In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine in adenosine deaminase-deficient patients.

The cytotoxic nucleoside 2'-deoxyadenosine is excreted in excessive amounts by individuals with genetic deficiency of adenosine deaminase, and may be in part responsible for the severe combined immune dysfunction from which they suffer. Earlier studies from this laboratory showed that 2'-deoxyadenosine causes the irreversible inactivation of the enzyme S-adenosylhomocysteine hydrolase by an active site-directed, "suicide-like" process. In this communication we have demonstrated similar inactivation of S-adenosylhomocysteine hydrolase in hemolysate and in intact erythrocytes, as well as a striking deficiency of S-adenosylhomocysteine hydrolase activity in the erythrocytes of three adenosine deaminase-deficient patients. In vivo suicide-like inactivation of S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine may contribute to the cytotoxicity of 2'-deoxyadenosine and to the immune dysfunction in adenosine deaminase deficiency.

Racial differences in breast cancer patients.

One thousand seventy-eight patients diagnosed with primary breast cancer were examined for racial differences in histopathologic and clinical parameters. There were no observed differences in tumor histopathologic type or tumor endocrine status between races. There were no differences with respect to time to breast tumor recurrence observed between black and white patients. However, differences were observed in factors that contributed to tumor stage at diagnosis and to tumor grade. Survival differences observed in univariant analysis of blacks vs. whites were explainable by the presence of more severe skin involvement, tumor grade, and tumor size at diagnosis in the black patients.

Presurgical serum immunoglobulin concentrations and the prognosis of operable breast cancer in women.

Serum concentrations of IgG, IgA, IgM, IgE, and allergen-specific IgE were measured in presurgical serum samples from 400 women admitted to a multidisciplinary study of primary breast cancer. The relationships between the serum immunoglobulins and patient survival were analyzed with the use of a Cox proportional hazards linear model. After adjustment for TNM stage, tumor histopathologic grade, and estrogen receptor (E2R) status, lower IgM concentrations were associated with longer survival. Lower IgE concentrations were also associated with longer survival, but only in patients whose tumors were E2R positive. IgG and IgA were not related to survival. Serum IgM and IgE concentrations, allergen-specific IgE scores, and the tumor E2R status were combined to construct a three-level risk classification that was more prognostic than any of the individual components. Cox model analysis demonstrated that this combination of immunologic and hormonal variables provided significant new information beyond that obtained from TNM staging and histopathologic grading of the tumors (P = .01). This new information may be useful to physicians in advising patients with primary, operable breast cancer about the relative risks and benefits of adjuvant therapy and in designing clinical trials of adjuvant therapy.

Prognostic significance of proliferation associated nucleolar antigen P120 in human breast carcinoma.

Nucleolar antigen P120 is detected in rapidly proliferating cells but not in normal resting cells or in many benign and slowly growing malignant tumors. The objective of the study was to determine whether the expression of P120 in breast cancer correlated with histopathological or biological properties associated with prognosis. In this retrospective study, 120 primary breast tumors were analyzed for P120; 114 of these tumors were also stained for the erbB-2 protein. Immunopositive staining was correlated with patient survival, nodal status, estrogen receptor levels, and number of mitoses. Sixty-nine % (83 of 120) of the tumors were positive for P120; 25% (28 of 114) stained positively for erbB-2. Of the 28 erbB-2 positive tumors 26 were also positive for the P120 protein. Forty-six % (55 of 120) of the specimens were from patients who later died from recurrent breast cancer; P120 was detected in 89% (49 of 55) of these specimens. In 52% of the survivors the P120 protein was also expressed. P120 negative tumors were highly correlative with survival (P = 0.0001); 84% (32 of 37) of patients with P120 negative tumors survived more than 7 years without evidence of recurrent disease. Multivariate analysis showed that the worst prognosis was for patients who had tumor positive nodes and expressed P120 (P = 0.0001); death occurred in 73% (30 of 41) of these patients. For the node negative patients who did not express P120, 5-year survival was 90% (19 of 21 patients); 5-year survival for the node negative patients who expressed P120 was significantly less (67%; 28 of 42 patients). Patients with P120 negative tumors had a good prognosis, irrespective of their nodal status. In this group, survival of node negative patients was 86% (18 of 21) and for those with positive nodes survival was 82% (13 of 16). A poor prognosis was found for patients with intense erbB-2 stained tumors (5 of 7 patients died). Weak staining of erbB-2 tumors (21 specimens) was not correlated with patient survival. Compared to P120 negative tumors, P120 positive tumors had greater numbers of mitoses (9.06 versus 6.65) and an almost 2-fold increase in the occurrence of positive nodes (one of every 4.67 versus one of every 8.81). The number of P120 positive tumors was greater in estrogen receptor positive tumors (75%) than in estrogen negative tumors (54%).(ABSTRACT TRUNCATED AT 250 WORDS)

