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Biomedical subjects

L C Hartmann

Publications and source records attributed to L C Hartmann.

At least 19 recordsLinked to original sources
PubMed2003

Single-cell nonphotochemical hole burning of ovarian surface epithelial carcinoma and normal cells.

Persistent spectral nonphotochemical hole-burning (NPHB) spectroscopy has recently been applied to dye molecules in cells. The sensitivity of NPHB to the nanoenvironment of the probe is well established. It has been shown that NPHB applied to bulk suspensions of cultured human cells can distinguish between normal and cancer cells. Thus, NPHB has potential as a diagnostic cancer tool. For this reason, the methodology is referred to as hole-burning imaging, by analogy with MRI. The optical dephasing time (T(2)) of the dye in hole-burning image replaces the proton T(1) relaxation time in MRI. In addition to the T(2) mode of operation, there are four other modes including measurement of the spectral hole growth kinetics (HGK). Reported here is that the selectivity and sensitivity of NPHB operating in the HGK mode allow for distinction between normal and carcinoma cells at the single-cell level. The ovarian cell lines are ovarian surface epithelial cells with temperature-sensitive large T antigens (analogously normal) and ovarian surface epithelial carcinoma (OV167) cells. The mitochondrial specific dye used was rhodamine 800 (Molecular Probes). This carbocationic dye is highly specific for the outer and inner membranes of mitochondria. In line with the results for bulk suspensions of the two cell lines, the hole-burning efficiency for OV167 cells was found to be significantly higher than that for normal cells. Theoretical analysis of the HGK data leads to the conclusion that the degree of structural heterogeneity for the probe-host configurations in OV167 cells is lower than in the normal cells. Possible reasons for this are given.

Epithelial Cells↗
PubMed2003

Carcinoma and SV40-transfected normal ovarian surface epithelial cell comparison by nonphotochemical hole burning.

Results are presented of nonphotochemical-hole-burning experiments on the mitochondrial specific dye rhodamine 800 incubated with two human ovarian surface epithelial cell lines: OSE(tsT)-14 normal cells and OV167 carcinoma cells. This dye is selective for the plasma and inner membranes of the mitochondria, as shown by confocal microscopy images. Dispersive hole-growth kinetics of zero-phonon holes are analyzed with theoretical fits, indicating that subcellular structural heterogeneity of the carcinoma cell line is lower relative to the analogous normal cell line. Broadening of holes in the presence of an applied electric field (Stark effect) was used to determine the permanent dipole moment change for the S(0)-->S(1) transition in the two cell lines. For the carcinoma cell line, the permanent dipole moment change value is a factor of 1.5 higher than for the normal cell line. It is speculated that this difference may be related to differences in mitochondrial membrane potentials in the two cell lines.

Epithelial Cells↗
PubMed2001

Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers.

BACKGROUND: In women with a family history of breast cancer, bilateral prophylactic mastectomy is associated with a decreased risk of subsequent breast cancer of approximately 90%. We examined the association between bilateral prophylactic mastectomy and breast cancer risk in women at high risk for breast cancer who also had mutations in BRCA1 and BRCA2 genes. METHODS: We obtained blood samples from 176 of the 214 high-risk women who participated in our previous retrospective cohort study of bilateral prophylactic mastectomy. We used conformation-sensitive gel electrophoresis and direct sequence analysis of the blood specimens to identify women with mutations in BRCA1 and BRCA2. The carriers' probabilities of developing breast cancer were estimated from two different penetrance models. RESULTS: We identified 26 women with an alteration in BRCA1 or BRCA2. Eighteen of the mutations were considered to be deleterious and eight to be of uncertain clinical significance. None of the 26 women has developed breast cancer after a median of 13.4 years of follow-up (range, 5.8-28.5 years). Three of the 214 women are known to have developed a breast cancer after prophylactic mastectomy. For two of these women, BRCA1 and BRCA2 screening was negative, and no blood specimen was available for the third. Estimations of the effectiveness of prophylactic mastectomy were performed, considering this woman as both a mutation carrier and a noncarrier. These calculations predicted that six to nine breast cancers should have developed among the mutation carriers, which translates into a risk reduction, after bilateral prophylactic mastectomy, of 89.5%-100% (95% confidence interval = 41.4% to 100%). CONCLUSIONS: Prophylactic mastectomy is associated with a substantial reduction in the incidence of subsequent breast cancer not only in women identified as being at high risk on the basis of a family history of breast cancer but also in known BRCA1 or BRCA2 mutation carriers.

