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Lynn C Hartmann

Publications and source records attributed to Lynn C Hartmann.

At least 19 recordsLinked to original sources
PubMed2006

Age-related lobular involution and risk of breast cancer.

BACKGROUND: As women age, the lobules in their breasts undergo involution or regression. We investigated whether lobular involution in women with benign breast disease was associated with subsequent breast cancer risk. METHODS: We examined biopsy specimens of 8736 women in the Mayo Benign Breast Disease Cohort from whom biopsy samples were taken between January 1, 1967, and December 31, 1991. Median follow-up for breast cancer outcomes was 17 years. We classified lobular involution in the background breast tissue as none (0% involuted lobules), partial (1%-74%), or complete (> or = 75%). Subsequent breast cancer events and data on other risk factors were obtained from medical records and follow-up questionnaires. To estimate relative risks (RRs), standardized incidence ratios were calculated by use of incidence rates from the Iowa Surveillance, Epidemiology, and End Results (SEER) Registry. All statistical tests were two-sided. RESULTS: Distribution of extent of involution was none among 1627 (18.6%) women, partial among 5197 (59.5%), and complete among 1912 (21.9%). Increased involution was positively associated with increased age and inversely associated with parity (both P<.001). The relative risk for the entire cohort of 8736 women, compared with the Iowa SEER population, was 1.40 (95% CI = 1.30 to 1.51). Risk of breast cancer was associated with the extent of involution (for no involution, RR [i.e., observed versus expected] = 1.88, 95% confidence interval [CI] = 1.59 to 2.21; for partial involution, RR = 1.47, 95% CI = 1.33 to 1.61; and for complete involution, RR = 0.91, 95% CI = 0.75 to 1.10; test for heterogeneity P<.001). Lobular involution modified risk in all subsets (e.g., among women with atypia, for no involution, RR = 7.79, 95% CI = 3.56 to 14.81; for partial involution, RR = 4.06, 95% CI = 3.03 to 5.33; and for complete involution, RR = 1.49, 95% CI = 0.41 to 3.82; P = .003). CONCLUSIONS: In this large cohort of women with benign breast disease, lobular involution was associated with reduced risk of breast cancer. Aberrant involution may be a biologically important phenomenon in breast cancer biology.

Adult↗
PubMed2006

The use of a tropism-modified measles virus in folate receptor-targeted virotherapy of ovarian cancer.

PURPOSE: Attenuated measles viruses are promising experimental anticancer agents currently being evaluated in a phase I dose escalation trial for ovarian cancer patients. Virus attachment, entry, and subsequent intercellular fusion between infected and uninfected neighboring cells are mediated via the two measles receptors (CD46 and SLAM). To minimize potential toxicity due to measles virus-associated immunosuppression and infection of nontarget tissues, we sought to develop an ovarian cancer exclusive fully retargeted measles virus. EXPERIMENTAL DESIGN AND RESULTS: Interactions of measles virus with its natural receptors were ablated, and a single-chain antibody (scFv) specific for alpha-folate receptor (FRalpha), a target overexpressed on 90% of nonmucinous ovarian cancer, was genetically engineered on the viral attachment protein (MV-alphaFR). Specificity of virus tropism was tested on tumor and normal cells. Biodistribution of measles virus infection was evaluated in measles-susceptible CD46 transgenic mice, whereas antitumor activity was monitored noninvasively by bioluminescence imaging in xenograft models. Tropism and fusogenic activity of MV-alphaFR was redirected exclusively to FRalpha without compromise to virus infectivity. In contrast to the parental virus, MV-alphaFR has no background infectivity on normal human cells. The antitumor activity of MV-alphaFR, as assessed by tumor volume reduction and overall survival increase, was equal to the parental virus in two models of human ovarian cancer (s.c. and i.p.). CONCLUSIONS: A FR-exclusive ovarian cancer targeted oncolytic virus was generated and shown to be therapeutically effective, thus introducing a new modality for FR targeting and a candidate measles virus for clinical testing.

Cancer Vaccines↗
PubMed2006

T-cell immunity to the folate receptor alpha is prevalent in women with breast or ovarian cancer.

