and tumors from esophagus and stomach and mechanisms regulating its expression by acid and bile acids. METHODS: Gene expression was examined by reverse-transcription polymerase chain reaction, promoter analysis, immunohistochemistry, immunoblotting, and functional analysis. Promoter transactivation was quantified by using luciferase constructs and mutational analysis. DNA binding of transcription factors was examined by electromobility shift analysis. RESULTS: GC-C mRNA and protein were ectopically expressed in approximately 80% of adenocarcinomas arising in, but not in normal, esophagus and stomach. Similarly, in OE19 human esophageal cancer cells, deoxycholate and acid induced expression of GC-C. This was associated with the induction of expression of Cdx2, a transcription factor required for GC-C expression. In turn, induction of Cdx2 expression by deoxycholate was mediated by binding sites in the proximal promoter for nuclear factor kappaB (NF-kappaB). Furthermore, deoxycholate increased NF-kappaB activity, associated with nuclear translocation and Cdx2 promoter binding of the NF-kappaB subunit p50. Moreover, a dominant negative construct for NF-kappaB prevented deoxycholate-induced p50 nuclear translocation and activation of the Cdx2 promoter. CONCLUSIONS: Transformation associated with reflux at the gastroesophageal junction reflects activation by bile acid and acid of a transcriptional program involving NF-kappaB and Cdx2, which mediate intestinal metaplasia and ectopic expression of GC-C.
Adenocarcinoma↗
Diversity in secreted PLA2-IIA activity among inbred mouse strains that are resistant or susceptible to Apc Min/+ tumorigenesis.
The secreted phospholipase A2 type IIA (Pla2g2a) gene was previously identified as a modifier of intestinal adenoma multiplicity in Apc Min/+ mice. To determine if intestinal secreted phospholipase A2 (sPLA2) activity was also attenuated in susceptible strains, we developed a sensitive assay to directly quantitate sPLA2 activity in the murine intestinal tract utilizing a fluorescent BODIPY-labeled phospholipid substrate. Here, we report assay conditions that distinguish between secreted and cytosolic PLA2 enzyme activities in extracts of intestinal tissue. The small intestine exhibited higher activity levels than the large intestine. Consistent with predictions from the sPLA2-IIA gene sequence in inbred strains, we detected low levels of enzyme activity in inbred strains containing sPLA2-IIA mutations; these strains were also associated with greater numbers of intestinal polyps. Additionally, the assay was able to distinguish differences in levels of sPLA2 activity between neoplasia-resistant strains, which were then shown by sequencing to carry variant wild-type sPLA2-IIA alleles. Immunohistochemical analyses of intestinal tissues were consistent with sPLA2-IIA activity levels. This approach enables further studies of the mechanisms of sPLA2 action influencing the development and tumorigenesis of the small intestine and colon in both mice and humans.
Amino Acid Sequence↗
MicroRNA gene expression deregulation in human breast cancer.
MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Their aberrant expression may be involved in human diseases, including cancer. Indeed, miRNA aberrant expression has been previously found in human chronic lymphocytic leukemias, where miRNA signatures were associated with specific clinicobiological features. Here, we show that, compared with normal breast tissue, miRNAs are also aberrantly expressed in human breast cancer. The overall miRNA expression could clearly separate normal versus cancer tissues, with the most significantly deregulated miRNAs being mir-125b, mir-145, mir-21, and mir-155. Results were confirmed by microarray and Northern blot analyses. We could identify miRNAs whose expression was correlated with specific breast cancer biopathologic features, such as estrogen and progesterone receptor expression, tumor stage, vascular invasion, or proliferation index.
Blotting, Northern↗
Guanylyl cyclase C is a marker of intestinal metaplasia, dysplasia, and adenocarcinoma of the gastrointestinal tract.