Breast Neoplasms↗
PubMed2001

Efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.

PURPOSE: To estimate the efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer. PATIENTS AND METHODS: We followed the course of 745 women with a first breast cancer and a family history of breast and/or ovarian cancer who underwent contralateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. Family history information and cancer follow-up information were obtained from the medical record, a study-specific questionnaire, and telephone follow-up. Life-tables for contralateral breast cancers, which consider age at first breast cancer, current age, and type of family history, were used to calculate the number of breast cancers expected in our cohort had they not had a prophylactic mastectomy. RESULTS: Of the 745 women in our cohort, 388 were premenopausal (age < 50 years) and 357 were post- menopausal. Eight women developed a contralateral breast cancer. Six events were observed among the premenopausal women, compared with 106.2 predicted, resulting in a risk reduction of 94.4% (95% confidence interval [CI], 87.7% to 97.9%). For the 357 postmenopausal women, 50.3 contralateral breast cancers were predicted, whereas only two were observed, representing a 96.0% risk reduction (95% CI, 85.6% to 99.5%). CONCLUSION: The incidence of contralateral breast cancer seems to be reduced significantly after contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.

Adult↗
PubMed2001

Genetic analysis of early- versus late-stage ovarian tumors.

In the United States, ovarian cancer is the fourth most common cause of cancer-related deaths among women. The most important prognostic factor for this cancer is tumor stage, or extent of disease at diagnosis. Although women with low-stage tumors have a relatively good prognosis, most women diagnosed with late-stage disease eventually succumb to their cancer. In an attempt to understand early events in ovarian carcinogenesis, and to explore steps in its progression, we have applied multiple molecular genetic techniques to the analysis of 21 early-stage (stage I/II) and 17 advanced-stage (stage III/IV) ovarian tumors. These techniques included expression profiling with cDNA microarrays containing approximately 18,000 expressed sequences, and comparative genomic hybridization to address the chromosomal locations of copy number gains as well as losses. Results from the analysis indicate that early-stage ovarian cancers exhibit profound alterations in gene expression, many of which are similar to those identified in late-stage tumors. However, differences observed at the genomic level suggest differences between the early- and late-stage tumors and provide support for a progression model for ovarian cancer development.

Disease Progression↗
PubMed2001

Loss of expression of a new member of the DNAJ protein family confers resistance to chemotherapeutic agents used in the treatment of ovarian cancer.

Differential display-PCR between ovarian tumor cell lines and short-term cultures of normal ovarian epithelial cell brushings was used to isolate a differentially expressed transcript and its corresponding gene. The gene, which mapped to 13q14.1, has partial homology in the DNAJ domain to a number of proteins with a similar domain and was designated as methylation-controlled J protein (MCJ). MCJ has the highest similarity to a functionally undefined protein from Caenorhabditis elegans. MCJ is expressed as a 1.2-kb transcript in several adult tissues, with testis showing the highest level of expression. Expression of MCJ was absent in three of seven ovarian cancer cell lines. Similarly, expression analysis using semiquantitative reverse transcription-PCR indicated that 12 of 18 primary ovarian tumors examined had either a complete absence or lower levels of expression of this gene. 5-Aza-2'-deoxycytidine treatment of the OV202 cell line induced MCJ expression in a dose-dependent manner, implicating methylation in this induction. Loss of heterozygosity and methylation-specific PCR analysis revealed that the loss of MCJ expression in primary tumors and cell lines was attributable to deletion of one allele and methylation of the other. To assess the potential functional significance of MCJ down-regulation, the sensitivity of parental (MCJ-nonexpressing) and MCJ-transfected OV167 cells to antineoplastic agents was evaluated. MCJ expression was associated with enhanced sensitivity to paclitaxel, topotecan, and cisplatin, suggesting that MCJ loss may play a role in de novo chemoresistance in ovarian carcinoma. These observations raise the possibility that MCJ loss may: (a) have potential prognostic significance in ovarian cancer; and (b) contribute to the malignant phenotype by conferring resistance to the most commonly used chemotherapeutic agents for ovarian cancer.

