Biomedical subjects
Publications and source records attributed to K S McCarty.
Sex steroid receptor analysis is an important tool in clinical oncology. Various techniques are described including labelled ligand methodology, histochemical methods, and very promising immunohistochemical techniques using antireceptor monoclonal antibody. Approaches to data acquisition and analyses for these methods are discussed.
While data concerning melanoma survival differences between the sexes as they relate to anatomic site, stage and age is scattered throughout the literature, few single studies on one large population of patients with melanoma have specifically addressed all the confounding variables proposed to account for such sex related survival differences. Data were collected for 1,489 patients with melanoma observed at Duke University Comprehensive Cancer Center. Females had a more favorable prognosis than males. This survival difference could not be fully explained by differences in the anatomic site of the primary, Clark level of invasion, histologic type or ulceration of the primary lesion or age at diagnosis between males and females. There is growing epidemiologic and biochemical evidence that melanoma may be affected by sex hormones.
Estrogen receptor (ER) analysis by sucrose density gradient analysis (SDGA) was compared with histochemical localization of estrogen binding using 6-carbomethoxy-bovine serum albumin-fluorescein isothiocyanode-estradiol (E2-6-CMO-BSA-FITC) (6FE), 17-thiosemicarbozene-BSA-FITC-estrogen (E-17-TSC-BSA-FITC) (17FE), and polyestradiol phosphate-antiestradiol antibody-FITC (PEP) on serial frozen sections of metastatic breast cancer lesions from 72 patients treated with hormonal therapy. A comparison of assays to clinical responses gave the following sensitivities: ER-SDGA, 90%; 6FE, 50%; 17FE, 55%; and PEP, 58%. Specificities were as follows: ER-SDGA, 81%; 6FE, 47%; 17FE, 41%; and PEP, 59%. The SDGA gave the highest predictive value for clinical response, while the predictive value for each of the three histologic techniques approximated that predicted by chance alone. These selected histochemical techniques for ER localization, despite impressive cytologic localization patterns, therefore, do not correlate with clinical response.
Elastosis in human breast cancer has been compared with various prognostic indicators, but few studies have compared elastosis directly with prognosis. We examined 100 primary breast cancers for estrogen receptor (ER) and progesterone receptor (PR) content, tumor grade, and extent of elastosis and compared these data with clinical follow-up in 71 patients. The ER content was greater than 10 femtomoles (fmole) per milligram of protein in 68% of tumors, while PR content was greater than 10 fmole/mg of protein in 48%. Histologic study showed that 22% of the tumors were grade 1, 28% were grade 2, and 50% were grade 3. Grade 2 or grade 3 elastosis was seen in 36% of the tumors and grade 0 or grade 1 elastosis was seen in 64%. There was a negative correlation between tumor grade and elastosis grade and a positive correlation between ER content and elastosis grade. Elastosis grade and PR content did not correlate. A significant positive correlation existed between lymph node positivity and elastosis. No significant direct relationship between elastosis and tumor recurrence could be demonstrated once lymph node status was accounted for. Tumor elastosis correlates with histologic grade, receptor content, and lymph node involvement but does not appear to be a direct marker of prognosis.
The accurate determination of sex steroid receptors at the time of mastectomy (MX) for breast carcinoma is important for the determination of subsequent therapy of patients who develop metastases in inaccessible sites. The estrogen (E) and progesterone (P) receptor (R) proteins are heat labile, and measured levels may be vulnerable to alterations once the tumor is devascularized. To evaluate potential differences in ER and PR determinations in tumor tissue acquired at biopsy as compared with tumor from the MX specimen, quantitative analyses of ER (21 patients) and PR (17 patients) were performed on dual samples acquired from the initial biopsy (BX) and the subsequent MX specimen. Receptor concentrations were determined both by sucrose density gradient analysis and titration analysis, and results were expressed as fmol/mg cytosol protein. ER values were classified as receptor-rich (greater than 10 fmol/mg), intermediate (3 to 10 fmol/mg), or receptor-poor (less than 3 fmol/mg); PR values greater than 3 fmol/mg were considered positive. ER BX values were found to be rich or intermediate in 18 patients. When compared with BX values, MX ER values were quantitatively unchanged in 11 patients, lower (MX less than BX) in four patients, and higher in three patients (MX greater than BX). In no patient was the BX ER rich or intermediate and the concomitant MX ER poor. In two patients the PR value was "positive" at BX but "negative" at MX. Accordingly, malignant tissue from a pre-MX biopsy specimen is preferred for receptor analysis although it is apparent that tumor tissue from a properly handled MX specimen is satisfactory for the determination of ER status for clinical purposes.