PURPOSE: Studies have demonstrated that the generation of immunity to tumor antigens is associated with improved prognosis for many cancers. A candidate antigen is the folate receptor alpha (FRalpha), which is overexpressed in breast and ovarian cancers. Our goal in this study was to attain a better understanding of the extent of endogenous FRalpha immunity. METHODS: Using a CD4+ T cell epitope prediction algorithm, we predicted promiscuous epitopes of FRalpha, and tested for immunity in 30 breast (n = 17) or ovarian (n = 13) cancer patients and 18 healthy donors using enzyme-linked immunospot analysis. RESULTS: Fourteen peptides were predicted, seven each from the carboxy- and amino-terminus halves of the protein. More than 70% of patients demonstrated immunity to at least one FRalpha peptide. Patients responded to an average of 3 +/- 0.5 peptides, whereas healthy donors responded to 1 +/- 0.4 peptides (P = .004). Five peptides were recognized by more than 25% of patients. Responses to three peptides were higher (P < .05) in patients than in healthy donors, suggesting augmented immunity. Compared with healthy individuals, patients developed higher immunity to the amino-terminus half of the receptor (P = .03). There was no difference between each group in the responses to nonspecific (P = .2) and viral stimuli (P = .5). Lastly, patients demonstrated elevated levels of FRalpha antibodies consistent with a coordinated immune response. CONCLUSION: These findings demonstrate that the FRalpha is a target of the immune system in breast and ovarian cancer patients. Understanding which antigens are targeted by the immune system may be important for prognosis or immune-based therapies.

Adult↗
PubMed2006

Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity.

Resistance to chemotherapy presents a serious challenge in the successful treatment of various cancers and is mainly responsible for mortality associated with disseminated cancers. Here we show that expression of HtrA1, which is frequently downregulated in ovarian cancer, influences tumor response to chemotherapy by modulating chemotherapy-induced cytotoxicity. Downregulation of HtrA1 attenuated cisplatin- and paclitaxel-induced cytotoxicity, while forced expression of HtrA1 enhanced cisplatin- and paclitaxel-induced cytotoxicity. HtrA1 expression was upregulated by both cisplatin and paclitaxel treatment. This upregulation resulted in limited autoproteolysis and activation of HtrA1. Active HtrA1 induces cell death in a serine protease-dependent manner. The potential role of HtrA1 as a predictive factor of clinical response to chemotherapy was assessed in both ovarian and gastric cancer patients receiving cisplatin-based regimens. Patients with ovarian or gastric tumors expressing higher levels of HtrA1 showed a higher response rate compared with those with lower levels of HtrA1 expression. These findings uncover what we believe to be a novel pathway by which serine protease HtrA1 mediates paclitaxel- and cisplatin-induced cytotoxicity and suggest that loss of HtrA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance.

Adult↗
PubMed2006

An analysis of breast cancer risk in women with single, multiple, and atypical papilloma.

Breast papillomas may be single or multiple and associated with atypical ductal or lobular hyperplasias (ADH/ALH). The risk of breast carcinoma development in patients with papillomas, particularly those with multiple or atypical lesions, is incompletely defined. Fibrocystic lesions were histopathologically classified in a benign breast disease cohort of 9155 who underwent biopsy from 1967 to 1991, with papilloma assessment in 9108. Individuals with papillomas (N=480) were classified into 4 groups: single papilloma (SP, N=372), single papilloma with ADH or ALH (SP+A, N=54), multiple (>5) papillomas (MP, N=41), and multiple papillomas with ADH or ALH (MP+A, N=13). Those without papillomas were classified as nonproliferative (NP, N=6053), proliferative without atypia (PDWA, N=2308), and ADH/ALH [atypical hyperplasia (AH), N=267]. The relative risk of cancer development within our cohort was compared to that expected in the general population using standardized incidence ratios. The relative risk of breast cancer development associated with SP [2.04, 95% confidence interval (CI) 1.43-2.81] was greater than NP (1.28, 95% CI 1.16-1.42) but similar to PDWA (1.90, 95% CI 1.66-2.16). The risk associated with SP+A (5.11, 95% CI 2.64-8.92) was highly elevated but not substantively different than atypical hyperplasia (4.17, 95% CI 3.10-5.50). Patients with MP are at increased risk compared with PDWA or SP (3.01, 95% CI 1.10-6.55), particularly those with MP+A (7.01, 95% CI 1.91-17.97). There was a marginal increase in breast cancer risk (16%) among patients with proliferative disease if a papilloma was present, but this did not reach statistical significance (P=0.29). The observed frequency of ipsilateral (vs. contralateral) breast cancer development in papilloma subsets was not significantly different than other patient groups. We conclude that SP imparts a cancer risk similar to conventional proliferative fibrocystic change. The presence of papilloma in, or associated with, atypia does not modify the risk connotation of ADH/ALH overall. MP constitutes a proliferative breast disease subset having unique clinical and biologic behavior.