Gastrointestinal (GI) tumors continue to be major causes of cancer-related mortality, in part, reflecting metastases that escape detection by histopathology. Moreover, although approximately 10% of carcinomas arise from unknown locations, these tumors frequently originate in the GI tract. Guanylyl cyclase C (GC-C) is a receptor selectively expressed by intestinal epithelial cells whose persistent expression by colorectal carcinomas and ectopic expression by adenocarcinomas of the upper GI tract suggest its use as a marker for GI malignancies. Here, expression of GC-C protein, identified by immunohistochemistry, was examined in tissues and tumors arising from the human GI tract. Guanylyl cyclase C protein was expressed by epithelial cells from the duodenum to the rectum, but not by those in normal esophagus and stomach. Expression was retained in tubular adenomas, inflammatory bowel disease, premalignant lesions, and in primary and metastatic adenocarcinomas from the colon, including metastases to lymph nodes and liver. Moreover, GC-C was ectopically expressed in all cases of dysplasia and adenocarcinomas arising from intestinal metaplasia in esophagus and stomach. Thus, GC-C appears to be an immunohistochemical marker for identifying adenocarcinomas of unknown origin, metastases in patients undergoing staging for GI adenocarcinomas, and intestinal metaplasia, dysplasia, and tumors arising therein in the upper GI tract.
Adenocarcinoma↗
GATA-3 expression as a predictor of hormone response in breast cancer.
BACKGROUND: Expression of estrogen receptor-alpha (ERalpha) as determined by immunohistochemistry of tumor tissue is currently the most clinically useful test to predict hormone responsiveness of breast cancer. Thirty percent of ERalpha-positive breast cancers do not respond to hormonal therapy. GATA-3 is a transcription factor that is expressed in association with ERalpha and there is evidence that GATA factors influence response to estrogen. In this pilot study, we investigated whether GATA-3 expression is associated with hormone response in breast cancer. STUDY DESIGN: Breast cancer tissue was stained for GATA-3 expression by immunohistochemistry in ERalpha-positive cancers from 28 patients, 14 of whom were defined as hormone unresponsive (cases) and 14 of whom were age-matched controls with hormone-responsive, ERalpha-positive cancers (controls). RESULTS: Comparing cases and controls, there were no differences in expression of ERalpha; progesterone receptor, ErbB2; or tumor grade. Using 20% nuclear staining to characterize tumors as GATA-3 positive or GATA-3 negative, 6 of 14 (43%) cancers in the hormone-unresponsive group and none of the controls were classified as GATA-3 negative (odds ratio, 8.2; 95% confidence interval, 1.2-infinity; p = 0.031). Using different cut points to characterize GATA-3 positivity yielded very similar results, indicating a positive association between lack of GATA-3 expression and lack of response to hormonal therapy. CONCLUSIONS: The study suggests that analyzing ERalpha-positive breast tumors for GATA-3 using immunohistochemistry might improve prediction of hormone responsiveness. The association between GATA-3 expression and hormone response suggests that GATA-3 may play a role in mechanisms controlling response to estrogen.
Adult↗
Endosonographic diagnosis of recurrent gastrointestinal stromal tumors associated with Carney's syndrome.
This is a report of a patient who manifests all of the features of Carney's syndrome, including gastrointestinal stromal tumors (GISTs), extra-adrenal paragangliomas, and pulmonary chondromas. The patient underwent surgical resection of a gastric GIST; a retroperitoneal, nonfunctional paraganglioma; and a mediastinal, catecholamine-secreting paraganglioma (pheochromocytoma). Recently, new gastric GISTs were diagnosed by endoscopic, ultrasound-guided, fine-needle aspiration (EUS-FNA) biopsy and were resected. Recurrence of stromal tumors following complete resection is common in Carney's syndrome and presents considerable management challenges. This case illustrates several important points: (1) Carney's syndrome, although rare, should be considered in patients with foregut GISTs; (2) GISTs associated with Carney's syndrome, like sporadic gastric GISTs, may have a more indolent clinical course; and (3) EUS-FNA may be useful for the diagnosis and management of GISTs in this syndrome.
Chondroma↗
Primary angiolipoma of the thyroid gland: a case report.
We report a case of an angiolipoma involving the thyroid gland of a 74-year-old woman. The patient presented with a multinodular goiter that was surgically removed. Gross examination of the specimen revealed an intrathyroidal well-circumscribed nodule that microscopically showed the typical features of an angiolipoma. There was no evidence of extrathyroidal extension, necrosis, or atypia. To our knowledge, this is the first reported case of a primary angiolipoma of the thyroid gland.
