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Nancy E Joste

Publications and source records attributed to Nancy E Joste.

12 recordsLinked to original sources
PubMed2006

Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumors.

Cancer arises from an accumulation of mutations that promote the selection of cells with progressively malignant phenotypes. Previous studies have shown that genomic instability, a hallmark of cancer cells, is a driving force in this process. In the present study, two markers of genomic instability, telomere DNA content and allelic imbalance, were examined in two independent cohorts of mammary carcinomas. Altered telomeres and unbalanced allelic loci were present in both tumors and surrounding histologically normal tissues at distances at least 1 cm from the visible tumor margins. Although the extent of these genetic changes decreases as a function of the distance from the visible tumor margin, unbalanced loci are conserved between the surrounding tissues and the tumors, implying cellular clonal evolution. Our results are in agreement with the concepts of "field cancerization" and "cancer field effect," concepts that were previously introduced to describe areas within tissues consisting of histologically normal, yet genetically aberrant, cells that represent fertile grounds for tumorigenesis. The finding that genomic instability occurs in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it has implications for the definition of appropriate tumor margins and the assessment of recurrence risk factors in the context of breast-sparing surgery.

Adolescent↗
PubMed2006

Telomere content correlates with stage and prognosis in breast cancer.

PURPOSE: To evaluate the hypothesis that telomere DNA content (TC) in breast tumor tissue correlates with TNM staging and prognosis. EXPERIMENTAL DESIGN: Slot blot assay was used to quantitate TC in 70 disease-free normal tissues from multiple organ sites, and two independent sets of breast tumors containing a total of 140 samples. Non-parametric Rank-Sums tests, logistic regression and Cox proportional hazards models were used to evaluate the relationships between TC and tumor size, nodal involvement, TNM stage, 5-year survival and disease-free interval. RESULTS: TC in 95% of normal tissues was 75-143% of that in the placental DNA standard, whereas only 50% of tumors had TC values in this range. TC was associated with tumor size (p=0.02), nodal involvement (p<0.0001), TNM stage (p=0.004), 5-year overall survival (p=0.0001) and 5-year disease-free survival (p=0.0004). A multivariable Cox model was developed using age at diagnosis, TNM stage and TC as independent predictors of breast cancer-free survival. Relative to the high TC group (>123% of standard), low TC (<101% of standard) conferred an adjusted relative hazard of 4.43 (95% CI 1.4-13.6, p=0.009). Receiver operating characteristic curves using thresholds defined by the TC distribution in normal tissues predicted 5-year breast cancer-free survival with 50% sensitivity and 95% specificity, and predicted death due to breast cancer with 75% sensitivity and 70% specificity. CONCLUSIONS: TC in breast cancer tissue is an independent predictor of clinical outcome and survival interval, and may discriminate by stage.

Adolescent↗
PubMed2006

Human papillomavirus type 16 integration in cervical carcinoma in situ and in invasive cervical cancer.

Integration of human papillomavirus type 16 (HPV-16) into the host DNA has been proposed as a potential marker of cervical neoplastic progression. In this study, a quantitative real-time PCR (qRT-PCR) was used to examine the physical status of HPV-16 in 126 cervical carcinoma in situ and 92 invasive cervical cancers. Based on criteria applied to results from this qRT-PCR assay, HPV-16 was characterized in carcinoma in situ cases as episomal (61.9%), mixed (i.e., episomal and integrated; 29.4%), and integrated (8.7%) forms. In invasive cervical cancer samples, HPV-16 was similarly characterized as episomal (39.1%), mixed (45.7%), and integrated (15.2%) forms. The difference in the frequency of integrated or episomal status estimated for carcinoma in situ and invasive cervical cancer cases was statistically significant (P = 0.003). Extensive mapping analysis of HPV-16 E1 and E2 genes in 37 selected tumors demonstrated deletions in both E1 and E2 genes with the maximum number of losses (78.4%) observed within the HPV-16 E2 hinge region. Specifically, deletions within the E2 hinge region were detected most often between nucleotides (nt) 3243 and 3539. The capacity to detect low-frequency HPV-16 integration events was highly limited due to the common presence and abundance of HPV episomal forms. HPV-16 E2 expressed from intact episomes may act in trans to regulate integrated genome expression of E6 and E7.

Base Sequence↗
PubMed2005

Noncorrelating Pap tests and cervical biopsies: histological predictors of subsequent correlation.

