A case of GNE myopathy mimicking hereditary motor neuropathy.

A 36-year-old woman who presented with upper limb distal weakness since the age of 15 years, with gradual progression to the lower limbs, is reported. Hereditary motor neuropathy was initially suspected based on distal weakness and hyporeflexia; however, whole exome sequencing accidentally revealed a compound heterozygous variant in the GNE gene, and ultrasound revealed increased homogeneous echogenicity in the involved muscles, which is characteristic of myopathic changes. Muscle magnetic resonance imaging revealed fatty infiltration in all limb muscles, sparing the triceps brachii, vastus lateralis and vastus medialis. Muscle biopsy revealed intracytoplasmic rimmed vacuole, supporting the diagnosis of GNE myopathy.

Pre-existing tumor-sensitized T cells are essential for eradication of established tumors by IL-12 and cyclophosphamide plus IL-12.

The antitumor immune response activated by IL-12, especially by a combination of cyclophosphamide and IL-12 (Cy+IL-12), is clinically significant in certain experimental tumor models, in that a number of well-established (10-20 mm in diameter) s.c. tumors are completely eradicated. Furthermore, Cy+IL-12 treatment is also able to eradicate well-established grossly detectable experimental lung metastases and advanced ascites tumors. Despite the dramatic antitumor effects seen in some tumor models, Cy+IL-12 fails to induce regression of other established tumors. Characterization of tumor immunogenicity shows that all tumors responding to IL-12 and Cy+IL-12 treatments are immunogenic tumors, in that an antitumor immune response is detectable in tumor-bearing hosts upon tumor establishment. In contrast, none of the nonimmunogenic tumor responds to IL-12 and Cy+IL-12 treatments. Analysis of cellular requirements for successful tumor rejection through an adoptive cell transfer approach reveals that the presence of tumor-sensitized, but not naive, T cells is essential for tumor rejection by IL-12 and Cy+IL-12. Transfer of these tumor-sensitized T cells must be conducted before, but not after, IL-12 treatment in order for tumor rejection to occur. The requirement of sensitized T cells is also tumor specific. In mice bearing immunogenic tumors, the presence of pre-existing tumor-sensitized T cells is demonstrated by adoptive cell transfer experiments using purified spleen T cells from these mice. Results from our study show that Cy+IL-12-based immunotherapy of cancer may be highly effective and that pre-existing tumor-sensitized T cells are essential for the success of the therapy.

Factors associated with continued participation in mammography screening.

BACKGROUND: Relatively little is known about factors that predict ongoing participation in mammography screening at regular intervals. Members of managed care plans have access to this preventive service; yet, many still do not receive it routinely. METHODS: Using administrative data from HIP Health Plan of New York, a group model HMO, 24,215 women ages 50-80 years identified as having a screening mammogram during the baseline period were followed for 2 years to determine demographic and utilization factors that might be related to having a subsequent mammogram within the recommended time interval. RESULTS: Of the 24,215 women with an index mammogram, 71.8;pc had a subsequent screening mammogram within 2 years. Women ages 65-74 years and those with Medicare coverage had the highest mammogram rates among the age and coverage categories. Number of primary care and gynecology physician visits was strongly related to having a subsequent mammogram. The average (mean) time between index and subsequent mammogram was 14.4 months. CONCLUSION: The significance of health plan visits in subsequent mammography underscores the importance of physician-patient communication in a managed care plan and the integration of health plan members into the HMO delivery system. Even in this environment with equal access for all types of coverage, Medicaid members were less likely to receive this preventive service.

A randomized intervention to improve ongoing participation in mammography.