Aged↗
PubMed2006

Helping people cope with bereavement: an opportunity for health care providers to link Web-based resources across Minnesota.

The death of a loved one has a profound effect on the surviving spouse or partner, family members, and friends. But the bereaved may not always get the help and support they need. This article reviews the toll that grief takes on individuals and society and highlights the importance of connecting grieving loved ones with resources that can help them. It also suggests a need for health care institutions across the state to share information about their particular resources via the Internet with health care providers and patients.

Adaptation, Psychological↗
PubMed2005

Satisfaction after contralateral prophylactic mastectomy: the significance of mastectomy type, reconstructive complications, and body appearance.

PURPOSE: Contralateral prophylactic mastectomy (CPM) is one option for reducing the risk of a second breast cancer in women with a personal and family history of breast cancer. Few data are available regarding satisfaction, psychological, and social function after CPM. The purpose of this research is to evaluate women's long-term satisfaction with CPM, factors influencing satisfaction, and psychological and social function after CPM. PATIENTS AND METHODS: This was a descriptive study of all women with a family history of breast cancer, known to be alive, who elected CPM at Mayo Clinic (Rochester, MN) between 1960 and 1993 (n = 621). Ninety-four percent of the women (n = 583) completed a study-specific questionnaire. RESULTS: A mean of 10.3 years after the procedure, the majority of women (83%) were satisfied with their CPM. A smaller number were neutral (8%) or dissatisfied (9%). Women who had a subcutaneous mastectomy had more problems with reconstruction, and fewer of these women were satisfied than women with simple mastectomy. Decreased satisfaction with CPM was associated with decreased satisfaction with appearance, complications with reconstruction, reconstruction after CPM, and increased level of stress in life. The majority of women experienced no change or favorable effects in self-esteem (83%), level of stress in life (83%), and emotional stability (88%). Satisfaction with body appearance, feelings of femininity, and sexual relationships were the most adversely affected with 33%, 26%, and 23% of the women responding negatively. CONCLUSION: Although most women are satisfied with CPM, each woman should weigh the benefits alongside the potential adverse effects.

Adaptation, Psychological↗
PubMed2005

Epigenetic silencing of TCEAL7 (Bex4) in ovarian cancer.

Epigenetic silencing by hypermethylation of CpGs represents a mechanism of inactivation of tumor suppressors. Here we report on the cloning of a novel candidate tumor suppressor gene TCEAL7 inactivated by methylation in ovarian cancer. TCEAL codes for a 1.35 kb transcript that was previously reported to be downregulated in ovarian cancer by cDNA microarray and suppression subtraction cDNA (SSH) analyses. This report focuses on the elucidation of mechanisms associated with TCEAL7 downregulation. Expression of TCEAL7 is downregulated in a majority of ovarian tumors and cancer cell lines but induced by 5-aza-2'-deoxycytidine treatment in a dose-dependant manner, implicating methylation as a mechanism of TCEAL7 inactivation. Sequence analyses of bisufite-modified genomic DNA from somatic cell hybrids with either the active or the inactive human X chromosome reveal that TCEAL7 is subjected to X chromosome inactivation. Loss of TCEAL7 expression in primary tumors and cell lines correlates with methylation of a CpG site within the promoter. In vitro methylation of the CpG site suppresses promoter activity whereas selective demethylation of the SmaI site attenuates the suppression. Finally, re-expression of TCEAL7 in cancer cell lines induces cell death and reduces colony formation efficiency. These data implicate TCEAL7 as a cell death regulatory protein that is frequently inactivated in ovarian cancers, and suggest that it may function as a tumor suppressor.

Amino Acid Sequence↗
PubMed2005

Breast biopsy utilization: a population-based study.

BACKGROUND: Breast biopsy, to determine the nature of a clinical or radiographic breast abnormality, was presumed to have increased in frequency with the widespread use of screening mammography. However, scant data exist regarding the utilization of breast biopsies in the community population. METHODS: Through the resources of the Rochester Epidemiology Project, the medical records of women 18 years and older who had a breast biopsy from January 1, 1988, through December 31, 1999, were reviewed for the type of biopsy, presentation at biopsy, and tissue pathological findings. The overall and age-specific utilization rates of breast biopsies were assessed, as were changes in the breast biopsy technique after the introduction of image-guided core-needle biopsy in 1992. RESULTS: The overall annual utilization rate of breast biopsies was 62.6 per 10 000 women per year and remained stable throughout the study. Excisional breast biopsies showed a decreasing trend and core-needle biopsies increased during the study duration. The age-adjusted incidence of benign results of breast biopsies for the study duration was 38.9 per 10 000 women. The benign-malignant ratio remained constant despite changes in the biopsy procedure. CONCLUSIONS: This population-based study provides much-needed data regarding the frequency of breast biopsies and benign results of breast biopsies in a community population. The utilization rate of breast biopsies remained fairly constant throughout the study period despite the introduction of the image-guided, core-needle biopsy procedure in 1992. A multidisciplinary breast practice, along with established guidelines for breast biopsy, can ensure appropriate use of new technology and thereby improve patient care.