Amino Acid Sequence↗
PubMed2001

Cigarette smoking increases risk for breast cancer in high-risk breast cancer families.

Most epidemiological studies of cigarette smoking and breast cancer have failed to demonstrate a strong association. Only one study has been performed on women at high genetic risk, and smoking was reported to be a protective factor. To further explore this observation, we examined the association of cigarette smoking with the risk of breast cancer in a historical cohort study of high-risk breast cancer families. A total of 426 families ascertained through a consecutive series of breast cancer patients (probands) between 1944 and 1952 were followed through 1996. Occurrence of breast cancer and detailed smoking histories for sisters, daughters, granddaughters, nieces, and marry-ins were obtained through telephone interviews between 1991 and 1996. Cox proportional hazards regression, accounting for age, birth cohort, and other risk factors, was used to calculate relative risks and 95% confidence intervals (CIs) of breast cancer. All of the models were constructed within strata defined by relationship to the index case (proband), with nonsmokers designated as the referent group. Of the 426 families in the cohort, 132 had at least three incident breast and/or ovarian cancers in the biological relatives at the end of the follow-up period. Among sisters and daughters in these 132 high-risk families, those who ever smoked were at 2.4-fold increased risk of breast cancer (95% CI, 1.2-5.1) relative to never-smokers. No association between breast cancer and smoking was observed among nieces and granddaughters of probands or among marry-ins. When the analysis was restricted to 35 families at highest genetic risk (each containing five breast and/or ovarian cancers), smoking became an even stronger risk factor. Among sisters and daughters, ever-smokers were at 5.8-fold greater risk than nonsmokers (95% CI, 1.4-23.9). Among nieces and granddaughters, the risk of breast cancer associated with smoking was increased 60% (95% CI, 0.8-3.2). These results suggest that smoking may increase risk for breast cancer in families with multiple cases of breast or ovarian cancer, especially those with the strongest apparent familial predisposition.

Adolescent↗
PubMed2000

Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer.

CONTEXT: Oral contraceptive (OC) use is weakly associated with breast cancer risk in the general population, but the association among women with a familial predisposition to breast cancer is less clear. OBJECTIVE: To determine whether the association between OC use and risk of breast cancer is influenced by family history of the disease. DESIGN AND SETTING: Historical cohort study of 426 families of breast cancer probands diagnosed between 1944 and 1952 at the Tumor Clinic of the University of Minnesota Hospital. Follow-up data on families were collected by telephone interview between 1991 and 1996. PARTICIPANTS: A total of 394 sisters and daughters of the probands, 3002 granddaughters and nieces, and 2754 women who married into the families. MAIN OUTCOME MEASURE: Relative risk (RR) of breast cancer associated with history of OC use by relationship to proband. RESULTS: After accounting for age and birth cohort, ever having used OCs was associated with significantly increased risk of breast cancer among sisters and daughters of the probands (RR, 3.3; 95% confidence interval [CI], 1.6-6.7), but not among granddaughters and nieces of the probands (RR, 1.2; 95% CI, 0.8-2.0) or among marry-ins (RR, 1.2; 95% CI, 0.8-1.9). Results were essentially unchanged after adjustment for parity, age at first birth, age at menarche, age at menopause, oophorectomy, smoking, and education. The elevated risk among women with a first-degree family history of breast cancer was most evident for OC use during or prior to 1975, when formulations were likely to contain higher dosages of estrogen and progestins (RR, 3.3; 95% CI, 1.5-7.2). A small number of breast cancer cases (n = 2) limited the statistical power to detect risk among women with a first-degree relative with breast cancer and OC use after 1975. CONCLUSIONS: These results suggest that women who have ever used earlier formulations of OCs and who also have a first-degree relative with breast cancer may be at particularly high risk for breast cancer. Further studies of women with a strong family history who have used more recent lower-dosage formulations of OCs are needed to determine how women with a familial predisposition to breast cancer should be advised regarding OC use today. JAMA. 2000;284:1791-1798.