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A reliable method for silver staining histones in Triton-acid-urea gels was developed. Optimum staining is achieved by treating the gels either with amido black or a colorless, water-soluble analog of amido black, 2,7-naphthalenedisulfonic acid, prior to staining with ammoniacal silver. Staining of purified calf thymus histones H2A, H2B, H3, and H4 by this method is 30 times more sensitive than staining with amido black alone, allowing the detection of each histone and its modified forms down to the nanogram level. The use of 2,7-naphthalenedisulfonic acid dramatically shortens the procedure permitting histone patterns to be visualized within 5 h.
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The cytosolic estrogen receptor (CER) content of 1037 primary breast carcinomas was evaluated by sucrose density gradient analysis. Tumor specimens from premenopausal patients had significantly lower levels of CER (14.6 +/- 1.5 (mean +/- SEM) 8S binding fmole/mg protein) compared with carcinomas from postmenopausal patients (57.5 +/- 3.9 fmole/mg protein; p less than 0.001). The proportion of specimens with CER levels above threshold values of 3, 7, or 10 fmoles/mg protein were significantly higher for postmenopausal patients (72%, 63%, 59%, respectively) than for premenopausal patients (56%, 42%, 36%, p less than 0.001). When compared within half-decades, no statistically significant differences between premenopausal and postmenopausal patients were observed for mean, median, or rank sums of CER levels (p greater than 0.3). When patients were compared by half-decades, both mean and ranked sums of CER levels were significantly different (p less than 0.001). The proportion of specimens that demonstrated CER levels above a threshold value of 10 fmole/mg protein increased sequentially from a low of 13/51 (26%) for patients less than 35 years to a high of 60/81 (74%) for patients greater than 75 years.
One of the most controversial areas in the management of malignant melanoma concerns the efficacy of prophylactic lymph node dissection. During a retrospective computer-aided data review of over 3000 melanoma patients referred to the Duke University Cancer Center, 613 patients with complete staging along with surgical and pathologic data, having trunk and extremity melanoma, were identified with Breslow thickness in the range of 0.76 to 4.0 mm. One hundred eighty-seven of these clinically node-negative patients received an elective lymph node dissection (WLE/ND). The remaining patients were treated only with an initial wide local excision (WLE) at the time of diagnosis of their melanomas. There was no difference in age at diagnosis or male-female ratio between the treatment groups. A higher percentage of the WLE/ND group (36% vs. 31%) showed ulceration of their primary lesions and a greater mean tumor thickness (1.81 +/- 0.80 mm vs. 1.60 +/- 0.73 mm) than the WLE patients. Despite the force of these two adverse prognostic factors in the WLE/ND group, only ten deaths (5%) have occurred in the elective lymph node group compared to 51 (12%) in the control group. Using a multifactorial analysis to control for the prognostic contribution of the two most informative variables in stage I melanoma, Breslow thickness and ulceration, WLE/ND had an independent favorable effect on survival (p = 0.01). There was no apparent additional benefit to lymph node dissection in patients whose primary lesion measured less than 0.76 mm or greater than 4.0 mm in thickness. The surgeon may use survival estimates with and without elective node dissection based on a prognostic equation ("prognostigram") as a quantitative aid to treatment planning.
gamma-Glutamyl transpeptidase (GGT) has been identified in many tissues. The enzyme is present in normal human serum and is accepted widely as an indicator of liver disease. gamma-Glutamyl transpeptidase has been characterized as a putative hepatocellular carcinoma marker in rats and humans and a similar role is suggested in carcinomas of other tissues, including breast, colon, and ovary. Using a histochemical technique to demonstrate GGT activity, we have defined characteristic staining patterns for 67 normal or benign, and 108 overtly malignant human breast lesions. Transitions between benign, atypical, and malignant tumors were observed as were differences between intraductal and infiltrating components of a tumor. Normal breast epithelium and nondysplastic proliferative lesions were characterized by concentrated apical and luminal staining with weak cytoplasmic activity. Malignant lesions exhibited diffuse cytoplasmic staining when staining was observed.