Node-negative breast cancer treated by modified radical mastectomy without adjuvant therapies: variables associated with disease recurrence and survivorship.

The present study attempts to identify poor prognosis subgroups of women with node-negative breast cancer that might benefit from systemic adjuvant therapy. The cases were collected through a cooperative effort of 57 surgeons at eight hospitals in the Detroit area and coordinated by the Michigan Cancer Foundation where data collection and analyses were completed. The primary treatment of all patients was a modified radical mastectomy. Of the 1,078 cases accessioned between October 1975 and April 1983, 537 were found to have no microscopic lymph node involvement and 462 of these cases received no adjuvant antineoplastic therapy. The period of follow-up of these cases (alive, n = 358) has been 78.75 +/- 24.6 months (mean +/- SD). Overall, the cumulative 6-year recurrence rate as calculated by life table analysis was 26%, with 16.8% dying of their disease. Tumor size was an important prognostic factor; the recurrence rate was 16.2% for those with primaries measuring less than or equal to 1 cm, with only a 6.3% mortality. Patients with tumors measuring greater than 5 cm also did well: 13.7% recurrence and 13.7% mortality rates at 6 years. The premenopausal women did slightly, but not statistically significantly, better than those who were postmenopausal. The presence or absence of quantifiable estrogen receptor protein (ER) was of little predictive value as far as rates of recurrence were concerned, but patients with an ER-positive tumor survived significantly longer. In postmenopausal women, those whose tumor lacked ER (n = 112) fared poorly: 30.4% experienced a recurrence by 6 years and 28% died of their disease. Recurrence rates and death rates were also high in a small group (n = 35) of postmenopausal women with ER+ tumors exhibiting nuclear pleomorphism (nuclear grade [NG]3) (38% and 24.3%, respectively). No poor prognosis group of premenopausal women was identified.

Increased incidence of infectious diseases during prospective follow-up of human T-lymphotropic virus type II- and I-infected blood donors. Retrovirus Epidemiology Donor Study.

BACKGROUND: To determine whether human T-lymphotropic virus type II (HTLV-II) infection is associated with an increased incidence of bacterial infections, we prospectively observed cohorts of HTLV-I- and HTLV-II-infected and seronegative subjects in 5 US cities. METHODS: Of 1340 present and former blood donors examined at enrollment, 1213 (90.5%) were re-examined after approximately 2 years, including 136 HTLV-I- and 337 HTLV-II-seropositive subjects and 740 demographically stratified HTLV-seronegative subjects. All subjects were seronegative for human immunodeficiency virus. Odds ratios (ORs) for incident disease outcomes were adjusted for covariates, including age, sex, race or ethnicity, education, and, if significantly associated with the outcome, blood center, donation type, income, smoking, alcohol intake, and injected drug use. RESULTS: Compared with seronegative status, HTLV-II infection was associated with an increased incidence of bronchitis (OR, 1.81; 95% confidence interval [CI], 1.20-2.75), bladder and/or kidney infection (OR, 1.94; 95% CI, 1.26-2.98), oral herpes infection (OR, 9.54; 95% CI, 3.33-27.32), and a borderline increased incidence of pneumonia (OR, 2.09; 95% CI, 0.92-4.76); HTLV-I infection was associated with an increased incidence of bladder and/or kidney infection (OR, 2.79; 95% CI, 1.63-4.79). One incident case of HTLV-I-positive adult T-cell leukemia was observed (incidence, 348 per 100,000 HTLV-I person-years), and 1 case of HTLV-II-positive tropical spastic paraparesis-HTLV-associated myelopathy was diagnosed (incidence, 140 per 100,000 HTLV-II person-years). CONCLUSIONS: These data support an increased incidence of infectious diseases among otherwise healthy HTLV-II- and HTLV-I-infected subjects. They are also consistent with the lymphoproliferative effects of HTLV-I, and with neuropathic effects of HTLV-I and HTLV-II.