OBJECTIVE: To test the effectiveness of interventions intended to increase rates of regular breast cancer screening, according to recommended guidelines. STUDY DESIGN: A randomized controlled trial of 2 outreach interventions (a mail reminder and a telephone reminder plus appointment scheduling) compared with a routine publicity campaign to encourage continued participation in mammography screening. PARTICIPANTS AND METHODS: Participants were 1908 women aged 50 to 75 years continuously enrolled in a large group-model HMO during the study who underwent a bilateral mammogram during the first quarter of 1994 and no subsequent mammogram during the next 18 to 21 months. Data were obtained from health plan administrative data files supplemented by medical chart review. Women were randomly assigned to receive (1) a mail reminder, (2) a telephone reminder, or (3) routine publicity on mammography for all women. The outcome measure was a mammogram received after the intervention period and within 2 years of the initial mammogram date. RESULTS: Bivariate and multivariate statistical analyses showed that participation was significantly higher for women contacted by telephone than through routine publicity. Mail reminders were no more effective than a routine publicity campaign. Primary care physician and gynecologist visits increased the likelihood of a subsequent mammogram for women in all intervention groups. CONCLUSIONS: Telephone contact by regular health plan staff was more successful than publicity in encouraging continued participation in mammography screening in women enrolled in a group-model managed health care plan. Because mailings did not influence participation in mammography screening, health plans should be cautious about investing in member mailings without first evaluating their effectiveness in the context of existing outreach efforts.

Self-reported Papanicolaou smears and hysterectomies among women in the United States.

OBJECTIVE: To evaluate the potential overuse of Papanicolaou smears among women who have had a hysterectomy. METHODS: We analyzed two surveys of US women aged 18 years or older, the Behavioral Risk Factor Surveillance System (1992-1997) and the National Health Interview Survey (1993-1994), and one survey of US hospitals (National Hospital Discharge Survey, 1980-1997). We examined the number of women who have had a hysterectomy who had a recent (within 3 years) Papanicolaou smear. We also examined trends in the proportions and rates of hysterectomies by diagnoses and type of procedure that potentially could require a Papanicolaou smear. RESULTS: From the Behavioral Risk Factor Surveillance System, an estimated 21.2% of US women have had a hysterectomy. Among women who have had a hysterectomy, 78.3% had a recent Papanicolaou smear. Among those reporting no hysterectomy, 82.1% had a recent Papanicolaou smear. Estimates from the National Health Interview Survey were similar. From the National Hospital Discharge Survey, an estimated 6.7% to 15.4% of women with a history of hysterectomy would require a subsequent Papanicolaou smear because they had a diagnosis related to cervical neoplasia or because they had undergone a supracervical hysterectomy. For an estimated 10.6-11.6 million of the 12.5 million women who had a hysterectomy and a recent Papanicolaou smear, that test could be considered unnecessary. CONCLUSION: Continued Papanicolaou screening of women without an intact uteri may result in excessive use of resources in time and money with minimal impact on decreasing cervical cancer.

Race-specific results of Papanicolaou testing and the rate of cervical neoplasia in the National Breast and Cervical Cancer Early Detection Program, 1991-1998 (United States).

OBJECTIVE: To describe differences in cervical screening and biopsy results by race or ethnicity from women in the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). METHODS: We examined the percentage of abnormalities detected by Papanicolaou (Pap) tests and the rate of biopsy-diagnosed high-grade precancerous or cancerous lesions by racial or ethnic group. RESULTS: Almost half the 628,085 women screened were members of racial or ethnic minority groups. American Indian or Alaska Native women were more likely than others to report never having had a prior Pap test. American Indian or Alaska Native women had the highest proportion of abnormal Pap tests for first program screens (4.4%), followed by blacks (3.2%), whites (3.0%), Hispanics (2.7%), and Asians or Pacific Islanders (1.9%). Whites had the highest biopsy detection rate of high-grade lesions for first program screens (9.9 per 1000 Pap tests), followed by Hispanics (7.6), blacks (7.1), American Indians or Alaska Natives (6.7), and Asians or Pacific Islanders (5.4). CONCLUSIONS: This program provides important data on the prevalence of cervical neoplasia among diverse populations. Our findings that black women with a high-grade Pap test were less likely to get a work-up are disconcerting and merit further study and ultimate correction.

Population-based estimates of the prevalence of family history of cancer among women.

