Legumain is an independent predictor for invasive recurrence in breast ductal carcinoma in situ.

Legumain is a proteolytic enzyme that plays a role in the regulation of cell proliferation in invasive breast cancer. Studies evaluating its role in ductal carcinoma in situ (DCIS) are lacking. Here, we aimed to characterize legumain protein expression in DCIS and evaluate its prognostic significance. Legumain was assessed immunohistochemically in a tissue microarray of a well-characterized cohort of DCIS (n = 776 pure DCIS and n = 239 DCIS associated with invasive breast cancer (DCIS-mixed)). Legumain immunoreactivity was scored in tumor cells and surrounding stroma and related to clinicopathological parameters and patient outcome. High legumain expression was observed in 23% of pure DCIS and was associated with features of high-risk DCIS including higher nuclear grade, comedo necrosis, hormone receptor negativity, HER2 positivity, and higher proliferation index. Legumain expression was higher in DCIS associated with invasive breast cancer than in pure DCIS (p < 0.0001). In the DCIS-mixed cohort, the invasive component showed higher legumain expression than the DCIS component (p < 0.0001). Legumain was an independent predictor of shorter local recurrencefree interval for all recurrences (p = 0.0003) and for invasive recurrences (p = 0.002). When incorporated with other risk factors, legumain provided better patient risk stratification. High legumain expression is associated with poor prognosis in DCIS and could be a potential marker to predict DCIS progression to invasive disease.

Oncogenic suppression of apoptosis uncovers a Rac1/JNK proliferation pathway activated by loss of Par3.

Disruption of epithelial organization and loss of growth control are universal features of carcinomas, yet how these features are linked during cancer progression remains poorly understood. Cell polarity proteins control cellular and tissue organization and are emerging as important mediators of cancer progression. The Par3 polarity protein is a molecular scaffold that functions to recruit and spatially organize signaling factors, and was recently identified as a suppressor of breast cancer invasion and metastasis. Here, we show that loss of Par3 in mammary epithelial cells promotes apoptosis, and that oncogenic Notch overcomes the apoptotic signal to reveal an unexpected pro-proliferative role for loss of Par3 in mammary tumors. In this context, loss of Par3 deregulates Rac1 activity to activate Jun N-terminal Kinase-dependent proliferation and tumor growth. Thus, we demonstrate a mechanism by which loss of Par3 promotes proliferation and tumorigenesis, which supports a tumor-suppressive function for Par3 in the mammary epithelium.

Rewiring cell polarity signaling in cancer.

Disrupted cell polarity is a feature of epithelial cancers. The Crumbs, Par and Scribble polarity complexes function to specify and maintain apical and basolateral membrane domains, which are essential to organize intracellular signaling pathways that maintain epithelial homeostasis. Disruption of apical-basal polarity proteins facilitates rewiring of oncogene and tumor suppressor signaling pathways to deregulate proliferation, apoptosis, invasion and metastasis. Moreover, apical-basal polarity integrates intracellular signaling with the microenvironment by regulating metabolic signaling, extracellular matrix remodeling and tissue level organization. In this review, we discuss recent advances in our understanding of how polarity proteins regulate diverse signaling pathways throughout cancer progression from initiation to metastasis.

Isolation and characterization of mutants defective in seed coat mucilage secretory cell development in Arabidopsis.

In Arabidopsis, fertilization induces the epidermal cells of the outer ovule integument to differentiate into a specialized seed coat cell type producing extracellular pectinaceous mucilage and a volcano-shaped secondary cell wall. Differentiation involves a regulated series of cytological events including growth, cytoplasmic rearrangement, mucilage synthesis, and secondary cell wall production. We have tested the potential of Arabidopsis seed coat epidermal cells as a model system for the genetic analysis of these processes. A screen for mutants defective in seed mucilage identified five novel genes (MUCILAGE-MODIFIED [MUM]1-5). The seed coat development of these mutants, and that of three previously identified ones (TRANSPARENT TESTA GLABRA1, GLABRA2, and APETALA2) were characterized. Our results show that the genes identified define several events in seed coat differentiation. Although APETALA2 is needed for differentiation of both outer layers of the seed coat, TRANSPARENT TESTA GLABRA1, GLABRA2, and MUM4 are required for complete mucilage synthesis and cytoplasmic rearrangement. MUM3 and MUM5 may be involved in the regulation of mucilage composition, whereas MUM1 and MUM2 appear to play novel roles in post-synthesis cell wall modifications necessary for mucilage extrusion.

