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J F Simpson

Publications and source records attributed to J F Simpson.

At least 55 records · Page 3Linked to original sources
PubMed1998

A high-risk lesion for invasive breast cancer, ductal carcinoma in situ, exhibits frequent overexpression of retinoid X receptor.

The development of prevention strategies for breast cancer will require a molecular map of carcinogenesis. We have investigated gene expression patterns in premalignant and early carcinomatous human breast lesions that confer to the patient varying risks for developing invasive breast cancer. The relative expression levels of one of the retinoid receptors, retinoid X receptor (RXR), was determined by in situ hybridization to 58 biopsy specimens; RXR mRNA grain density over each lesion was compared to that over the normal ductal/lobular units in each section. Overexpression of RXR mRNA was observed in 66% of noncomedo ductal carcinoma in situ (DCIS), which confer a >8-fold increase in breast cancer risk, and 88% of comedo DCIS lesions, which are associated with a yet higher risk. In contrast, only 8% of lesions that confer little or no increase in breast cancer risk overexpressed RXR mRNA (P = 0.0008). Limited in situ hybridization data using retinoic acid receptor (RAR) riboprobes showed overexpression of RAR alpha, but not RAR beta or -gamma, in only a modest percentage (36%) of cases, suggesting that all members of the retinoid receptor superfamily are not similarly regulated. Immunohistochemistry performed on 52 DCIS specimens for alpha, beta, and gamma isoforms of RXR confirmed its overexpression at the protein level and implicate RXR alpha as the predominant overexpressed form. The data indicate that RXR overexpression is associated with an increased risk for the development of invasive breast cancer in human breast lesions and suggest the hypothesis that it is causally involved in breast oncogenesis. The implications for retinoid chemoprevention are discussed.

Biomarkers, Tumor↗
PubMed1998

Premalignant and malignant disease of the breast: the roles of the pathologist.

This review targets the current role of the pathologist in the diagnosis and management of breast disease, a responsibility that evolved along with an increasingly complex approach to human breast cancer. We will focus on the three major areas of this responsibility: premalignancy, highlighting the atypical hyperplasias; the carcinomas in situ, highlighting low grade ductal carcinoma in situ; and the stratification and prognosis of invasive carcinomas. It will be evident that with the advent of an increasingly rich menu of treatment options, the challenge to identify an optimal categorization of breast cancer and its putative precursors is not static.

Breast↗
PubMed1997

Pathology of preinvasive and excellent-prognosis breast cancer.

Our review of recent developments in breast cancer involving evaluation of cellular and tissue samples is targeted at indicators of elevated risk of sufficient magnitude to attain clinical significance; lesions unassociated with metastatic capacity but of sufficient risk to attain that capacity that formal treatment is necessary, ie, ductal carcinoma in situ; and indicators of good prognosis in invasive cancer. Ductal carcinoma in situ has been the subject of much recent discussion. We highlight particularly the area of stratification or classification within this group of lesions. The importance of the extensiveness of ductal carcinoma in situ in the prediction of local recurrence within the conserved breast is included. Also discussed are advances in diagnostic techniques, specifically core needle biopsies performed under mammographic and ultrasonographic guidance.

Breast Neoplasms↗
PubMed1997

Amplification of CCND1 and expression of its protein product, cyclin D1, in ductal carcinoma in situ of the breast.

Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous disease clinically and biologically. The few available studies of its natural history implicate DCIS as a non-obligate precursor for invasive carcinoma. We have used fluorescence in situ hybridization (FISH) to detect gene amplification of the cell cycle regulator gene CCND1 in 88 examples of formalin-fixed, paraffin-embedded DCIS. Expression of its protein product cyclin D1 was detected by immunohistochemistry. CCND1 was amplified in 18% of DCIS cases. High grade DCIS was more likely to show amplification than low grade DCIS (32% versus 8%; P = 0.08). Gene amplification was associated with cyclin D1 protein expression (P = 0.001), although cyclin D1 was detected in cases that did not demonstrate gene amplification. Overall, cyclin D1 protein was detected in 50% of DCIS cases. Although only 2 of 23 (8%) cases of low grade DCIS had CCND1 amplification, over 50% (13/23) of these cases expressed cyclin D1 protein. Low grade DCIS had a higher mean percentage of nuclei expressing cyclin D1 than did intermediate or high grade DCIS (P = 0.007). Mechanisms other than gene amplification may be responsible for increased cyclin D1 protein in DCIS, especially in low grade DCIS. Identifying mechanisms that control cell cycle progression in DCIS may yield clues to its biological behavior.

Analysis of Variance↗
PubMed1996

Endothelial area as a prognostic indicator for invasive breast carcinoma.