Delayed hypersensitivity skin testing to mumps and Candida albicans antigens is normal in middle-aged HTLV-I- and-II-infected U.S. cohorts.

It has been reported that human T cell lymphotropic virus (HTLV)-I-infected persons in Japan have decreased delayed hypersensitivity skin test reactivity to tuberculin purified protein derivative (PPD), but HTLV-I- or -II-infected persons do not generally develop opportunistic infections. We administered standardized intradermal testing with PPD, mumps, and Candida albicans antigens to 31 HTLV-I, 48 HTLV-II, and 143 seronegative subjects in the United States. Reactivity at 48 hr was compared among the three groups. Response rates to PPD were very low in all subjects. Fifty-five percent of seronegative subjects did not react to mumps antigen, compared with 55% of HTLV-I [adjusted odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.27-2.33] and 38% of HTLV-II (OR = 0.73, 95% CI 0.33-1.64). Fifty-one percent of seronegatives did not react to Candida albicans antigen, compared with 34% of HTLV-I (OR = 0.37, 95% CI 0.15-0.93) and 46% of HTLV-II (OR = 0.71, 95% CI 0.34-1.52). Anergy was present in 33% of seronegatives, 28% of HTLV-I (OR = 0.60, 95% CI 0.20-1.78), and 19% of HTLV-II (OR = 0.56, 95% CI 0.22-1.44). HTLV-I- and -II-infected persons appear to have intact delayed hypersensitivity skin test responses to mumps and Candida albicans antigens.

A retrospective analysis of breast cancer based on outcome differences.

We reviewed tumors from two groups of patients with breast cancer, distinguished by differences in outcome. One group (85 cases) survived more than 8.5 years without tumor recurrence; the other 85 cases had recurrent disease within 2 years. Histologic and immunocytochemical studies on all cases were performed without patient identifiers and prior to review of clinical prognostic factors. As expected, lymph node and estrogen receptor status differed substantially between the groups, but menopausal status and family history for breast cancer did not. We noted that 27% of node-negative patients died within 5 years, and nine patients with four or more tumor-containing nodes were symptom-free for over 8.5 years. Histologic grade (degree of tubule formation) and nuclear grade (including mitotic rate) differed significantly between the groups, as did vascular invasion, including both lymphatics and blood vessels. Prognostic value attached to tumor border only when fat was invaded without fibroblastic or inflammatory response (P = .012). Subgrouping cases of infiltrating ductal carcinoma (not otherwise specified) was prognostically informative in the B subgroup, 69% of whom were in the rapidly recurrent tumor group. Immunocytochemical staining for c-erbB-2 was positive in 19.3% of cases, but was equally distributed between the two outcome groups. We conclude that traditional histologic parameters are highly informative, and that c-erbB-2 studies do not increase the value of histologic diagnosis.

Predictors of recurrence and survival of patients with breast cancer.