Cause-specific mortality coding. methods in the collaborative ocular melanoma study coms report no. 14.

Ascertainment of cause of death is often sought in clinical trials in which mortality is an outcome of interest. Standardized methods of coding all-cause and disease-specific mortality were developed and evaluated in the Collaborative Ocular Melanoma Study randomized trial of pre-enucleation radiation of large choroidal melanoma. All available clinical and pathologic materials documenting events prior to each reported death were reviewed systematically by a Mortality Coding Committee (MCC) to determine whether melanoma metastasis or local recurrence was present at the time of death. A level of certainty was assigned based on availability of local or central review of pathology materials. The outcome of the mortality coding protocol was evaluated both by assessing agreement between the judgment of the MCC and the presumed cause of death reported by the clinical center and, for a subset of patients, by assessing agreement between the MCC classification and the cause of death reported on the death certificate. As of July 31, 1997 (the cutoff date for the initial mortality report), 435 (95%) of 457 deceased patient files had been reviewed. The MCC classified 269 patients (62%) as dead with melanoma metastasis, 22 (5%) as dead with another malignant tumor, and 92 (21%) as dead with a malignant tumor of uncertain origin. Thirty-eight patients (9%) died with no evidence of malignancy; in 14 cases (3%), the presence or absence of malignancy could not be established due to lack of clinical information. Fair agreement (kappa = 0.34) was observed between the determinations of the MCC based on detailed review of materials and the cause of death reported on the death certificate, but death certificates alone underestimated the proportion of deaths due to metastatic choroidal melanoma. Detailed mortality coding identified difficulties associated with accurate reporting of cause-specific mortality in patients with choroidal melanoma.

Quality of life in patients with choroidal melanoma: a pilot study.

PURPOSE: To assess the internal consistency of a short, widely-used health-related quality of life instrument in patients with choroidal melanoma, its appropriateness for use in a large clinical trial in patients with that disease, and the feasibility of various methods of instrument administration. METHODS: The SF-36 was administered to 31 choroidal melanoma patients identified from two ocular oncology practices. Fifteen patients were interviewed by telephone, 4 were interviewed in person at the clinic, and 12 patients completed the instrument themselves while at the clinic. RESULTS: Twenty-three patients had already been treated for choroidal melanoma; 20 patients were treated with some form of radiation. The remaining 8 patients had not yet been treated. Metastasis had not been diagnosed in any of the patients. Patient age ranged from 37 to 85 years with a median of 59 years; 55% of the patients were female. The in-person and telephone interviews performed better than self-administered interviews in terms of missing items due to non-response (0% vs. 3.2%). The overall SF-36 health profile for the choroidal melanoma patients was similar in shape to that expected for a general U.S. population sample with the same age and gender distribution, although the choroidal melanoma patients averaged 4 to 11 points higher, indicating better health-related quality of life, for all scales except the role functioning-emotional scale. CONCLUSIONS: The results supported the internal consistency of the SF-36 in this population. Interviewer administration of the SF-36 either in-person or by telephone was acceptable to the patients and provided more complete data.

A case-control and family study of Waldenstrom's macroglobulinemia.

Waldenstrom's macroglobulinemia (WM) is a rare disorder of lymphoid and plasma cells characterized by an immunoglobulin M (IgM) monoclonal gammopathy, clinical and immunopathologic similarities with other lymphoproliferative neoplasms, but the etiology of which is unknown. We undertook the first case-control study of this disorder among 65 cases, comprising 87% of all WM patients diagnosed during 1969-1983 in the greater Baltimore, Maryland area. Compared with 213 hospital controls without cancer, cases were slightly better educated, but there were otherwise no differences in sociodemographic factors, history of prior medical conditions, medication use, cigarette smoking, alcohol consumption, specific occupational exposures, employment in any particular industries or occupations, or familial cancer history. Cases were more likely than controls to have first-degree relatives with a history of pneumonia, diphtheria, rheumatic fever, and diabetes mellitus. An exploratory evaluation of immunologic profiles of first-degree relatives of 48% of families of cases revealed that relatives of two cases had asymptomatic IgM (> 750 mg/dl) monoclonal gammopathy and close to 40% of the 109 evaluated had diverse immunologic abnormalities. Larger population-based case-control studies are needed to further evaluate the suggestive evidence of immune dysfunction among families of WM cases.

Altering residency curriculum in response to a changing practice environment: use of the Mayo internal medicine residency alumni survey.

