Martin L. Lesser

Oral candidiasis in high-risk patients as the initial manifestation of the acquired immunodeficiency syndrome.

We studied the frequency with which unexplained oral candidiasis led to unequivocal acquired immunodeficiency syndrome (AIDS) in patients at risk. Twenty-two previously healthy adults with unexplained oral candidiasis, of whom the 19 tested had a reversed T4/T8 ratio and 20 had generalized lymphadenopathy, were compared with 20 similar patients with a reversed T4/T8 ratio and generalized lymphadenopathy who did not have oral candidiasis. All were intravenous-drug abusers, homosexual or bisexual men, or both. Thirteen of the 22 patients with oral candidiasis (59 per cent) acquired a major opportunistic infection or Kaposis sarcoma at a median of three months (range, 1 to 23) as compared with none of 20 patients with generalized lymphadenopathy and immunodeficiency but without candidiasis who were followed for a median of 12 months (range, 5 to 21) (P less than 0.001). AIDS developed in 12 of 15 patients with candidiasis and T4/T8 ratios less than or equal to 0.51, as compared with none of four with ratios equal to or greater than 0.60 (P less than 0.01). We conclude that in patients at high risk for AIDS, the presence of unexplained oral candidiasis predicts the development of serious opportunistic infections more than 50 per cent of the time. Whether the remainder will have AIDS is not yet known.

Prediction of early relapse in patients with operable breast cancer by detection of occult bone marrow micrometastases.

We used monoclonal antibodies to identify occult micrometastases in the bone marrow of 49 patients with operable (stage I and II) breast carcinoma. Follow-up (mean, 29 months; median, 30 months) revealed that 12 patients recurred. The presence of bone marrow micrometastases (BMM) was significantly associated with early recurrence (P less than .04). The estimated 2-year recurrence rate for patients with no BMM detected (BMM-) was 3%; in patients with BMM, the 2-year recurrence rate was 33%. When BMM and axillary lymph node (LN) status were combined, groups of patients at low risk (LN-, BMM-; 2-year recurrence rate, 0%) and high risk (LN+, BMM+; 2-year recurrence rate, 42%) for early recurrence were identified. Bone marrow tumor burden was related to early recurrence. Among patients with BMM, those who did not recur had on average fewer extrinsic cells in their marrow than those who recurred (15 v 43 cells, respectively). Multivariate analysis comparing BMM, LN+ versus LN-, and tumor size (less than or equal to 2 cm v greater than 2 cm) revealed no factor independently associated with early recurrence. Peripheral tumor burden of BMM (0 or less than 10 extrinsic cells v greater than or equal to 10 extrinsic cells) was the only independent predictor of early recurrence (P less than .003). In conjunction with conventional prognostic factors, particularly axillary LN status, evaluation for BMM might be used to stratify patients for adjuvant treatment programs. Because this pilot study involved few patients with short-term follow-up, the results should be interpreted with caution. The examination of bone marrow for micrometastases remains an experimental procedure; the clinical usefulness of the test will be established through larger studies with long-term follow-up.

BRCA-associated breast cancer in young women.

PURPOSE To delineate the clinical characteristics and outcomes of breast cancer that arises in the setting of a germline BRCA mutation and to compare BRCA-associated breast cancers (BABC) with those that arise in women without mutations. PATIENTS AND METHODS We reviewed the clinical records of 91 Ashkenazi Jewish women ascertained during studies of the genetics of early-onset breast cancer. All women underwent testing for the BRCA1 mutations 185delAG and 5382insC. After the discovery of BRCA2, 79 women were also tested for the BRCA2 mutation 6174delT. RESULTS Mutations were identified in 30 women (33%). BABC were less likely to present with stage I disease than cases in women without mutations (27% v 46%), more likely to have axillary nodal involvement (54% v46%), and more likely to have extensive axillary involvement (25% v 17%). These differences were not statistically significant. BABC were significantly more likely to be histologic grade III (100% v 59%, P=.04) and to be estrogen receptor-negative (70% v 34%, P=.04). In the entire cohort, there were no significant differences between BABC and non-BRCA-associated cancers in 5-year relapse-free survival (65% v 69%, P=not significant [NS]), 5-year event-free survival (57% v 68%, P=NS), or 5-year overall survival. However, among cases diagnosed within 2 years of study entry, there was a trend toward shorter event-free survival in BRCA heterozygotes, but not relapse-free survival. Women with germline BRCA mutations were significantly more likely to develop contralateral breast cancer at 5 years (31% v 4%, P=.0007). CONCLUSION BABC present with adverse clinical and histopathologic features when compared with cases not associated with BRCA mutations. However, the prognosis of BABC appears to be similar to that of nonassociated cancer. Further studies of incident cases are necessary to define the independent prognostic significance of germline BRCA mutations.