OBJECTIVE: Family history of cancer is recognized as one of the most important risk factors in predicting personal cancer risk. Nevertheless, there are few published population-based estimates of family history prevalence by age categories. METHODS: We used responses of female controls (n = 4,754) from the population-based Cancer and Steroid Hormone study (1980-1982) to estimate the frequency of family history of various cancers among female relatives. We determined the age- and race-specific prevalence of family history of breast, ovarian, endometrial, and other cancers in first-degree female relatives of women aged 20-54 years. To evaluate changes in reporting family history over time, we also analyzed responses of control women (n = 1,544) from the Women's Interview Study on Health (WISH) (1990-1992) to estimate the prevalence of family history of breast cancer. RESULTS: The prevalence of a first-degree family history of breast, ovarian, endometrial, and cervical cancers was 6.4% (95% CI 5.7-7.1%), 1.1% (0.8-1.4%), 3.5% (3.0-4.0%), and 2.1% (1.7-2.5%), respectively. Among first-degree female relatives, the prevalence of family history of colon, lung, and thyroid cancers was 2.4% (2.1-2.9%), 1.5% (1.2-1.8%), and 0.5% (0.3-0.7%), respectively. The prevalence of family history of breast and colon cancers increased significantly with respondent's age. Similar results for family history of breast cancer were obtained from an analysis of responses from the WISH. CONCLUSIONS: In addition to providing a point of reference for research and health policy, these results may be of interest to providers who care for female patients because of the usefulness of information about family history of cancer for assessing lifetime risk of cancer.

Early-stage breast cancer treatment among medically underserved women diagnosed in a national screening program, 1992-1995.

BACKGROUND: Little research has been conducted on the breast cancer treatment of low income, underserved women. This study was designed to describe initial treatment of breast cancer among low-income women diagnosed through federally funded screening programs in Detroit, Michigan, and the states of New Mexico and California; and to compare the treatment received by program women with early-stage breast cancer with that of all women diagnosed in those regions. METHODS: Data from the three screening programs were linked with cancer registry data from the corresponding geographic areas. All women diagnosed between 1992 and 1995 through the state-based screening programs and all women contemporaneously diagnosed with breast cancer in the three regions were studied. Descriptive analyses were done of the proportion of women with breast cancer receiving treatment; the proportion of early-stage breast cancer (stage I or II) cases treated with breast-conserving surgery, and the proportion treated with mastectomy; and among women with breast-conserving surgery, the proportion receiving radiation therapy. Logistic regression models controlled for age and stage at diagnosis, race or ethnicity and geographic region. RESULTS: Less than 2% of program women diagnosed with breast cancer received no treatment. More than two of five women with early-stage breast cancer underwent breast-conserving surgery, with 72% of these women receiving radiation therapy. Multivariate regression analysis revealed that women with stage IIA or IIB breast cancer had lower odds of undergoing breast-conserving surgery than women with stage I (0.51 [95% CI = 0.30-0.87] and 0.36 [95% CI = 0.19-0.70], respectively). Women over age 65 and those with incompletely staged cancer had the lowest odds for receiving radiation therapy after breast-conserving surgery (0.29 [95% CI = 0.09-0.99] and 0.14 [95% CI = 0.03-0.72], respectively). Women diagnosed through the screening programs had odds of undergoing breast-conserving surgery similar to those of all women in the regions (1.11 [95% CI= 0.89-1.39]). CONCLUSIONS: Treatment patterns for women diagnosed with early-stage breast cancer through three state-based screening programs appear to have been similar to those reported in the literature. In addition, their treatment appears to have been similar to that of other women during the same time period.

Mammography and breast cancer detection by race and Hispanic ethnicity: results from a national program (United States).

OBJECTIVE: Some of the racial and ethnic variation in breast cancer incidence rates may reflect differential use of mammography. We report breast cancer rates using mammography and diagnostic data from five race/ethnicity groups. METHODS: Mammography data were analyzed for 573,751 women who received breast cancer screening between July 1991 and March 1998 from the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). Abnormal mammography rates, breast cancer detection rates, and cancer stage distribution data are presented by race/ethnicity and screening round (first or subsequent). RESULTS: For the first screening round, percentages of abnormal mammographies ranged from 7.3% among black women to 9.3% among Asian/Pacific Islander women. Cancer detection rates ranged from 4.9 cancers per 1000 mammograms for Hispanic and American Indian/Alaska Native (AI/AN) women to 7.7 per 1000 for white women. Subsequent round rates were lower but varied similarly. AI/AN women had the highest percentage (68%) of first-round cancers detected in the early stage (range for the other groups: 52-63%). CONCLUSIONS: Breast cancer detection rates for racial and ethnic groups in this program varied less than published population-based incidence rates. Differential use of mammography among these groups may account for some of the variation reported for breast cancer incidence.