Adult↗
PubMed2000

Long-term satisfaction and psychological and social function following bilateral prophylactic mastectomy.

CONTEXT: Prophylactic mastectomy is a preventive option for women who wish to reduce their risk of breast cancer. There has been concern about possible negative psychological sequelae following this procedure. However, few data are available regarding long-term satisfaction and psychological and social function following this procedure. OBJECTIVE: To evaluate patients' long-term satisfaction and psychological and social function following prophylactic mastectomy. DESIGN, SETTING, AND PARTICIPANTS: Descriptive study of all women known to be alive (n = 609) who had a family history of breast cancer and elected to undergo bilateral prophylactic mastectomy at a large, tertiary US health care clinic between 1960 and 1993, 94% (n = 572) of whom completed a study questionnaire. MAIN OUTCOME MEASURES: Satisfaction with procedure and effects on psychological and social function, based on responses to the study-specific questionnaire. RESULTS: Mean time from prophylactic mastectomy to last follow-up was 14.5 years. Most women (70%) were satisfied with the procedure; 11% were neutral; and 19% were dissatisfied. Among the psychological and social variables, the most striking finding was that 74% reported a diminished level of emotional concern about developing breast cancer. The majority of women reported no change/favorable effects in levels of emotional stability (68%/23%), level of stress (58%/28%), self-esteem (69%/13%), sexual relationships (73%/4%), and feelings of femininity (67%/8%). Forty-eight percent reported no change in their level of satisfaction with body appearance; 16% reported favorable effects. However, 9%, 14%, 18%, 23%, 25%, and 36% reported negative effects in these 6 variables, respectively. CONCLUSIONS: This study suggests that positive outcomes following prophylactic mastectomy include decreased emotional concern about developing breast cancer and generally favorable psychological and social outcomes. These must be weighed against the irreversibility of the decision, potential problems with implants and reconstructive surgery, and occurrence of adverse psychological and social outcomes in some women. JAMA. 2000;284:319-324

Adaptation, Psychological↗
PubMed2000

A phase II study of paclitaxel plus carboplatin as first-line chemotherapy for women with metastatic breast carcinoma.

BACKGROUND: This Phase II multicenter study evaluated the efficacy and toxicity of paclitaxel (200 mg/m(2) by 3-hour infusion) with carboplatin (area under the curve 6 mg/mL per minute) administered every 3 weeks as first-line therapy for women with metastatic breast carcinoma. METHODS: Eligible patients had measurable metastatic disease and an Eastern Cooperative Oncology Group performance status of 0-2. Prior adjuvant chemotherapy, including anthracycline-based therapy, was allowed, as was prior hormonal therapy as part of either adjuvant treatment or treatment for metastasis. Prior therapy with taxanes or platinum was not allowed. RESULTS: A total of 53 patients were enrolled in this study, with 50 patients evaluable for response and toxicity. The overall response rate was 62% (95% confidence interval ¿CI, 48-75%); 16% of patients had complete responses and 46% had partial responses. The median time to progression was 7.3 months (95% CI, 5.9-12.9), and the 12-month survival estimate was 72% (95% CI, 61-86%). Therapy was generally well tolerated. Grade 3-4 neutropenia was the predominant toxicity, observed in 82% of patients, but there were no episodes of febrile neutropenia or sepsis. Hematopoietic growth factors were not routinely necessary. Grade 3 peripheral neuropathy occurred in 16% of patients. CONCLUSIONS: Paclitaxel (200 mg/m(2)) with carboplatin (area under the curve 6 mg/mL per minute) demonstrated substantial efficacy in patients with metastatic breast carcinoma, and the 12-month survival rate of 72% was encouraging. This therapy represents a viable option for patients with metastatic disease.

Adult↗
PubMed2000

Genetic heterogeneity in Peutz-Jeghers syndrome.