In this study, the characteristics of 646 patient's primary breast carcinomas, including histologic grade (HG), nuclear grade (NG), mitotic grade (MG), final grade (FG), estrogen receptor (E2R) status, and patient's lymph node status (LN) at the time of surgery were correlated with recurrence-free interval and patient survival in order to determine whether any one parameter or group of parameters serve as adequate predictors of tumor behavior and, therefore, patient's prognosis. The authors' results showed that LN, tumor size, and tumor grade were themselves significant predictors of early recurrence and breast cancer death. Each unit increase in LN or MG increased the risk of death by a factor of 1.5 and 2.0, respectively. However, prediction of time to recurrence or death was considerably more accurate when those parameters were used in conjunction, rather than individually. E2R was also significant in predicting death. MG separated patients within a single LN group or E2R group into two subsets having clinically and statistically different prognoses. It was found that patients who had negative lymph nodes and whose tumors were MG1 had a better prognosis than those with MG2,3 tumors; in these latter patients recurrence and death patterns were similar to those of patients with MG1 tumors having one to three positive lymph nodes. Similarly, whereas patients with four or more positive lymph nodes had bad prognoses, those bearing MG1 tumors tended to behave more like those with MG2,3 tumors and having only one to three positive lymph nodes.

Treating patients before and after irradiation.

Patients undergoing irradiation treatment for head and neck cancer need not lose their teeth. Careful treatment planning improves patients' quality of life.

First year donation patterns predict long-term commitment for first-time donors.

BACKGROUND AND OBJECTIVES: Converting first-time donors to become regular donors continues to be a challenge facing blood centres. We examined whether first-time donors with frequent return in the first 12 months were more likely to become regular donors. SUBJECTS AND METHODS: The donation histories of 179 409 community whole-blood donors, whose first-time donation in 1991 was negative on donor screening tests, were evaluated. Donors were categorized by the number of donations made in the 12 months after (and including) their first donation. The donor return pattern in the subsequent 6 years, and its association with first-year donation frequency and demographics, was evaluated by using logistic regression analysis. A 'regular donor' was defined as one who returned to donate in at least 4 of the 6 years of follow-up. RESULTS: First-year donation frequency was significantly correlated with long-term donor return (P < 0.0001). Among those giving 1, 2, 3, 4 and > or = 5 donations in the first year, 4%, 11%, 21%, 32% and 42%, respectively, became regular donors (P < 0.0001). Similar associations between donation pattern and donor return behaviour were observed after adjusting for demographic variables (P < 0.0001). CONCLUSIONS: Strategies aimed at encouraging current donors to donate more frequently during the first year may help to establish a regular donation behaviour.

Osteoradionecrosis of the jaws.

One hundred nine cases involving patients who had received radiation therapy for head and neck cancer were reviewed. Osteoradionecrosis of the mandible developed in only three patients in this group. Postirradiation extractions were not identified as a significant risk factor for such necrosis.

Evaluation of the predictive power of progesterone receptor levels in primary breast cancer: a comparison with other criteria in 559 cases with a mean follow-up of 74.8 months. The Breast Cancer Prognostic Study Associates.

A total of 559 women with primary breast cancer treated by modified radical mastectomy were followed for a mean of 74.8 months to evaluate the relationship of sex hormone receptor content in the tumor with time to first recurrence and to death due to breast cancer. The prognostic significance of progesterone receptor (PgR) status was evaluated in terms of estrogen receptor (ER) status, age (less than or equal to 49 years, greater than or equal to 50 years), extent of lymph node involvement, tumor size, and morphologic characteristics. Overall, patients with PgR positive (greater than 9 femtomoles/10 mg wet weight tissue) tumors experienced a significantly longer period to both first recurrence and death due to breast cancer, but this advantage was restricted to those whose cancer had metastasized to their axillary lymph nodes. For women with nodal involvement, the extent of this involvement and the size of the primary lesion had the greatest predictive value followed by nuclear grade and PgR status. In these node-positive patients, PgR positivity, although strongly associated with ER positivity, had a greater predictive value than that of the estrogen receptor per se.

The prevalence of anti-latex IgE antibodies in 1000 volunteer blood donors.