To elicit the opinions of practicing internists who had graduated from a single internal medicine residency program about the adequacy of their training and its relevance to their medical practice, we mailed a survey to 1,342 physicians who had spent at least 1 year in the Mayo internal medicine residency training program. Of this group, 703 alumni (52%) responded to the survey, 532 of whom were currently practicing internal medicine. Our detailed analysis was based on responses from these 532 and, for some aspects of evaluation, on the 121 general internists who had completed residency training after 1970. Of the respondents, 42% spent more than 80% of their time in general medicine, and 53% had at least some subspecialty practice; 55% were involved in teaching, 20% in some research, and 37% in various administrative duties. In 27%, all patient-care activities involved primary care, an increase from 18% in a 1979 survey and 9% in 1972. Of those who were subspecialists, 67% spent more than half their time in subspecialty practice. Of those who were trained after 1970, 90% were board certified. Most respondents thought that their training in the internal medicine subspecialties was adequate, that additional procedure training was needed in joint aspiration, line placement, and flexible sigmoidoscopy, and that many allied medical areas were important to their practice and necessitated additional training. Although virtually all respondents assessed their inpatient training as adequate, only 42% were fully satisfied with their outpatient training. Alumni surveys can be useful in restructuring a residency program to meet the needs of the trainees.

Familial cancer history and chronic lymphocytic leukemia. A case-control study.

In a population-based case-control study carried out in the Baltimore, Maryland metropolitan area, family cancer history for 342 chronic lymphocytic leukemia cases diagnosed in 1969-1982 revealed significantly higher risks of leukemia as well as other hematolymphoproliferative neoplasms and breast cancer among their first-degree relatives compared with reported occurrence of these neoplasms in first-degree relatives of 342 matched cancer controls and 342 matched controls without cancer. Siblings of case subjects also had a significant elevation of kidney cancer compared with siblings of controls. Only one of the affected case families (and no control family) included more than one additional member with leukemia. The results suggest a genetic component for leukemia occurrence in several case families, although the majority of cases of chronic lymphocytic leukemia appeared to be sporadic. The similarity of findings between the two comparisons (cases vs. cancer controls and cases vs. controls without cancer) diminishes the likelihood of recall bias as an explanation for the observed excess risks.

A comparison of interview data and medical records for previous medical conditions and surgery.

Although interview information is usually the sole source of data in case-control studies, the accuracy of such data is infrequently assessed. We compared interview data on selected medical conditions and surgical procedures with medical records of subjects with chronic lymphocytic leukemia. We examined agreement by type of respondent (self or surrogate), age, sex, race, and type of hospital. The strength of agreement between the two data sources (as measured by kappa statistics) was substantial kappa greater than 0.6) for splenectomy, appendectomy, asthma, and systemic lupus erythematosus; moderate kappa greater than 0.4) for tonsillectomy/adenoidectomy, tuberculosis, diverticulitis, hepatitis, rheumatic fever, and drug allergy; and poor kappa less than 0.3) for chronic bronchitis, chronic sinusitis, psoriasis, rheumatoid arthritis, and most other types of allergy. In general, self respondents had more accurate recall than surrogate respondents. Among self respondents the strength of agreement tended to be greater for males than females, for whites than blacks, and for subjects from referral hospitals than for community hospitals. No consistent patterns were apparent by age. Despite a number of limitations, the findings of the study provide an addition to the scant epidemiologic literature on this topic, and suggest that for certain conditions medical record data collection may be needed to supplement interview information.

HLA antigens in chronic lymphocytic leukemia.

HLA-A, B, and C phenotypes of 88 white and 14 black patients with chronic lymphocytic leukemia (CLL) were compared with those of 3761 white and 660 black laboratory population controls, and HLA-DR phenotypes were compared with 742 white and 236 black controls from the same population. Several statistically significant associations were found, one of which (a strongly positive association with Cw6 for whites) persisted after correction for the number of antigens tested.

Serum protein electrophoresis patterns in chronic lymphocytic leukemia. Clinical and epidemiologic correlations.