BACKGROUND: Vascular enumeration using antibodies to Factor VIII has been reported to be an independent prognostic indicator of invasive breast carcinoma. METHODS: To eliminate potential subjectivity in distinguishing between individual vessels, especially in areas of tangled capillaries, total endothelial area (EA) was assessed using a Samba 4000 image analyzer. One hundred seventy-eight invasive breast carcinomas (Stage 1 and 2, mean follow-up: 71 months) were immumostained for the presence of CD34, the human hematopoietic progenitor cell antigen also present in endothelium, and EA was quantitated within 5 adjacent 20X fields (0.74 mm2). Additionally, these same vessels were manually counted from the image analyzer. Manual counts were also made from a photomicrograph representative of a single 10X field (1.06 mm2). RESULTS: High grade carcinomas contained greater endothelial area than low grade carcinomas (P = 0.0001). Endothelial area was prognostically significant (P = 0.004) in univariate analysis of disease-free survival (DFS) and overall survival (OS), as were stage of disease, tumor size, and combined histologic grade (P < or = 0.024). Manual vessel counts from the monitor were significant for OS only. Manual vessel counts from photomicrographs showed no statistically significant association with DFS or OS. In multivariate analysis, EA, but not vessel enumeration, remained as an independent predictor for OS (lymph node negative patients only, n = 87) and for DFS (lymph node positive patients only, n = 91). For the entire group of patients (lymph node negative and lymph node positive) independent predictors of DFS and OS were tumor grade and size (P < or = 0.006). CONCLUSIONS: Of the three methods used to evaluate tumor angiogenesis, total endothelial area, as objectively evaluated by image analysis, was the only independent prognostic indicator for OS for patients with lymph node negative invasive breast carcinoma.

Adult↗
PubMed1996

p27/Kip1 mutation found in breast cancer.

The p27/Kip1 protein belongs to the recently identified family of proteins called cyclin-dependent kinase inhibitors. These proteins play an important role as negative regulators of cell cycle-dependent kinase activity during progression of the cell cycle. Since cyclin-dependent kinase inhibitors can inhibit cell proliferation, they may have a role as tumor suppressor genes. To determine whether p27 alterations may be involved in tumorigenesis, we examined its mutational status in 36 primary breast carcinomas and 9 breast cancer cell lines using PCR-single-strand conformational polymorphism, direct DNA sequencing, and Southern blot analysis. Southern blot analysis showed no homozygous deletions of the p27 gene in either the clinical samples or cell lines. Two point mutations were found in primary tumors. One represents a previously undescribed polymorphism at codon 142; another is a nonsense mutation at codon 104. The latter mutation was absent in the normal matched control sample, and, in addition, it was accompanied with the loss of heterozygosity (LOH) of a microsatellite marker in the vicinity of the p27 gene on chromosome 12p13. These data indicate that p27 mutations are a rare event in breast cancer, but may play an important role in the development of a minority of these cancers. Furthermore, LOH analysis of the 12p13 locus revealed that an additional four of six matched DNA samples had LOH at 12p13 but did not have an alteration of the p27 gene, suggesting that another tumor suppressor gene is located on the short arm of human chromosome 12 which may be frequently involved in the pathogenesis of breast cancers.

Base Sequence↗
PubMed1996

Histopathologic effects of tamoxifen on the uterine epithelium of breast cancer patients: analysis by menopausal status.

We evaluated the histopathologic changes of the uterine epithelium in 73 breast cancer patients with tamoxifen stratified by menopausal status. Clinicopathologic data at the time of breast cancer diagnosis and endometrial sampling were analyzed and compared with 122 breast cancer patients not receiving the drug. The incidence of endocervical and/or endometrial polyps was increased in tamoxifen-treated postmenopausal patients compared with untreated patients, 43% (25 of 58) and 24% (16 of 68), respectively (odds ratio=2.46, P=0.02). In contrast, there was no increase in polyps in premenopausal tamoxifen-treated patients. This finding suggests that the effects of tamoxifen on the endometrium may vary with menopausal status.

Adenocarcinoma↗
PubMed1996

Bladder augmentation in the prevention of cyclophosphamide-induced haemorrhagic cystitis in the rat model.