BACKGROUND: Latex allergy has been recognized as a medical problem with increasing frequency since the mid 1980s. Although certain groups of individuals, such as health care workers, have been recognized as having increased risk for latex allergy, little is known about the prevalence of latex allergy in the general population. METHODS: To estimate the prevalence of latex allergy among healthy adults, we measured anti-latex IgE antibodies in residual serum samples from 1000 volunteer Red Cross blood donors. The 1000 samples were from a sample of blood units collected from workplace mobile sites throughout Southeastern Michigan. Samples collected from mobile sites operating at health care institutions were excluded to minimize sampling of health care workers. Anti-latex IgE antibodies were measured by using the AlaSTAT assay (Diagnostic Products Corp., Los Angeles, Calif.) according to the manufacturer's directions. Samples with anti-latex IgE concentrations of 0.35 IU/ml or greater were classified as positive and samples with IgE concentrations of 1.50 IU/ml or greater were classified as strongly positive. All positive samples were assayed a second time to confirm the result. All positive samples were also measured with the CAP assay (Pharmacia Diagnostics, Dublin, Ohio). RESULTS: The samples tested were from donors with a mean age of 37.8 years, and 47% were women. Sixty-four (6.4%, 95% confidence interval = 4.9-8.1%) of the samples were confirmed as repeatedly positive for anti-latex IgE, and 23 of the 64 positive samples were strongly positive (2.3% of the 1000). Sixty-one percent of the samples positive as determined by the AlaSTAT assay were also positive as determined by the CAP assay. Samples from male donors were more likely to be positive than those from female donors (8.7% vs 4.1%, p = 0.003). Prevalence of positive samples was not related to age or race. CONCLUSIONS: We conclude that the prevalence of detectable anti-latex IgE antibodies, in a large and relatively unselected adult population, is higher than previous estimates have suggested. Although the clinical significance of these observations needs further evaluation, the data suggest that latex allergy is not confined to individuals in previously recognized high-risk groups.

Bilateral breast cancer: one disease or two?

Our purpose was to determine whether bilateral breast cancer depends upon genetic predisposition to multiple tumors or, alternatively, represents two independent sporadic events. Biological concordance of hormone receptors and histopathology in bilateral tumors, family history of breast cancer, age at diagnosis, and survival were evaluated in 88 patients. The immunoreactivity of paired tumors from 51 patients to six different immunocytochemical markers was compared. Neither histologic patterns nor immunocytochemical reactions showed concordance between bilateral tumors. Absence of concordance (other than for estrogen receptors) and lack of associations with positive family history and early age of onset support an interpretation of independent tumor origins and does not suggest a major role for genetic determinants in the majority of cases of bilateral breast cancer.

Peripheral lymphocyte and eosinophil counts as indicators of prognosis in primary breast cancer.

As a part of a major study on the pathophysiologic indices for recurrence of human breast cancer, preoperative eosinophil and lymphocyte counts were determined on 419 and 581 primary breast cancer patients, respectively. Patients with lymphocyte counts less than or equal to 1500/mm3 and/or eosinophil counts of less than 55/mm3 had significantly higher risk of recurrent disease than those patients who had normal or high levels of eosinophils and/or lymphocytes. These findings may indicate that the immunologic activities of eosinophils and lymphocytes enhance the patients' ability to respond against disease.

Relationship of tumor prostaglandin levels to early recurrence in women with primary breast cancer: clinical update.

We have determined the levels of prostaglandin E (PGE) and PGF in 94 and 111 primary breast carcinoma specimens, respectively. Tumor specimens were obtained at the time of surgery for primary breast cancer from women without detectable metastatic disease (other than local lymph nodes). Prostaglandins were solvent extracted from tissue homogenates, separated into class by silicic acid chromatography and PG levels determined by radioimmunoassay. These findings were compared to clinically established prognostic indicators. All samples analyzed contained measurable amounts of both PG with a high correlation between levels of PGE and PGF. No association was seen between PG levels and either degree of lymph node involvement, or estrogen receptor. With increasing tumor grade (less differentiation, more pleomorphic nuclei, numerous mitotic figures) higher levels of both PGs were seen, but this association was not statistically significant. These women have been observed for an average of 30 months postsurgery. During that period 20% of tumors have recurred. No significant association were seen between either prostaglandin and the development of recurrent disease or death due to breast cancer. In contrast to published findings, we saw lower than average levels of both E and F in tumors metastasizing to the bone.