Adipose Tissue↗
The prognostic significance of multiple morphologic features and biologic markers in ductal carcinoma in situ of the breast: a study of a large cohort of patients treated with surgery alone.
BACKGROUND: A number of conventional histopathologic features have been associated with recurrence of ductal carcinoma in situ (DCIS) after surgery alone and are included in the Van Nuys Pathologic Classification and Prognostic Index. To the authors' knowledge, very little is known regarding the prognostic significance of the many biologic markers that have been studied in DCIS in the past decade. METHODS: Clinical and pathologic data were analyzed from 151 patients who underwent wide local excision alone for DCIS that was diagnosed by mammography or as an incidental finding between 1982 and 2000. Using local disease recurrence as an endpoint, the authors sought to determine the prognostic significance of a large number of histopathologic parameters as well as biologic markers (estrogen receptor [ER], progesterone receptor [PR], p53, HER-2/neu, Ki-67, p21, and bcl-2), as determined by immunohistochemical staining of contemporary or archival tissue. RESULTS: With a median follow-up of 65 months, 42 recurrences were reported to occur between 11 months and 97 months after definitive surgery. In a univariate analysis, tumor size, Van Nuys pathologic classification, and degree of necrosis demonstrated significant correlations with the rate of recurrence. Tumor size, necrosis, nuclear grade, and comedonecrosis were found to be associated significantly with the time to disease recurrence. None of the biologic markers demonstrated a significant association with the rate of recurrence or the time to disease recurrence. In a multivariate analysis, only large tumor size (Van Nuys 2 or 3) and higher degrees of necrosis (Van Nuys 2 or 3) were found to be associated significantly with both the rate of recurrence and the time to recurrence. No biologic marker showed a significant correlation with recurrence. Using Classification and Regression-Tree Analysis and Tree-Structured Survival Analysis, PR > 3.5% and bcl-2 < 97.5% were associated with a higher recurrence rate in the subgroup of patients with small tumor size (Van Nuys size 1) and higher degrees of tumor necrosis (Van Nuys 2 or 3). CONCLUSIONS: The current results confirmed the value of conventional histopathologic parameters, as outlined in the Van Nuys classification system, in predicting local recurrence of DCIS. Using traditional logistic analyses, no significant correlation was found between a variety of biologic markers and disease recurrence.
Adult↗
Colonic crypt changes during adenoma development in familial adenomatous polyposis: immunohistochemical evidence for expansion of the crypt base cell population.
Familial adenomatous polyposis patients, who have a germline APC mutation, develop adenomas in normal-appearing colonic mucosa, and in the process usually acquire a mutation in the other APC allele as well. Nonetheless, the cellular mechanisms that link these initiating genetic changes with the earliest tissue changes (upward shift in the labeling index) in colon tumorigenesis are unclear. Based on the tenet that colorectal cancer originates from crypt stem cells (SCs) and on our kinetic modeling, we hypothesized that overpopulation of mutant colonic SCs is the missing link. Directly testing this hypothesis requires measuring changes in the size of the SC population, but specific markers for human colonic SCs are lacking. Hence, we used immunohistochemical mapping to study crypt base cells, of which SCs are a subset. Using colectomy specimens from 16 familial adenomatous polyposis and 11 control cases, we determined the topographic profiles of various cell populations along the crypt axis and the proportions of each cell type. In the formation of adenomatous crypts, the distribution of cells expressing crypt base cell markers (MSH2, Bcl-2, survivin) expanded toward the crypt surface and showed the greatest proportional increase (fivefold to eightfold). Cells expressing a marker for the upper crypt (p27(kip1)) shifted to the crypt bottom and showed the smallest increase. This suggests that: 1) during adenoma development, APC mutations cause expansion of the crypt base cell population, including crypt SCs; 2) SC overpopulation can explain the shifts in pattern of proliferative crypt cell populations in early colon tumorigenesis, and 3) mutant crypt SCs clonally expand to form colonic adenomas and carcinomas.
Adenoma↗
Insular carcinoma of the thyroid.