OBJECTIVE: To evaluate the effects of cyclophosphamide on the bowel mucosa of the rat and to determine whether urothelium can be protected from the effects of haemorrhagic cystitis which can occur after treatment with cyclophosphamide. MATERIALS AND METHODS: Thirty Sprague-Dawley rats were divided into three groups, 10 undergoing a control (sham) operation, 10 an ileal bladder augmentation and 10 a colonic bladder augmentation. Each rat underwent the appropriate surgical procedure and after a recovery period of 2 weeks, was injected with cyclophosphamide. Urine specimens were collected 24 h after the injection and analysed for gross and microscopic haematuria. The rats were killed humanely 48 h after injection and the bladders examined for haemorrhage, oedema, attenuation, inflammation and erosion. RESULTS: None of the 20 augmented rats developed gross haematuria and only four developed microscopic haematuria, compared with the control rats where six of 10 developed gross haematuria and nine developed microscopic haematuria. In addition, the control rats had moderate to severe haemorrhage, oedema and attenuation compared with only mild changes in the augmented rats. This protection was significant for both the bowel mucosa and urothelium. CONCLUSIONS: It is possible that the administration of cyclophosphamide in patients with urinary diversion carries little risk of haemorrhagic cystitis. We propose that this protective mechanism is secondary to a substance secreted by the intestinal mucosa that may bind acrolein and render it inactive. Alternatively, this may be secondary to the production of mucus and its ability to coat and protect the epithelium.

Animals↗
PubMed1996

Pathology of preinvasive and excellent-prognosis breast cancer.

This review of developments in breast cancer is targeted at two broad areas: 1) indicators of increased risk of sufficient magnitude to attain clinical significance (including precursors) and 2) indicators of good prognosis in invasive breast cancer. A specific and important group that appears in a somewhat intermediate position is the carcinomas in situ, particularly those of the ductal type. This area has attained great importance because of its continually increasing incidence in North America and elsewhere where mammography is used extensively. In addition to discussing in general the advancing subspeciation of these premalignant and low-malignant conditions, we also discuss advances in diagnostic techniques. This specifically relates to the great increase in the utilization of core needle biopsies under mammographic and ultrasonographic guidance.

Adenocarcinoma↗
PubMed1996

The role of pathology in premalignancy and as a guide for treatment and prognosis in breast cancer.

This review emphasizes tissue pathology and its practical relevance to patient management in premalignant breast disease and established breast cancer. The rationale and criteria for recognizing benign lesions that indicate a subsequent increased risk for cancer development are now well established, having been confirmed in several large epidemiologic studies. Our understanding of the heterogeneous nature of ductal carcinoma in situ (DCIS) continues to evolve. Recent efforts to classify DCIS into clinically meaningful categories underscore the central role of histopathology in the management of this disease. Through long term follow up studies, small examples of noncomedo DCIS treated by biopsy alone may predict local recurrence. Adequate surgical excision, however, avoids this possibility in the predominance of such cases. For invasive carcinomas, prognostic issues extend beyond predicting survival after local treatment. Now that the efficacy of systemic chemotherapy is established, the question is whether this therapy will be of use to a particular patient or group of similar patients. The list of possible clinically useful subcategories of prediction is growing and under active development. Prognostic factors that are in general use, having been repeatedly validated, particularly stage and histologic grade, as well as those that are emerging but in need of validation, are reviewed.

Breast Neoplasms↗
PubMed1996

Genetic heterogeneity of primary and metastatic breast carcinoma defined by fluorescence in situ hybridization.

Breast carcinoma is frequently associated with nonrandom chromosomal aberrations, but their identification by standard cytogenetics (SC) is often limited by technical difficulties. Fluorescence in situ hybridization (FISH) studies of interphase nuclei can circumvent some of these difficulties and has the potential to identify nonrandom molecular cytogenetic events occurring in breast cancer. FISH was performed on tumor nuclei isolated from 15 formalin-fixed, paraffin-embedded archival breast carcinomas using a panel of chromosome-specific alpha-satellite probes for enumerating chromosomes in interphase nuclei. Freshly isolated cells from these same cases had previously been studied by standard cytogenetics and FISH. In addition to archival primary carcinoma, archival metastases and normal tissue were also studied by FISH. Genetic numerical alterations were identified by standard cytogenetics or FISH in 14 of 15 carcinomas. Numeric alterations initially identified by standard cytogenetics were confirmed by FISH in 9 of 10 cases. Results of FISH performed on nuclei isolated from paraffin-embedded material were in agreement with FISH performed on freshly isolated cells. Clonal numeric alterations were observed in the archival primary tumor as well as in metastases. Archival normal tissue was consistently disomic.

Adult↗
PubMed1995

Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions.

The elucidation of molecular alterations that occur during human breast cancer progression may contribute to the development of preventative strategies. Using in situ hybridizations on a cohort of 94 biopsy lesions, quantitatively increased cyclin D mRNA expression levels were observed in only 18% of benign lesions, which confer no or slightly increased breast cancer risk, and 18% of premalignant atypical ductal hyperplasias, which confer a four to fivefold increase in breast cancer risk. The transition to carcinoma was accompanied by frequent cyclin D mRNA overexpression in 76% of low-grade ductal carcinomas in situ, 87% of higher grade comedo ductal carcinomas in situ and 83% of infiltrating ductal breast carcinomas. The data identify a molecular event that may separate benign and premalignant human breast lesions from any form of breast carcinoma.