LKB1, the human gene encoding a serine threonine kinase, was recently identified as a susceptibility gene for Peutz-Jeghers syndrome (PJS), a disease characterized by the constellation of intestinal hamartomata, oral mucocutaneous hyperpigmentation, and an increased risk for gastrointestinal as well as extraintestinal malignancies. To date, the majority of individuals with PJS have been found to have genetic alterations in LKB1, most of which result in protein truncation. Additionally, linkage analyses have suggested a modicum of genetic heterogeneity, with the majority of PJS families showing linkage to the LKB1 locus. In this study, we evaluated five kindreds with greater than two affected family members, five PJS probands with only one other affected family member, as well as 23 individuals with sporadic PJS for mutations within the LKB1 gene. Conformation sensitive gel electrophoresis was utilized for the initial screen, followed by direct sequence analysis for characterization. Long-range PCR was used for the detection of larger genetic insertions or deletions. Mutation analysis revealed genetic alterations in LKB1 in two probands who had a family history of PJS. LKB1 mutations were detected in only four of the remaining 23 cases of sporadic PJS. These data suggest the presence of significant genetic heterogeneity for PJS and the involvement of other loci in this syndrome.

AMP-Activated Protein Kinase Kinases↗
PubMed2000

Breast cancer prevention trials.

A new option for women at increased risk for breast cancer is chemoprevention--namely, an attempt to decrease breast cancer incidence by means of drug therapy. The efficacy of tamoxifen as a chemopreventive agent has been studied to date in three randomized, controlled trials, with varying results. Investigators with the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial found that tamoxifen reduced the incidence of breast cancer by almost half, whereas British and Italian researchers found no significant benefit. This disparity is due, in part, to differences in the baseline breast cancer risk characteristics among the study populations, differing cohort sizes, variable use of hormone replacement therapy, and other factors. In this article, we review the eligibility criteria, treatment plans, and results from the three published randomized trials of tamoxifen versus placebo. We also review the data on raloxifene and breast cancer incidence. Chemoprevention with tamoxifen, in a non-study setting, is one option for women at increased risk for breast cancer. The ongoing Study of Tamoxifen and Raloxifene (STAR) is a randomized, double-blinded trial comparing the effectiveness of raloxifene with that of tamoxifen in postmenopausal women at increased risk for developing breast cancer. Until the results of this trial are available, it is premature to use raloxifene for primary breast cancer prevention.

Adult↗
PubMed2000

Endometrial cancer in Olmsted County, MN: trends in incidence, risk factors and survival.

PURPOSE: We updated an earlier study in this community from 1945-1974 in order to assess trends in the incidence of, risk factors for, and survival from endometrial cancer in 1975-1991. METHODS: Incidence rates were based on all new cases of endometrial cancer diagnosed among Olmsted County, Minnesota, women during the years 1975-1991, with the population denominator from decennial census data. Risk factors were assessed with conditional logistic regression comparing the incidence cases to age- and gender-matched controls with intact uteri seen the same year the case was diagnosed. Survival was assessed using the Kaplan-Meier method. RESULTS: The incidence of endometrial cancer (age-adjusted to 1970 United States total) in 1975-1991 was 14.3 per 100,000 person-years, which is slightly increased from 1965-74. The rate was 21.7 per 100,000 person-years after adjustment for hysterectomy prevalence. As in the previous study, conjugated estrogen use for six months or more (odds ratio [OR] 2.71; 95% confidence interval [CI] 1.14-6.46) and body mass index (OR 1.06; 95% CI 1.01-1.11) increased the risk of endometrial cancer. The five-year relative survival rate (82%) was not improved over the earlier study. CONCLUSIONS: A small increase in endometrial cancer incidence was linked to the same risk factors identified in an earlier study in this community. No improvement in survival was seen.

Case-Control Studies↗
PubMed2000

The epidemiology of ovarian cancer: a population-based study in Olmsted County, Minnesota, 1935-1991.