Adult↗
PubMed2005

Benign breast disease and the risk of breast cancer.

BACKGROUND: Benign breast disease is an important risk factor for breast cancer. We studied a large group of women with benign breast disease to obtain reliable estimates of this risk. METHODS: We identified all women who received a diagnosis of benign breast disease at the Mayo Clinic between 1967 and 1991. Breast-cancer events were obtained from medical records and questionnaires. To estimate relative risks, we compared the number of observed breast cancers with the number expected on the basis of the rates of breast cancer in the Iowa Surveillance, Epidemiology, and End Results registry. RESULTS: We followed 9087 women for a median of 15 years. The histologic findings were nonproliferative lesions in 67 percent of women, proliferative lesions without atypia in 30 percent, and atypical hyperplasia in 4 percent. To date, 707 breast cancers have developed. The relative risk of breast cancer for the cohort was 1.56 (95 percent confidence interval, 1.45 to 1.68), and this increased risk persisted for at least 25 years after biopsy. The relative risk associated with atypia was 4.24 (95 percent confidence interval, 3.26 to 5.41), as compared with a relative risk of 1.88 (95 percent confidence interval, 1.66 to 2.12) for proliferative changes without atypia and of 1.27 (95 percent confidence interval, 1.15 to 1.41) for nonproliferative lesions. The strength of the family history of breast cancer, available for 4808 women, was a risk factor that was independent of histologic findings. No increased risk was found among women with no family history and nonproliferative findings. In the first 10 years after the initial biopsy, an excess of cancers occurred in the same breast, especially in women with atypia. CONCLUSIONS: Risk factors for breast cancer after the diagnosis of benign breast disease include the histologic classification of a benign breast lesion and a family history of breast cancer.

Adult↗
PubMed2005

Gene expression profiles predict early relapse in ovarian cancer after platinum-paclitaxel chemotherapy.

PURPOSE: Women with advanced epithelial ovarian cancer are routinely treated with platinum-paclitaxel chemotherapy following cytoreductive surgery, yet only approximately 20% achieve long-term disease-free survival. We hypothesized that differences in gene expression before treatment could distinguish patients with short versus long time to recurrence after administration of platinum-paclitaxel combination chemotherapy. EXPERIMENTAL DESIGN: To test this hypothesis, gene expression profiling of 79 primary surgically resected tumors from women with advanced-stage, high-grade epithelial ovarian cancer was done using cDNA microarrays containing 30,721 genes. Supervised learning algorithms were applied in an effort to develop a binary classifier that could discriminate women at risk for early (< or =21 months) versus late (>21 months) relapse after initial chemotherapy. RESULTS: A 14-gene predictive model was developed using a set of training samples (n = 51) and subsequently tested using an independent set of test samples (n = 28). This model correctly predicted the outcome of 24 of the 28 test samples (86% accuracy) with 95% positive predictive value for early relapse. CONCLUSIONS: Predictive markers for early recurrence can be identified for platinum-paclitaxel combination chemotherapy in primary ovarian carcinoma. The proposed 14-gene model requires further validation.

Adult↗
PubMed2005

Elevated fibroblast growth factor 23 in women with malignant ovarian tumors.