Breast Neoplasms↗
PubMed1995

Pathology of preinvasive and excellent-prognosis breast cancer.

Little has been added in the past year to our knowledge of the premalignant lesions that have implications of increased subsequent cancer risk. However, studies of molecular biologic associations of these lesions are proceeding. The heterogeneous nature of ductal carcinoma in situ and its clinical implications continues to evolve. Several studies of ductal carcinoma in situ have confirmed that this entity extends in continuity within the breast whether associated with invasive carcinoma or not. Therapeutic stratification of ductal carcinoma in situ lesions depending on their grade and size is widely accepted, however, formal larger cooperative studies are necessary. Therapeutic use of histologic grading and recognizing special histologic subtypes continues to gain importance. Studies detailing the the use of grading as an additive measure of the predictiveness of staging, as well as documentation of interobserver agreement when fostered by rule-structured agreement, dominate the current literature on this subject. The use of stereotactically guided needle biopsy is rapidly gaining a broad consensus. Precise guidelines for management of borderline diagnoses are under development.

Breast Neoplasms↗
PubMed1995

Medullary carcinoma of the breast: interobserver variability in histopathologic diagnosis.

To assess the interobserver reproducibility for the diagnosis of medullary carcinoma of the breast (MC), 53 previously diagnosed MCs were independently assessed by six observers for growth pattern, nuclear grade (NG), inflammation, tumor margin, intraductal component, and glandular features. Tumors were reclassified as MC, atypical MC, or infiltrating ductal carcinoma according to the histopathologic criteria of Ridolfi et al. (Cancer 40:1365, 1977), Wargotz and Silverberg (Hum Pathol 19:1340, 1988), and Pedersen et al. (Br J Cancer 63:591, 1991). NG was the most reproducible parameter, and tumor margin was the least, with consensus agreement by four of six observers for 49 (92%) and 26 (49%) of cases, respectively. Utilizing the histopathologic criteria proposed by Ridolfi et al., Wargotz and Silverberg, and Pedersen et al., consensus diagnoses were achieved in 37 cases (70%), 46 cases (87%), and 51 cases (96%), respectively. A consensus diagnosis of MC in all three systems was unassociated with tumor size, axillary lymph node status or overall survival (median follow-up: 89 mo). The consensus (or better) reclassification of 44/53 (83%), 35/53 (66%), and 27/53 (51%) previously diagnosed MC as atypical MC or infiltrating ductal carcinoma by the criteria of Ridolfi et al., Wargotz and Silverberg, and Pedersen et al., respectively, suggests that MC was previously over-diagnosed. While the scheme of Pedersen et al. is the most reproducible, additional follow-up information is necessary to determine the biological significance of this classification system. To minimize these difficulties in practice, pathologists should carefully adhere to published criteria and indicate the classification system utilized.

Adult↗
PubMed1994

Mammalian DNA polymerases alpha, beta, gamma, delta, and epsilon incorporate fialuridine (FIAU) monophosphate into DNA and are inhibited competitively by FIAU Triphosphate.

Fialuridine [FIAU, 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5- iodouridine] was used in clinical trials for chronic hepatitis B virus infection and was extremely toxic. Evidence suggested targets of FIAU toxicity included mitochondria, but toxic mechanisms were unclear. Since FIAU is a thymidine analog, we reasoned that triphosphorylated FIAU (FIAUTP) could be incorporated into mitochondrial DNA by DNA pol-gamma and into genomic DNA by DNA polymerases alpha, beta, delta, and epsilon. All five purified mammalian DNA polymerases incorporated FIAUMP into the nascent DNA chain during in vitro DNA synthesis. When FIAUTP was substituted for dTTP, oligonucleotide products were generated efficiently by DNA pol-gamma and were similar to those generated in the presence of the four normal dNTPs. In contrast, oligonucleotide products generated by the four nuclear DNA polymerases in the presence of FIAUTP were significantly reduced in length relative to those generated in the presence of dTTP. In parallel kinetic assays, FIAUTP competitively inhibited the accumulation of radiolabeled dTTP into DNA by DNA pol-gamma. The Ki with DNA pol-gamma was 0.04 microM, the lowest Ki among the mammalian DNA polymerases. Competition between FIAUTP and dTTP and the relative ease of accumulation of FIAUMP in mitochondrial DNA by DNA pol-gamma in vitro together may relate to clinical FIAU toxicity.

Animals↗