Thyroid surgeons are becoming increasingly more aware of a histologically distinct subset of thyroid carcinoma whose classification falls between well-differentiated and anaplastic carcinomas with respect to both cell differentiation and clinical behavior. This subtype of tumors has been categorized as poorly differentiated or insular carcinoma, based on its characteristic cell groupings. Although the differentiation of insular carcinoma from other thyroid carcinomas has important prognostic and therapeutic significance, relatively little about insular carcinoma has been published in the otolaryngology literature. In this article, we describe a new case of insular carcinoma and we discuss the findings of our review of the literature. We conclude that insular thyroid carcinoma warrants aggressive management with total thyroidectomy followed by radioactive iodine ablation of any remaining thyroid tissue.
Biopsy, Needle↗
Surgical management of adrenal cysts.
Adrenal cysts are rare and are often found incidentally during abdominal imaging for another reason. We describe two cases of adrenal cysts, one of which was found to be a cystic pheochromocytoma. Most cystic pheochromocytomas are not diagnosed by urinary screening studies, and the first indication of a pheochromocytoma may be hemodynamic instability during resection. We review the literature on adrenal cysts and make recommendations for the management of cystic adrenal masses.
Adrenal Gland Diseases↗
Association of human polyomavirus JCV with colon cancer: evidence for interaction of viral T-antigen and beta-catenin.
Infection of the gastrointestinal tract by the human polyomavirus, JCV, which has been frequently detected in raw urban sewage, can occur via intake of contaminated water and food. In light of earlier reports on the tumorigenecity of JCV, we investigated the presence of the JCV genome and the expression of viral proteins in a collection of 27 well-characterized epithelial malignant tumors of the large intestine. Results from gene amplification revealed the presence of the viral early genome in 22 of 27 samples. Expression of the viral oncogenic early protein, T-antigen, and the late auxiliary protein, Agnoprotein, was observed in >50% of the samples. The absence of the viral capsid protein in the tumor cells excludes productive replication of the virus in neoplastic cells. Laser capture microdissection confirmed the presence of the JCV genome and expression of T-antigen in precancerous villous adenomas and regions of invasive adenocarcinoma. The ability of JCV T-antigen to interact with beta-catenin and the nuclear detection of beta-catenin in T-antigen-positive cells suggests dysregulation of the Wnt pathway in the tumor cells. The coproduction of T-antigen and beta-catenin in colon cancer cells enhanced transcription of the c-myc promoter, the downstream target of beta-catenin. These observations provide evidence for a possible association of JCV with colon cancer and suggest a novel regulatory role for T-antigen in the deregulation of the Wnt signaling pathway through beta-catenin in tumors of the gastrointestinal tract.
Adenocarcinoma↗
Exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant genetic predisposition syndrome that accounts for 2-7% of all colorectal cancers. Diagnosis of HNPCC is based on family history (defined by Amsterdam or Bethesda Criteria), which often includes a history of multiple synchronous or metachronous cancers. The majority of HNPCC results from germ-line mutations in the DNA mismatch repair (MMR) genes hMSH2 and hMLH1 with rare alterations in hMSH6 and hPMS2 in atypical families. Both HNPCC and sporadic MMR-deficient tumors invariably display high microsatellite instability (MSI-H). Two types of HNPCC families can be distinguished: type I (Lynch I) with tumors exclusively located in the colon; and type II (Lynch II) with tumors found in the endometrium, stomach, ovary, and upper urinary tract in addition to the colon. A proposed association of breast cancer with type II HNPCC is controversial. To address this important clinical question, we examined MSI in a series of 27 female patients who presented with synchronous or metachronous breast plus colorectal cancer. Although MSI-H was found in 5 of 27 (18.5%) of the colon cancers, in all cases the matched breast cancer was microsatellite stable. We also examined the breast tumors from three women who were carriers of MMR gene mutations from HNPCC families. None of these three breast tumors displayed MSI nor was the expression of MMR proteins altered in these tumors. We conclude that breast cancer largely arises sporadically in HNPCC patients and is rarely associated with the HNPCC syndrome.
Breast Neoplasms↗