Colorectal cancer screening participation by older women.

OBJECTIVE: Although recent screening guidelines recommend annual fecal occult blood testing (FOBT) for adults aged > or = 50, a number of studies report that these tests are underused. Systematic efforts to increase awareness of colorectal cancer (CRC) and to promote screening participation are needed to meet national objectives for CRC control. METHODS: This study examined CRC-screening practices and evaluated factors related to recent participation in screening by FOBT in a sample of women aged 50 to 80 who were surveyed about their use of clinical preventive services at Group Health Cooperative, a managed care organization in western Washington State. RESULTS: Of the 931 women eligible for analysis, 75% reported ever having been screened by FOBT and 48% reported having been screened within 2 years before the survey. Participation in screening did not vary by demographic characteristics or by perceived or actual risk of CRC. Women with a positive attitudes toward CRC screening had sevenfold greater odds of recent screening by FOBT (odds ratio=7.1; 95% confidence interval, 4.4 to 11.6). Only 58% of study women reported that their physicians encouraged CRC screening, but this factor was strongly related to participation (odds ratio=12.7; 95% confidence interval, 6.6 to 24.4). CONCLUSIONS: We identified several areas in which understanding of CRC risk may be low. As a whole, these findings suggest that effective strategies to control CRC may include efforts to improve knowledge of risk and prevention, but must also appeal directly to primary care physicians to identify and address their barriers to screening recommendations.

Frequency of cervical smear abnormalities within 3 years of normal cytology.

OBJECTIVE: To compare cervical screening outcomes associated with age and three screening intervals, 1, 2, and 3 years. METHODS: We did a prospective cohort study comprising 128,805 women at community-based clinics throughout the United States who were screened for cervical cancer within 3 years of normal smears through the National Breast and Cervical Cancer Early Detection Program. We determined the incidence of cytologic abnormalities defined as atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (SIL), high-grade SIL, and suggestive of squamous cell cancer. RESULTS: Over the 3 years after normal smear results, the incidence of new smears interpreted as high-grade SIL or suggestive of squamous cell cancer (high-grade SIL or worse) was 66 of 10,000 for women under 30 years old, 22 of 10, 000 for those 30-49 years, 15 of 10,000 for those 50-64 years, and 10 of 10,000 for those over 65 years. Age-adjusted incidence rates of high-grade SIL or worse were similar for women screened at 9-12 months (25 of 10,000), 13-24 months (29 of 10,000), and 25-36 months (33 of 10,000) after normal smears (P =.46). Age-adjusted incidence rates of ASCUS, the most common cytologic abnormality, did not change (P =.36). Incidence of smears interpreted as low-grade SIL increased as time from the normal smear increased (P =.01). CONCLUSIONS: Within 3 years after normal cytology results, cervical smears interpreted as high-grade SIL or worse are uncommon, and the incidence rate is unrelated to the time since last normal smear. Optimal screening strategies for women with recent normal cytology results should be based on comprehensive modeling studies that incorporate the true risks and benefits of repetitive screening.

Findings from 752,081 clinical breast examinations reported to a national screening program from 1995 through 1998.

BACKGROUND AND METHODS: Mammography programs have received extensive study, but little is known about the outcome of clinical breast examinations (CBEs) performed in community settings. Consequently, we analyzed data from the National Breast and Cervical Cancer Early Detection Program on CBEs provided to low-income women from 1995 through 1998 and determined the percentage of CBEs considered to be abnormal, suspicious for cancer; the rates of cancer detection; and the sensitivity, specificity, and positive predictive value of CBEs. RESULTS: We analyzed data from 752081 CBEs and found that 6.9% of all CBEs were coded abnormal, suspicious for cancer, and that 5.0 cancers were detected per 1000 examinations (95% confidence interval [CI] = 4.9-5.2). The values observed for sensitivity (58.8%) and specificity (93.4%) were comparable to those reported for the CBE component of clinical trials. The observed positive predictive value was 4.3%. About 74% of all records also reported mammography results. The cancer-detection rate among records reporting an abnormal CBE and normal mammography was 7.4 cancers per 1000 records (95% CI = 6. 3-8.4). When the CBE was normal but the mammography was abnormal, the rate was 42.0 cancers per 1000 records (95% CI = 39.9-44.1). When both CBE and mammography results were abnormal, the rate was 170.3 cancers per 1000 records (95% CI = 162.7-177.9). Cancer detection could not be attributed entirely to CBE or mammography on 38% of the records in the latter subset because the tests were performed on the same day. CONCLUSION: CBEs performed in community-based screening programs can detect breast cancers as effectively as CBEs performed in clinical trials and may modestly improve early-detection campaigns.