Patients who are diagnosed initially as having metastatic melanoma with no known cutaneous, mucosal or ocular primary are a perplexing clinical problem. In the Duke University Melanoma Clinic, 124 patients have been identified as meeting the criteria of an unknown primary melanoma. This represents 4.8 per cent of the total melanoma population seen at this institution. There were 2.5 times as many males as females with an average age at diagnosis of 47.9 years. Regional lymph node disease was the most common presentation with 64 per cent of the patients falling into this category. Those patients who showed initial evidence of hematogenous spread of their melanoma had a worse prognosis than their counterparts who manifested primarily lymphatic spread. When compared with control population groups with known primary melanoma, the unknown primary group had equal survival emphasizing that surgical treatment should be similar for both groups.
A subclone of Chinese hamster ovary cells, R40F, has been selected for its unusually high resistance to lethal concentrations of Cd and Zn. Although there is a 33% loss in Cd resistance when R40F cells are cultured in the absence of exogenous metals, the Zn resistance remains unaltered. These cells are 80% tetraploid and demonstrate an increased capacity for metallothionein protein synthesis. When compared to wild type cells cultured in the absence of exogenous metals, R40F cells exposed to 200 M Cd for 48 h exhibited an approximate 200-fold increase in metallothionein-I (MT-I) protein. A 32P-labeled mouse MT-I cDNA was employed in solution hybridization studies to measure the level of MT-I mRNA in wild type and R40F cells. Cd (0.5 M) induces MT-I mRNA about 2.5- and 5-fold in wild type and resistant Chinese hamster ovary cells, respectively. When optimally induced, the resistant cells have about 80-fold more MT-I mRNA than the sensitive cells. Southern blot analysis of HincII-cleaved DNA indicates that the MT-I gene is amplified approximately 60- to 75-fold in R40F cells.
In an attempt to clarify further the relationship between ovarian function and uterine leiomyomas, we investigated the cytoplasmic estrogen and progesterone receptor content in these uterine tumors. The study population consisted of 17 women of reproductive age at various stages of ovulatory menstrual cycles. Serum samples were analyzed for estrogen and progesterone content; tissue samples from endometrium, myometrium, and leiomyomas were analyzed for cytoplasmic estrogen and progesterone receptor content. The levels of cytoplasmic estrogen and progesterone receptor in leiomyomas demonstrated the same quantitative and qualitative cyclic changes throughout the menstrual cycle apparently in response to variations in circulating estrogen and progesterone as found in endometrium and myometrium.
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In 62 patients in whom modified radical mastectomy was accompanied by immediate breast reconstruction, the operative and pathologic findings are compared to the clinical results. Immediate reconstruction following modified radical mastectomy appears to offer several advantages over delayed reconstruction. The data indicate that immediate reconstruction provides excellent technical results, is associated with less expense and morbidity as compared to delayed reconstruction, and does not adversely affect the natural course of the disease within the follow-up period studied. No adverse effect of adjuvant chemotherapy on the reconstructive effect was noted in this series of 62 patients when the initiation of adjuvant chemotherapy was timed so as to avoid difficulties with hemostasis. The technical aspects of the immediate reconstruction are described.
Metastatic adenocarcinoma in the axillary lymph nodes of a female patient often originates from a primary tumor in the ipsilateral breast. Mastectomy may be recommended if adenocarcinoma is found in the axillary nodes even when the primary tumor is not clinically detectable. In these circumstances, the recommendation for mastectomy should be based on the firm histologic diagnosis of adenocarcinoma. In the present report, five female patients are discussed who presented with axillary lymphadenopathy without clinically evident breast masses or mammographic evidence of malignancy. Axillary lymph node biopsies, performed in each patient, were inconclusive after conventional light microscopic examination. Electron microscopy established the diagnosis of adenocarcinoma. These findings were complemented by sex steroid analyses of the tumors where possible. Each patient underwent ipsilateral mastectomy, and in each specimen an occult breast carcinoma was found. The necessity of making a precise tissue diagnosis in all cases of metastatic cancer from an unknown primary is stressed, and special techniques to accomplish this must be considered preoperatively. This is particularly important in the female patient with metastatic breast carcinoma in an isolated axillary lymph node, since ipsilateral mastectomy may be curative.