PURPOSE: To determine trends in incidence and survival between 1935 and 1991 and to evaluate risk factors for ovarian cancer among Olmsted County, Minnesota women. METHODS: All newly diagnosed cases of ovarian cancer among Olmsted County women in 1975-1991 were identified using the medical records linkage system of the Rochester Epidemiology Project. In order to assess trends, incidence rates in the subset of Rochester women were compared with Rochester rates for 1935-1974. Survival was evaluated by the Kaplan-Meier product-limit method. A case-control analysis of risk factors compared Olmsted County women with invasive epithelial ovarian cancer and an age-matched group of women from the community by logistic regression. RESULTS: Altogether, 129 Olmsted County women were newly diagnosed with ovarian cancer in 1975-1991. The age-adjusted (to 1970 United States whites) incidence rate was 22.5 per 100,000 person-years. Median survival from initial diagnosis was 3.7 years. Compared to an equal number of controls, the 103 women with invasive epithelial disease were more likely to be nulliparous (odds ratio [OR] 1.9; 95% CI 0.95-3.9) but less likely to have a history of thyroid disease (OR 0.4; 95% CI 0.2-0.8), hypertension (OR 0.4; 95% CI 0.1-0.9) or nonsteroidal estrogen use (OR 0.5; 95% CI 0.2-0.9). Prior hysterectomy (OR 0.5; 95% CI 0.2-0.9) and unilateral oophorectomy (OR 0.2; 95% CI 0.04-0.7) were also associated with reduced risk. CONCLUSION: The incidence of ovarian cancer in this community in 1975-1991 was little changed from rates 20 years earlier. There has been some improvement in survival from ovarian cancer in this population compared to 1935-1974, but still less than 50% survive for 5 years. Prior hysterectomy and unilateral oophorectomy appear protective for ovarian cancer.

Adult↗
PubMed2000

Association of Peutz-Jeghers-like mucocutaneous pigmentation with breast and gynecologic carcinomas in women.

Most reports describe an increased risk of malignancy in Peutz-Jeghers syndrome (PJS). We identified individuals with PJS-like pigmentation but no polyposis, designated as isolated mucocutaneous melanotic pigmentation (IMMP), and 1) characterized their clinical features, 2) assessed them for cancer events, and 3) screened a sample of these subjects for mutations in LKB1, a gene responsible for a portion of PJS cases. Review of Mayo Clinic records from 1945 to 1996 identified 26 patients with IMMP. All were then interviewed or their medical records reviewed to determine if cancer had developed. Conformation-sensitive gel electrophoresis (CSGE) screening for LKB1 mutations was followed by direct sequencing. Ten of these 26 individuals (38%) developed 12 malignancies that arose in the cervix (n = 3), endometrium (n = 3), breast (n = 1), kidney (n = 1), lung (n = 2), colon (n = 1), and lymphatic tissue (n = 1). In females with IMMP, the relative risk for cancer was 3.2 (95% CI, 1.2-6.9), while that for males was not increased. The relative risk for breast and gynecologic cancers was 7.8 (95% CI, 2.5-18.1) in affected females. Of 9 individuals tested, no LKB1 mutations were detected. Classical PJS is associated with an increased cancer risk. Our results indicate that IMMP is another lentiginosis with cancer predisposition. In particular, the relative risk for cancer in females with IMMP was significantly increased, as is true in females with PJS. However, LKB1 mutations did not contribute to the development of IMMP in the patients tested.

Adult↗
PubMed2000

Management of cancer pain. Safe, adequate analgesia to improve quality of life.

Pain is one of the most common problems for cancer patients, and its management is often hindered by barriers created by patients and physicians alike. By avoiding potential barriers and understanding the principles of pain management and drug selection and titration provided here by Dr Hartmann and colleagues, physicians can safely administer adequate pain relief to their patients in need.

Analgesics↗
PubMed2000

Prophylactic surgery for women at high risk for breast cancer.

Women at high risk for the development of breast cancer have several options open to them including increased cancer surveillance, prophylactic mastectomy and/or oophorectomy, and chemoprevention. We consider high-risk women to be those with known BRCA mutations or a strong family history characterized by multiple relatives with breast cancer, early age at diagnosis, and in some families, ovarian cancer. We present existing data regarding prophylactic surgery for these women. Essentially, a woman at high risk for breast cancer may choose to undergo bilateral prophylactic mastectomy, with or without reconstruction. For patients who have a known breast cancer, contralateral mastectomy is also an option. Finally, for women in families with a strong incidence of ovarian cancer, prophylactic oophorectomy can be considered.

Age of Onset↗