Lack of transmission of HTLV-III/LAV infection to household contacts of patients with AIDS or AIDS-related complex with oral candidiasis.

To determine the risk of transmission of human T-cell lymphotropic virus Type III/lymphadenopathy-associated virus (HTLV-III/LAV) to close but nonsexual contacts of patients with the acquired immunodeficiency syndrome (AIDS), we studied the nonsexual household contacts of patients with AIDS or the AIDS-related complex with oral candidiasis. Detailed interviews, physical examinations, and tests for serum antibody to HTLV-III/LAV were performed on 101 household contacts of 39 AIDS patients (68 children and 33 adults), all of whom had lived in the same household with an index patient for at least three months. These contacts had shared household items and facilities and had close personal interaction with the patient for a median of 22 months (range, 3 to 48) during the period of presumed infectivity. Only 1 of 101 household contacts--a five-year-old child--had evidence of infection with the virus, which had probably been acquired perinatally rather than through horizontal transmission. This study indicates that household contacts who are not sexual partners of, or born to, patients with AIDS are at minimal or no risk of infection with HTLV-III/LAV.

Obesity at Diagnosis of Breast Carcinoma Influences Duration of Disease-free Survival

OBJECTIVE To study disease-free survival at 10 years in relation to obesity at the time of diagnosis. DESIGN A prospective study of consecutively treated patients with primary breast cancer. SETTING Memorial Sloan-Kettering Cancer Center, New York. PATIENTS Nine hundred twenty-three women treated by mastectomy and axillary dissection. MAIN RESULTS Women who were obese (25% or more over optimal weight for height) at the time of primary breast cancer treatment were at significantly greater risk for recurrence (42%) compared with nonobese patients (32%) 10 years after diagnosis (P less than 0.01). In multivariate analyses, obesity remained a statistically significant prognostic factor after controlling for measured tumor size, number of positive axillary lymph nodes, age at diagnosis, and adjuvant chemotherapy with a hazard ratio of 1.29 (95% CI, 1.0 to 1.67). When analyses were restricted to the 557 patients free of lymph node metastases, the hazard ratio of recurrence associated with obesity was 1.59 (CI, 1.06 to 2.39); 32% of obese patients developed recurrent disease compared with 19% of nonobese women. CONCLUSIONS Obesity at the time of diagnosis is a significant prognostic factor that may limit the reduction in breast cancer mortality attainable through detection at an early stage of disease. Because obesity and the risk for breast cancer increase with age, interventions that encourage weight control may influence breast cancer survival rates.

A randomized trial of ascorbic acid in polyposis coli

The possibility of pharmacological control of large bowel adenomas has been suggested by effectiveness of antioxidants in experimental tumor models and by the results of a limited clinical study using ascorbic acid. Over a two year period we tested this hypothesis in a randomized, double‐blind study of 49 patients with polyposis coli. Of 36 patients who were evaluable at completion, 19 had received ascorbic acid, 3g/day, and 17 had received a placebo. We found a reduction in polyp area in the ascorbic acid‐treated group at nine months of follow‐up (P < 0.03) and trends toward reduction in both number and area of rectal polyps during the middle of the trial. A labeling study of rectal epithelium with tritiated thymidine also hinted at a treatment effect. Our data suggest that ascorbic acid temporarily influenced polyp growth or turnover. Although these results have no current therapeutic value, our findings support continued studies of chemoprevention in this and other high risk settings.

Discontinuous or "skip" metastases in breast carcinoma. Analysis of 1228 axillary dissections.

Patterns of axillary lymph node metastases were analyzed in 1228 recently performed modified, radical, and extended radical mastectomies. In these specimens the position or level of lymph nodes was designated intraoperatively by the surgeon. No lymph node metastases were found in 720 (58) of the specimens while the remainder (508 or 41%) had at least one affected lymph node. The distribution of involvement by level showed progressive spread from level I to III as the number of positive lymph nodes increased. Discontinuous or “skip” metastases not following this pattern occurred in 1.6% of all cases and 3% of those with lymph node metastases (95% confidence interval, 1–5%). Half of those with “skip” metastases had tumor limited to level II. The presence of “skip” metastases was not related to the size, location in the breast, or histologic type of the primary tumor. It is apparent that the potential risk from “skip” metastases is not great and that this should not be a major consideration in therapeutic decisions. The risk is likely to be negligible for women treated by axillary dissections that include level II.

p53 in node-negative breast carcinoma: an immunohistochemical study of epidemiologic risk factors, histologic features, and prognosis.