Lack of correlation between dysplastic cervicovaginal Papanicolaou (Pap) tests and subsequent cervical biopsies raises the concern that a significant squamous intraepithelial lesion (SIL) may go unconfirmed. Additional tissue sections of cervical biopsies may detect SILs after noncorrelation on initial sections. Complete step sectioning of paraffin blocks was undertaken on 111 noncorrelating biopsy specimens from 95 patients and selected slides were reviewed for the presence of SIL. The initial negative biopsy slides were evaluated for four histological features: chronic cervicitis, acute cervicitis, mucosal erosion, and squamous atypia. Twenty-seven biopsies (24.3%) demonstrated the presence of a SIL in deeper levels. The presence of squamous atypia was significantly associated with the presence of dysplasia deeper in the block (P < 0.002). Acute and chronic cervicitis was seen roughly equally. Additional tissue levels are a productive way of confirming SILs, and squamous atypia allows a refined selection of negative cervical biopsies most likely to reveal an SIL on review of deeper levels.

Acute Disease↗
PubMed2005

p57KIP2 immunohistochemistry in early molar pregnancies: emphasis on its complementary role in the differential diagnosis of hydropic abortuses.

Morphologic examination still forms the main diagnostic tool in the differential diagnosis of molar pregnancies. However, the criteria are subjective and show considerable interobserver variability among pathologists. Once a diagnosis of molar pregnancy is made, DNA ploidy studies help to differentiate a triploid partial mole from diploid complete mole (CM). However, with earlier diagnosis and therapeutic evacuation of molar pregnancies, the differentiation of molar pregnancies from early nonmolar placentation is becoming increasingly difficult. The p57(KIP2) gene ( CDKN1C ) is strongly paternally imprinted and expressed from the maternal allele. Because CM lacks a maternal genome, p57(KIP2) immunostaining is correspondingly absent, whereas hydropic abortuses and partial mole show positive staining. We compared the use of p57(KIP2) staining in the differential diagnosis of 68 morphologically challenging cases of early first-trimester hydropic placentas. Diagnosis based on p57(KIP2) staining was compared with the original diagnosis based on morphology and DNA ploidy analysis. Concordant results were obtained in 65 of 68 cases studied. In 2 of 3 cases with a discordant diagnosis, microsatellite DNA genotyping analysis agreed with the results of p57(KIP2) staining, confirming that positive p57(KIP2) staining is a highly sensitive and specific marker for excluding CM in this setting. In addition, p57(KIP2) staining has the advantage of differentiating hydropic abortuses from CMs, a distinction not made by ploidy analysis. p57(KIP2) staining can be used in concert with ploidy studies to refine the diagnosis of early molar pregnancies.

Adult↗
PubMed2005

Association between cancer-free survival and telomere DNA content in prostate tumors.

PURPOSE: We evaluated the hypothesis that telomere DNA content (TC) in prostate tumor tissue is associated with time to prostate cancer recurrence. MATERIALS AND METHODS: The cohort was comprised of 77 men who underwent prostatectomy between 1982 and 1995. Slot blot assay was used to measure TC in DNA extracted from paraffin embedded tumor and nearby, histologically normal prostate (NHN) tissues. Multivariate Cox proportional hazards analysis was done to relate TC, patient age at diagnosis, Gleason sum and pelvic node involvement to time of prostate cancer recurrence. Regression analysis was done to relate TC in paired tumor and NHN tissues. Nonparametric Kruskal-Wallis analysis was done to relate TC in tumor and NHN tissues with 72-month disease-free survival. RESULTS: TC was a predictor of time to prostate cancer recurrence when controlling for age at diagnosis, Gleason sum and pelvic node involvement (RH = 5.02, 95% CI 1.40 to 17.96, p = 0.0132). TC in tumor tissue was associated with TC in NHN tissue (R = 0.601, p <0.0001). Median TC in tumor and NHN tissues from men in whom cancer recurred within 6 years was approximately half that in men who remained disease-free (p = 0.012 and 0.024, respectively). CONCLUSIONS: Decreased TC in prostate tissues obtained by radical prostatectomy predicts prostate cancer recurrence independent of age at diagnosis, Gleason sum and pelvic node involvement. TC in tumor tissue is also associated with TC in NHN prostate tissue. Thus, mechanisms known to generate genomic instability are operative in fields of cells beyond the tumor margins prior to histological changes.

Aged↗
PubMed2005

Quantitative and spatial measurements of telomerase reverse transcriptase expression within normal and malignant human breast tissues.

The enzyme telomerase catalyzes the de novo synthesis of telomere repeats, thereby maintaining telomere length, which is necessary for unlimited cellular proliferation. Telomerase reverse transcriptase (TERT), the catalytic domain of telomerase, is the rate-limiting factor for telomerase activity and is expressed in virtually all tumors. Thus, TERT has been proposed as a marker with diagnostic and prognostic potential in breast cancer as well as a basis for breast cancer therapeutics. In these contexts, it is important to define the sites and extent of TERT expression in normal and cancerous human breast tissues. In this study, levels of TERT mRNA were measured within a set of 36 breast carcinomas and 5 normal breast samples by quantitative real-time reverse transcription-PCR, and we subsequently identified and characterized the cells expressing TERT mRNA within these tissues using in situ hybridization. The results show that (a) detectable TERT mRNA expression is specific to the epithelial cells; (b) TERT is expressed in both normal and malignant breast tissues; (c) the pattern and level of TERT expression are heterogeneous, with approximately 75% of tumors expressing bulk TERT mRNA levels equal to or less than those within normal breast tissue; and (d) tumors expressing above-normal levels of TERT mRNA are more likely to be histopathologic grade 3 (P = 0.002), contain high fraction of cells in S phase (P = 0.004), and have increased levels of MYC mRNA (P = 0.034).