Serum protein electrophoresis (SPEP) data obtained at diagnosis were available for 98 of 342 patients with chronic lymphocytic leukemia (CLL) identified in a population-based case-control epidemiologic study. Patients tested with SPEP at diagnosis were significantly younger, more likely to have lymphadenopathy, and more likely to have had their conditions diagnosed at a university hospital than those not tested. Four categories of electrophoretic patterns were identified: normal (N = 56), hypogammaglobulinemia (N = 28), hypergammaglobulinemia (N = 11), and monoclonal gammopathy (N = 3). A higher proportion of those with hypergammaglobulinemia were black, and patients with hypergammaglobulinemia and monoclonal gammopathy were more likely to die within the first year following diagnosis than patients in the other SPEP groups. No association was found, however, between SPEP pattern and a clinical staging classification for CLL. These findings suggest that SPEP may be a useful adjunct in categorizing possible subtypes of CLL and developing future clinical staging classifications.

Comparison of methods for determining occupational exposure in a case-control interview study of chronic lymphocytic leukemia.

A comparison was made between two indirect methods for linking reported lifetime occupations and industries of employment with specific exposures and with directly reported exposure information, using data from a population-based case-control interview study of chronic lymphocytic leukemia (CLL). Exposures previously suspected of being associated with CLL were examined using a job-exposure matrix developed by Hoar et al and a linkage between observed occupational exposures and specific occupations, by industry, based on data collected in the National Occupational Hazard Survey (NOHS). In general, concordance on exposure for the two occupation-exposure linkage methods was fairly poor, although it was better for some of the exposures studied (butadiene and asbestos, for which most kappas were between 0.40 and 0.60) than for others (carbon tetrachloride and benzene with kappas ranging from 0.01 to 0.12). Higher proportions of cases and controls directly reported exposure to benzene and asbestos than was determined using the two more indirect methods, neither of which showed consistently greater agreement with direct reporting.

Chronic lymphocytic leukemia and acquired disorders affecting the immune system: a case-control study.

The relationship of a number of subacute or chronic infectious diseases, connective tissue or autoimmune disorders, allergic conditions, and surgical excision of lymphoid tissue with chronic lymphocytic leukemia (CLL) was examined in a case-control study involving 342 cases and 342 matched controls. In both analyses of all matched pairs and those pairs in which both subjects were respondents, no statistically significant association was found between a history of subacute viral infections or subacute and chronic bacterial infections and CLL. Connective tissue or autoimmune disorders also were found not to be associated with CLL. Examination of the association between several allergic conditions and CLL suggested a protective effect as did a "dose-response" analysis, although none of the individual disorders showed a statistically significant relationship; however, a test for linear trend was significant (P = .04). Similarly, examination of the relationship between surgical excision of lymphoid tissue in several anatomic locations and CLL showed a protective effect, statistically significant for tonsillectomy-adenoidectomy (odds ratio = 0.69; 95% confidence interval = 0.48, 0.98). A statistically significant negative dose-response relationship, substantiating the protectiveness of the effect, was found.

Incidence of aplastic anemia in a three county area in South Carolina.

An apparent cluster of four aplastic anemia (AA) cases in teenagers residing in a small South Carolina town was further investigated. Incidence of AA in all age groups in a surrounding three county area (TCA) over a 12-year time interval was determined and compared with AA incidence rates in Baltimore, representing the only known population based United States incidence data. The same general age-specific incidence pattern (based on 27 cases in the TCA and 118 in Baltimore) was found in the two areas, both overall and for the four race-sex groups. Although based on small numbers, nonwhite average annual age-adjusted rates for males and females were higher in the TCA (6.8 and 13.7 per million) than in Baltimore (4.7 and 7.3). For whites, TCA rates were 11.7 and 5.4 (for males and females) and Baltimore rates were 7.1 and 5.4. The differences for non-whites in the two areas may indicate a greater prevalence of risk factors for AA in the TCA than in Baltimore, but the small numbers of cases and the lack of comparable data from other areas of the country, together with the possibility of misdiagnosis of the disease, make definitive conclusions impossible.

An apparent cluster of aplastic anemia in a small population of teenagers.

Four teenagers with severe aplastic anemia, initially diagnosed and evaluated over a seven-year period at The Johns Hopkins Bone Marrow Transplant Unit, Baltimore, were residents of the same small town in South Carolina. Estimated annual incidence for that age group in the town, based on the four cases, was 100 times the expected rate. All four of the teenagers had attended one of two junior high schools. An exploratory survey of all high-school students, comparing risk factors of those who had attended the "affected" junior high school with those who had attended the "unaffected" junior high school, showed no associations with exposure to glue, paint or varnishes, pesticides, history of hepatitis or infectious mononucleosis, or use of chloramphenicol or other suspected drugs. Weak associations were found between the affected junior high school and employment in the textile industry and in agriculture (specifically peach orchards).