PURPOSE The present study explores p53 in relation to the following four aspects of node-negative breast carcinoma: epidemiologic risk factors, tumor histopathology, prognosis, and HER2/neu (HER) expression. MATERIALS AND METHODS Immunohistochemical (IH) staining for p53 was performed on formaldehyde-fixed, paraffin-embedded primary invasive carcinomas from 440 node-negative patients with a median follow-up duration of 119 months. RESULTS The IH expression, or lack thereof, of p53 separately or in combination with HER did not prove to be prognostically significant and there was no consistent association of p53 with epidemiologic risk factors. p53 was expressed in 68% of medullary carcinomas (MEDs), which is a significantly higher frequency (P < .001) than in lobular (9%) and duct (23%) carcinomas. p53 was not found in some types of low-grade carcinomas (tubular and papillary), and was observed in a minority of mucinous carcinomas. p53 was present significantly more often in carcinomas with high-grade or poorly differentiated nuclear grade than in low- or intermediate-grade tumors. There was an inverse statistically significant relationship between estrogen receptor (ER) positivity and p53 expression. Tumors with the p53(+)/HER(-) immunophenotype tended to be MEDs or duct carcinomas with a marked lymphoplasmacytic reaction. Infiltrating lobular carcinomas (IFLCs) were largely p53(-)/HER(-). p53(+)/HER(+) carcinomas had the best prognosis. The poorest outcome was associated with the p53(-)/HER(+) immunophenotype. This trend was statistically significant for recurrence-free and overall survival in patients with T1NOMO infiltrating duct carcinoma (IFDC). CONCLUSION The IH demonstration of p53 was not a reliable prognostic indicator in the node-negative breast carcinoma patients studied and it was not associated with major epidemiologic risk factors. The combined immunophenotypic expression of p53 and HER was significantly associated with some histologic types of breast carcinoma and with prognosis in T1NOMO breast carcinoma.

Breast self-examination and medical examination related to breast cancer stage.

The frequency and type of breast examinations reported by 1,216 primary breast cancer patients was studied in relation to local stage of disease. No significant relationship was found between the reported frequency of breast self-examination (BSE) and stage of disease; however, annual medical examination was significantly associated with small tumor size (P less than .04) and absence of axillary lymph node metastases (P less than .001). Regardless of the frequency of any method of examination, the majority (80 per cent) of tumors were first detected by the patients. Among those who detected their lesion, a greater frequency of medical examination was associated with an earlier pathological stage of disease (P less than .001). Patients who were examined more frequently by a physician appeared to be more sensitive to clinically significant breast abnormalities. These findings underscore the importance of examiner skill in the successful use of palpation to detect breast cancer. Instruction in BSE by a health professional during periodic examinations may provide the optimal opportunity for improved proficiency in self-examination.

Timing of breast cancer excision during the menstrual cycle influences duration of disease-free survival.

OBJECTIVE To study disease-free survival at 10 years in relation to timing of breast tumor excision during the menstrual cycle. DESIGN A prospective study of consecutively treated patients with primary breast cancer. SETTING Memorial Sloan-Kettering Cancer Center, New York. PATIENTS Two hundred and eighty-three premenopausal patients treated by mastectomy and axillary dissection. MAIN RESULTS When the tumor was excised during the follicular phase, approximated by setting the putative day of ovulation on day 14 after the onset of last menses, a higher recurrence risk (43%) was observed compared with excision later in the menstrual cycle (29%, P = 0.02). The rate peaked among patients treated between days 7 and 14 and was lowest between days 20 and 30. Multivariate analysis using the Cox regression model to control for tumor size, nodal status, estrogen receptor status, adjuvant chemotherapy, and family history indicated that the hazard rate of breast cancer recurrence after excision during the follicular phase was 1.53 (95% Cl, 1.02 to 2.29). Stratification by nodal status indicated that the effect of phase was statistically significant only among patients with positive nodes (hazard ratio, 2.10; Cl, 1.19 to 3.70). CONCLUSIONS Our results support the hypothesis that the risk for recurrence may be affected by the hormonal milieu of the menstrual cycle; these findings must be confirmed, however, by a prospective study in which cycle phase at time of tumor excision is biochemically documented.