A meta-analysis of estrogen replacement therapy and risk of epithelial ovarian cancer.

Estrogen replacement therapy (ERT) has not been associated with epithelial ovarian cancer in most reported epidemiologic studies that have looked for an association. Some studies may have found weak statistically nonsignificant associations because the number of cases or number of women who reported estrogen use was small. We performed a meta-analysis of data from 15 case-control studies that provided data on ERT and risk of epithelial ovarian cancer. The 15 combined studies were statistically heterogeneous (chi(2) (14) = 26. 3, P < 0.05) in terms of the effect they found. When we combined these studies using a random effects model, we did not find a significant association of ERT with ovarian cancer (odds ratio = 1.1, 95% confidence interval = 0.9-1.3). There was no clear evidence of a dose-response relation with increasing duration of estrogen use in a subset of five studies that reported estrogen use by duration (overall slope = 0.0012, 95% confidence interval = -0.0055 to 0. 0080). The influences of statistical outliers, study design (hospital or clinic controls vs. community controls), and location (U.S. and Canada vs. Europe and Australia) were examined. The odds ratio was 1.3 (95% confidence interval = 1.0-1.6) in the relatively homogeneous subset of four U.S. case-control studies with community controls, but we cannot rule out the possibility of uncontrolled confounding. The odds ratios for estrogen use for other subgroups defined by geographic location and type of control group were not significantly different from one.

Multiple endocrine neoplasia type 2B--genetic basis and clinical expression.

Multiple endocrine neoplasia (MEN) type 2B is a heritable endocrine disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, multiple mucosal neuromas, and a marfanoid habitus. Intestinal ganglioneuromatosis, corneal nerve thickening and skeletal abnormalities are also often present. The disease is inherited in an autosomal dominant fashion and is caused by a single mutation in the RET proto-oncogene, with a methionine to threonine substitution at codon 918. The MTC in MEN 2B presents at an earlier age and tends to be more aggressive than the MTC in MEN 2A. It is multicentric and bilateral and occurs as young as age 3, with early lymph node metastases. Pheochromocytoma is also often bilateral but is rarely malignant. If pheochromocytoma is detected, adrenalectomy should precede thyroidectomy to avoid intraoperative catecholamine crisis. Patients at risk for MEN 2B should undergo genetic screening in infancy. Total thyroidectomy should be performed on all patients positive for RET mutations even prior to the onset of clinical symptoms.

Antimetastatic efficacy of adjuvant gemcitabine in a pancreatic cancer orthotopic model.

Gemcitabine is a promising new agent that has been recently studied for palliation of advanced (stage IV) unresectable pancreatic cancer. We hypothesized that adjuvant gemcitabine would reduce recurrence and metastases following surgical resection of pancreatic cancer. To test this hypothesis, we evaluated gemcitabine on a green fluorescent protein (GFP) transductant of the human pancreatic cancer cell line BxPC-3 (BxPC-3-GFP) using surgical orthotopic implantation (SOI) in nude mice. GFP enabled high resolution fluorescent visualization of primary and metastatic growth. Five weeks after SOI, the mice were randomized into three groups: Group I received exploratory laparotomy only. Group II underwent surgical resection of the pancreatic tumor without further treatment. Group III underwent tumor resection followed by adjuvant treatment with gemcitabine, 100 mg/kg every three days for a total of four doses, starting two days after resection. The mice were sacrificed at thirteen weeks following implantation and the presence and location of recurrent tumor was recorded. Gemcitabine reduced the recurrence rate to 28.6% compared to 70.6% with resection only (P = 0.02) and reduced metastatic events 58% in the adjuvant group compared to resection only. This study, demonstrating that gemcitabine is effective as adjuvant chemotherapy post-pancreatectomy, suggests this new indication of the drug clinically.