Biomarkers, Tumor↗
PubMed2005

Estrogen receptor expression in papillary urothelial carcinoma of the bladder and ovarian transitional cell carcinoma.

CONTEXT: Relatively little is known about estrogen receptor (ER) expression in papillary urothelial carcinoma (PUC) of the bladder. Greater understanding of this feature of PUCs could aid with the treatment and identification of the origin of metastases, particularly with relation to the morphologically similar entity of ovarian transitional cell carcinoma (TCC). OBJECTIVE: To assess the presence of ERs in PUC of the bladder, its metastases, and ovarian TCC. DESIGN: Formalin-fixed, paraffin-embedded archival tissue from 92 primary bladder PUCs, 11 PUC metastases, and 11 primary or metastatic ovarian TCCs was immunostained with a monoclonal antibody against the human ER beta-molecule. The ER-positive and ER-negative tumors were compared by the patients' sex and age, tumor grade, and the presence or absence of invasion. Statistical analysis was performed on the PUC results, first defining a positive result as staining of at least 10% of nuclei and then repeated using any percentage of staining as a positive result. RESULTS: By the 10% criterion, 11% of PUCs of the bladder were ER positive. Invasive PUCs were more likely to be ER positive (P = .10). Women with ER-positive PUCs were older than their male counterparts (P = .03). By the second criterion, 22% of all PUCs were ER positive, and both higher grade and the presence of invasion were significantly associated with ER expression (P = .004 and .01, respectively). All 11 PUC metastases were totally ER negative. Ten of the 11 ovarian TCC cases exhibited strong and diffuse ER expression. CONCLUSION: Depending on the criterion used, up to 22% of bladder PUCs were ER positive. Higher grade and the presence of invasion were significantly associated with ER expression in these bladder carcinomas. In contrast, almost all of the ovarian TCCs marked strongly for ERs, a characteristic that may help differentiate these lesions from PUCs metastatic to the ovary.

Adult↗
PubMed2004

Clonal chromosome abnormalities in a plexiform cellular schwannoma.

Cellular schwannomas are uncommon tumors of Schwann cells that can rarely have a plexiform architecture. Cellular schwannomas can be confused with low-grade malignant peripheral nerve sheath tumors (MPNST) but have been noted to have a benign clinical course. There are few published cytogenetic analyses of cellular schwannomas and, to our knowledge, there are no reports of the plexiform variant of cellular schwannoma to date. Cellular schwannomas are reported to have cytogenetic changes similar to those seen in benign schwannomas with near-diploid karyotypes having simple numerical changes often involving chromosomes 22, 7, and the sex chromosomes. MPNST are markedly different, with extensive genetic heterogeneity and complex karyotypes. We report clonal numerical changes in a cellular schwannoma with plexiform architecture: 47,XY,+17 and 48,XY,+17,+18. These findings add to the karyotypic spectrum of peripheral nerve sheath tumors.

Chromosome Aberrations↗
PubMed2002

Atypical glandular cells of undetermined significance (AGUS): Interobserver reproducibility in cervical smears and corresponding thin-layer preparations.

Five panelists independently reviewed 135 consecutive conventional cervical smears (CPs) originally classified as atypical glandular cells of undetermined significance (AGUS). A thin-layer slide (TP), prepared from the residual material, also was reviewed in each case. All patients underwent colposcopy that yielded at least 1 histologic specimen. Three or more of 5 reviewers retained the AGUS interpretation for 29% of CPs and 12% of the corresponding TPs. Interobserver variability infrequency of use of AGUS was marked, and interobserver agreement was poor. Agreement was improved for cases cytologically interpreted as a high-grade lesion, especially in TPs. Four of 5 reviewers retained the AGUS classification in CPs for all 7 biopsy-proven neoplastic glandular lesions. Of 95 CP interpretations made by 5 reviewers in the 19 histologically diagnosed high-grade lesions, 8 were "negative/reactive" and 6 were AGUS "favor reactive." AGUS is a poorly reproducible cytologic interpretation. Although most neoplastic glandular lesions may be distinguished by cytopathologists experienced in this area from mimics originally considered AGUS, attempts to increase the diagnostic specificity of AGUS may diminish sensitivity for an underlying high-grade precursor. Interobserver agreement was better for TPs than for the corresponding CPs. However, the split-sample TP slides may not have been fully comparable to the CPs.

Adenocarcinoma↗