Seasonal variation in tumor size at diagnosis and immunologic responses in human breast cancer.

Seasonal variations were observed in tumor size and a number of immunologic responses among patients entered in the Breast Cancer Prognostic Study. A significantly larger number of cases were diagnosed with smaller tumors, less than 2 cm, during December through February. It was also noted that elevated inflammatory reactions were seen in breast tumors removed during November, December and January. Seasonal changes were also observed in the serum IgM and IgE concentrations at the time of the patient's mastectomy. Elevated fall-winter leukocyte migration inhibition response to MCF-7 extracts correlated with the same seasonal elevations observed with serum IgM response. Implications of seasonal variation as a reflection of immune events are considered.

Infectious disease markers in young blood donors. Retrovirus Epidemiology Donor Study.

BACKGROUND: To evaluate whether the active recruitment of young donors of high school and college age could affect the safety of the blood supply, prevalence and incidence rates of infectious disease markers among donors aged 17 to 18 and 19 to 22 were compared to those in donors 23 years of age and older. STUDY DESIGN AND METHODS: Over 15 percent of 4.97 million whole blood donations were collected from donors aged 17 to 18 and 19 to 22. Prevalence (per 100,000 first-time donors) and incidence (per 100,000 person-years) rates for confirmed infectious diseases were compared between age groups. RESULTS: The prevalence estimates for HIV, HCV, HTLV-I and -II, and serologic tests for syphilis (STS) were significantly lower among first-time donors aged 17 to 18 and 19 to 22 than among those 23 to 44 years of age. HBsAg prevalence was higher in the first-time donors in the younger groups than in first-time donors in the older group because of higher prevalences among Asians and blacks. The incidence rates of HIV, HCV, and HTLV were similar in the younger groups and the older group. Donors 19 to 22 years of age had a higher incidence rate of estimated HBV than did donors aged 23 to 44 and 45+ (p<0.001), but the incidence rate of STS was lower in donors aged 17 to 18 and 19 to 22 than in donors 23 to 44 and 45+ years of age (p<0.001). CONCLUSION: Aggressive recruitment of school-age donors should not result in an increased risk of transmission-transmitted infections, with the possible exception of HBV.

Evidence among blood donors for a 30-year-old epidemic of human T lymphotropic virus type II infection in the United States.

The demographic and geographic determinants of human T lymphotropic virus types I and II (HTLV-I and -II) are not well defined in the United States. Antibodies to HTLV-I and -II were measured in 1.7 million donors at five US blood centers during 1991-1995. Among those tested, 156 (9.1/10(5)) were HTLV-I seropositive and 384 (22.3/10(5)) were HTLV-II seropositive. In contrast to monotonously increasing age-specific HTLV-I seroprevalence, HTLV-II prevalence rose until age 40-49 years and declined thereafter, suggesting a birth cohort effect. HTLV-II infection was independently associated with an age of 40-49 years (odds ratio [OR], 12.4; 95% confidence interval [CI], 8.8-18.9), female sex (OR, 3.3; 95% CI, 2.6-4.1), high school or lower education (OR, 1.7; 95% CI, 1.3-2.1), hepatitis C seropositivity (OR, 25.0; 95% CI, 17.5-35.8), and first-time blood donation (OR, 3.6; 95% CI, 2.8-4.7). HTLV-II seroprevalence was highest at the two West Coast blood centers. These data are consistent with a 30-year-old epidemic of HTLV-II in the United States due to injection drug use and secondary sexual transmission and with an apparent West Coast focus.