Comparison of self-reported fecal occult blood testing with automated laboratory records among older women in a health maintenance organization.

Screening guidelines for colorectal cancer recommend annual fecal occult blood (FOB) testing for adults aged 50 years and older. Self-reported history of screening is frequently the sole source of data available to researchers and clinicians. This study validated FOB testing in a sample of 1,021 older women. Testing rates based on self-reported data exceeded rates based on computerized laboratory records by 13.9%. Agreement was moderate (kappa = 0.52; 95% confidence interval 0.47, 0.58). Sensitivity was 0.92 and specificity 0.58. Logistic regression analysis showed that older age and physician encouragement for FOB testing were associated with accurate recall (p<0.05). Self-report is the most commonly available information about the occurrence and timing of cancer detection procedures. These data suggest cautious use of self-reported screening by FOB for clinical decision making and for research and surveillance.

Patterns and characteristics of repeat mammography among women 50 years and older.

Whereas efforts encouraging women to obtain initial mammograms are laudable, the importance of returning for subsequent routine mammograms cannot be minimized. The purpose of this study was to measure the timing, patterns, and characteristics of repeat screening mammography over time in a defined population of health maintenance organization members for whom mammography was a fully covered benefit. We identified all women ages 50-74 years who were enrolled in a southeastern Michigan health maintenance organization, assigned to a large medical group, and received at least one screening mammogram with a normal result between January 1, 1989 and December 31, 1996. Using administrative and radiology data, we calculated the proportion of women who received a subsequent mammogram within 2 years and the time to subsequent screening, both overall and stratified by demographic characteristics. We also examined screening patterns over a 5-year period. Of the 8749 women included in this study, 66.0% [95% confidence interval (CI), 65.0-67.0%] were subsequently screened within 2 years. We found slightly higher rates among Caucasians and married women. The proportion of women who received repeat mammography increased with estimated household income [9.5% difference between the highest and lowest categories (95% CI, 6.5-12.5%)]. The median time to subsequent screening was 17.7 months, and the probability of repeat screening was higher for women whose initial mammogram was between January 1992 and December 1994 compared to those receiving an initial mammogram between January 1989 and December 1991 (9.6% difference; 95% CI, 7.5-11.7%). Repeat mammography has improved over time; however, socioeconomic status could contribute to longer-than-intended intervals between screening when translated into real-world clinical practice. In a setting where most physicians recommended annual screening, we found that the median time to subsequent screening was delayed by 6 months. If annual mammography is the goal, recommendations should be made with the understanding of how the timing of repeat screening occurs in clinical practice.

Cervical cancer screening among low-income women: results of a national screening program, 1991-1995.

OBJECTIVE: To evaluate the results of cervical cytology screening in the National Breast and Cervical Cancer Early Detection Program and to compare the findings with results from other screening programs. METHODS: We analyzed data on 312,858 women aged 18 years and older who received one or more Papanicolaou smears, and follow-up if indicated, from October 1991 through June 1995 at screening sites across the United States providing comprehensive National Breast and Cervical Cancer Early Detection Program services. RESULTS: Of the women screened, more than half were 40 years or older; slightly less than half (44%) were of racial and ethnic minorities. During the first screening cycle, 3.8% of Papanicolaou tests were reported as abnormal (squamous intraepithelial lesion [SIL] or squamous cell cancer); proportions of abnormals decreased with increasing age. The age-adjusted rate of biopsy-confirmed cervical intraepithelial neoplasia (CIN) II or worse among women screened was 7.4 per 1000 Papanicolaou tests; rates of CIN were highest among young women, but cancer rates peaked among women in their 50s and 60s. The percentages of first screening cycle-Papanicolaou tests interpreted as high-grade SIL and squamous cell carcinoma associated with biopsy-confirmed CIN II or worse (the positive predictive value) were 56.0% for CIN II/III and 3.7% for invasive cancer. Of the 150 invasive cancers diagnosed, 54.0% were classified as local disease. CONCLUSION: Observed results emphasize the duality of cervical neoplasia-CIN in younger women and invasive cancer in older women. This finding points to the importance of reaching both younger and older women for cervical cancer screening.