Inhibition of Clostridium botulinum in Comminuted Bacon by Short-Chain Alkynoic and Alkenoic Acids and Esters.

Several short-chain alkynoic and aikenoic acids and esters were screened for inhibition of gas production by Clostridium botulinum in cans of comminuted, nitrite-free, temperature-abused bacon. The most active compounds were propiolic (2-propynoic) acid, methyl and ethyl propiolate, 2-propenoic acid, methyl and ethyl propenoate, and mono- and dimethyl and ethyl fumarate. Maleic acid, methylmaleic acid, ethyl maleate, 2-methyl propenoic acid, trans-2-methyl crotonic acid, 3-methyl-2-butenoic acid, 3-methylallyl alcohol, vinyl crotonate, methylmalonic acid, dimethyl glutarate, 2,4-hexadien-1-ol, cis-3-hexenoic acid, 4-pentenoic acid, trans-2-pentenoic acid and ethylidene acetic acid were less active. A more comprehensive study on the inhibition of toxin formation by C. botulinum in comminuted nitrite-free bacon was done by comparing equimolar quantities of some of these compounds with NaNO2 at 120 µg/g and sorbic acid at 9 and 18 mM (0.10 and 0.20%). These studies showed that propiolic acid was more effective than either nitrite or sorbic acid. Compounds in this study less active than nitrite or sorbic acid were 3-methylallyl alcohol, 2,4-hexadien-1-ol, dimethyl glutarate and methylmaleic acid.

Acute cystitis: a prospective study of laboratory tests and duration of therapy.

The efficacy of single-dose therapy with trimethoprim-sulfamethoxazole (TMP-SMZ) and the cost-effectiveness of routine urinalyses and cultures were studied in a prospective randomized trial of 200 women who presented with symptoms of acute lower urinary tract infection. Without the physician's knowledge of the results of urinalysis or culture, the patients were randomly assigned to receive either a single dose or a 10-day multiple-dose course of TMP-SMZ and were followed up for 6 months. Of the 136 patients with positive urine cultures, 68 received single-dose therapy with TMP-SMZ--10 of whom had relapses--and 68 received multiple-dose therapy with TMP-SMZ--only 2 of whom had relapses (P less than 0.02). Fifteen patients in each treatment group experienced reinfection. Side effects of rash and vaginitis were more common in patients who received multiple-dose therapy, but they were mild and well tolerated. Of the 51 patients with urethral syndrome, 48 became asymptomatic after therapy. None of the following tests predicted treatment outcome: pretreatment urinalysis, urine culture or susceptibility testing, antibody-coated bacteria testing, or routine follow-up urinalyses or urine cultures. Empiric therapy with TMP-SMZ in selected women with symptoms of acute uncomplicated urinary tract infection seems practical, safe, and cost-efficient. Considerable savings can be achieved by reserving urinalyses and urine cultures for patients with persistent or recurrent symptoms. Higher cure rates can be expected in patients who receive a standard 10-day course of therapy with TMP-SMZ compared with those who receive single-dose therapy with TMP-SMZ.

The relationship of genital tract actinomycetes and the development of pelvic inflammatory disease.

As a corollary to a case-control study evaluating the risk of pelvic inflammatory disease (PID) among users of an intrauterine contraceptive device (IUD), Papanicolaou smears were studied to detect the presence of actinomycetes. Forty-six PID case patients and 108 control patients were included in the corollary study. The presence of actinomycetes was noted only among current or past wearers of an IUD. Women with actinomycetes present on Papanicolaou smear had a 3.6-fold risk of hospitalization for PID, as compared to women without actinomycetes. This trend persisted when only IUD users were evaluated. Of patients with PID who had actinomycetes noted on the Papanicolaou smear, 87 1/2% had a tuboovarian abscess, compared to 28.9% of patients without actinomycetes. In addition, patients with actinomycetes present had PID treated surgically more frequently.

Head and neck manifestations of relapsing polychondritis: review of 29 cases.

This review of 29 patients with relapsing polychondritis seen at the Mayo Clinic between 1962 and 1976 emphasizes the head and neck manifestations of the disease and the role of the otolaryngologist in its diagnosis and treatment. The major clinical features included inflammation of the pinna, eye involvement, nasal cartilage involvement, laryngotracheal involvement, arthropathy, hearing loss, costal chondritis, and fever. The erythrocyte sedimentation rate was often elevated, and mild anemia was not uncommon.