OBJECTIVE: To determine whether fibroblast growth factor 23 (FGF23) concentrations are altered in women with ovarian cancers in which FGF physiology is known to be abnormal. PATIENTS AND METHODS: Between May 2002 and September 2003 at the Mayo Clinic in Rochester, Minn, plasma or serum FGF23 concentrations were measured in 39 healthy women and in 14 with benign ovarian tumors, 14 with early-stage ovarian cancer, and 13 with advanced-stage ovarian cancer. Immunohistochemistry using anti-human FGF23 antibodies was performed on tissue from benign masses and advanced-stage tumors. RESULTS: Serum or plasma FGF23 concentrations were significantly higher in women with advanced-stage ovarian cancer compared with concentrations in women with early-stage ovarian cancer or benign disease or in healthy women. A significant positive correlation was seen between serum iFGF23 and cFGF23 concentrations and stage of disease. Serum iFGF23 and cFGF23 concentrations were positively correlated with serum phosphorus among women with ovarian cancer. No patients with elevated iFGF23 or cFGF23 concentrations had hypophosphatemia. Immunohistochemistry detected FGF23 tissue staining in malignant ovarian cancer cells. CONCLUSION: Serum or plasma FGF23 concentrations are elevated in patients with advanced-stage epithellal ovarian cancer without reductions in serum phosphate concentrations. The presence of elevated FGF23 concentrations in patients with an ovarian mass should suggest advanced-stage disease.

Adult↗
PubMed2005

Estrogen bioactivation, genetic polymorphisms, and ovarian cancer.

Recent experimental evidence has shown that catechol estrogens can be activated through metabolism to form depurinating DNA adducts and thereby initiate cancer. Limited data are available regarding this pathway in epithelial ovarian cancer. We conducted a case-control study of 503 incident epithelial ovarian cancer cases at the Mayo Clinic in Rochester, MN, and Jacksonville, FL, and a 48-county region in North Carolina. Six hundred nine cancer-free controls were frequency matched to the cases on age, race, and residence. After an interview to obtain data on risk factors, a sample of blood was collected for DNA isolation. Subjects were genotyped for seven common single nucleotide polymorphisms in four genes involved in catechol estrogen formation (CYP1A1 and CYP1B1) or conjugation (COMT and SULT1A1). Data were analyzed using logistic regression, stratified by race, and with adjustment for design factors and potential confounders. None of the individual genotypes were significantly associated with ovarian cancer risk. However, an oligogenic model that considered the joint effects of the four candidate genes provided evidence for an association between combinations of these genes and ovarian cancer status (P = 0.015). Although preliminary, this study provides some support for the hypothesis that low-penetrance susceptibility alleles may influence risk of epithelial ovarian cancer.

Adult↗
PubMed2004

ERBB2, TBX2, RPS6KB1, and MYC alterations in breast tissues of BRCA1 and BRCA2 mutation carriers.

Breast cancer risk is greatly increased in women who carry mutations in the BRCA1 or BRCA2 genes. Because breast cancer initiation is different between BRCA1/2 mutation carriers and women who do not carry mutations, it is possible that the mechanism of breast cancer progression is also different. Histopathologic and genetic studies have supported this hypothesis. To test this hypothesis further, we utilized a large cohort of women who underwent therapeutic mastectomy (TM) and contralateral prophylactic mastectomy (PM). From this cohort, we developed case groups of women with a family history of breast cancer with BRCA1/2 deleterious mutations, with unclassified variant alterations, and with no detected mutation and matched these cases with sporadic controls from the same TM and PM cohort. Fluorescence in situ hybridization was performed on paraffin sections by use of dual-color probes for ERBB2/CEP17, MYC/CEP8, TBX2/CEP17, and RPS6KB1/CEP17. All malignant and benign lesions, including putative precursor lesions, were studied. The invasive cancers from deleterious mutation carriers had a higher prevalence of duplication of MYC (P = 0.006) and TBX2 (P = 0.0008) compared to controls and a lower prevalence of ERBB2 amplification (P = 0.011). Coduplication of MYC and TBX2 was common in the in situ and invasive lesions from the deleterious mutation carriers. The odds ratio of having a BRCA1/2 mutation is 31.4 (95% CI = 1.7-569) when MYC and TBX2 are coduplicated but ERBB2 is normal. Unclassified variant carriers/no mutation detected and sporadic controls had a similar prevalence of alterations, suggesting that hereditary patients with no deleterious mutations follow a progression pathway similar to that of sporadic cases. With the exception of one atypical ductal hyperplasia lesion, no putative precursor lesion showed any detectable alteration of the probes tested. There was no significant intratumoral heterogeneity of genetic alterations. Our data confirm that a specific pattern of genomic instability characterizes BRCA1/2-related cancers and that this pattern has implications for the biology of these cancers. Moreover, our current and previous results emphasize the interaction between phenotype and genotype in BRCA1/2-related breast cancers and that a combination of morphologic features and alterations of ERBB2, MYC, and TBX2 may better define mechanisms of tumor progression, as well as determine which patients are more likely to carry BRCA1/2 mutations.

Adult↗