Preliminary report on 10 patients treated with radiotherapy after radical prostatectomy for isolated elevation of serum PSA levels.

Since 1987, 10 patients have been treated with irradiation to a limited pelvic volume for elevation of serum prostate-specific antigen (PSA) level above expected post-radical prostatectomy levels without clinical or radiological evidence of either metastatic or locoregional disease. The patients were treated 3 to 43 months after radical prostatectomy, using bilateral 120 degrees arcs to deliver 6000 cGy to the prostatic bed. The pathologic findings of the initial surgical specimens for all patients were reviewed. Eight patients had pathologic Stage C disease, and five patients had one or more positive margins. All patients had negative staging lymphadenectomies. After irradiation, eight patients had decreases in PSA levels indicative of response of isolated local disease. Through preliminary, these results suggest that post-prostatectomy PSA levels are useful for detecting subclinical local recurrence or persistence in the prostatic bed, as well as monitoring these patients' response to therapy. The value of this elective treatment remains to be documented.

Procoagulant activity of endocardial vegetations and blood monocytes in rabbits with Streptococcus sanguis endocarditis.

To investigate activation of the coagulation system in bacterial endocarditis, we determined the procoagulant activity of blood monocytes isolated from rabbits with Streptococcus sanguis-infected or sterile catheter-induced endocardial vegetations. This activity was determined directly after isolation from the peripheral blood and after stimulation in vitro by either endotoxin or by phagocytosis of S. sanguis. The procoagulant activity of the vegetations of these rabbits was also determined. The procoagulant activity of blood monocytes of rabbits with S. sanguis endocarditis was found to be similar to the activity of monocytes of rabbits with sterile vegetations, both at the time of isolation and after stimulation in vitro by exposure to endotoxin or phagocytosis of bacteria. The procoagulant activity of infected vegetations was significantly higher than that of sterile vegetations. We conclude that in bacterial endocarditis the coagulation system is activated locally at the site of the vegetation. Triggering probably occurs by thromboplastin generated by monocytes activated by phagocytosis of bacteria on the vegetational surface.

Presence of human papilloma viral antigens in juvenile multiple laryngeal papilloma.

Juvenile laryngeal papillomas, solitary laryngeal papillomas of the adult, and cylindric cell papillomas of the nose and sinuses were examined for the presence of papillomavirus antigens by means of immunocytochemistry. By using an antiserum capable of recognizing a common group antigen that reacts with papillomavirus antigens of different species, it was found that half of the juvenile laryngeal papillomas studied contained cells staining for papillomavirus antigens. No positive cells were found in adult solitary papillomas or cylindric cell papillomas. These results strongly implicate a human papillomavirus as the causative agent of juvenile multiple laryngeal papillomas.

Hemilaryngectomy for T3 (fixed cord) epidermoid carcinoma of larynx.

This clinicopathologic study was undertaken to determine whether true vocal cord fixation produced by epidermoid carcinoma is an absolute contra-indication to treatment by hemilaryngectomy. In a consecutive series of 114 hemilaryngectomies performed at McMillan Hospital (1960-1967) for previously untreated epidermoid carcinoma, 18 patients had fixation of the involved true vocal cord. Each hemilaryngectomy specimen (serial step sections in the longitudinal plane) was re-examined to ascertain the cause of vocal cord fixation; the adequacy of margin; and the presence of blood vessel, nerve sheath and cartilage invasion. Clinical follow-up on each patient was current through December, 1972 (5-12 years postop). All of these cases were seen initially by one of the authors (J.H.O.). Serial sections revealed that true vocal cord fixation was caused by muscle invasion in 14 of the 18 patients. "Positive margins" were present in eight patients but no immediate treatment was given. Two of these patients developed biopsy proven local recurrences, and both were cured with Co60 irradiation. Among the 18 patients with T3 epidermoid carcinoma treated by hemilaryngectomy: a. Three local recurrences developed, all in the anterior commissure. Two were cured with irradiation. The third had a laryngectomy but died from persistent cancer. b. Two patients developed cervical metastases (without local recurrence), and one was salvaged with radical neck dissection. c. Four patients died of other causes, cancer free, three to five years postoperatively. Of the 14 determinant patients, two patients died of cancer. Twelve (85 percent) were alive and free of cancer five years postoperatively. Two had received full course irradiation; one had a radical neck dissection, and all 12 had a functioning larynx. When Ogura's patients are added to the reports of other hemilaryngectomies performed despite true vocal cord fixation (Leroux-Robert [1950] 18/24, Kirchner, Som [1971] 13/19), a determinant salvage rate of 78 percent can be expected. True vocal cord fixation is generally caused by invasion of the vocalis muscle and thus may be well encompassed by a hemilaryngectomy. The precise anatomical limits of the lesion should dictate the type of surgery required for cure.

The significance of positive margins in hemilaryngectomy specimens.

This clinicopathologic study was undertaken to determine the meaning of surgical margins "involved" with carcinoma. The fate of hemilaryngectomy patients whose specimens had this finding was comparared with that of patients who had "uninvolved" margins. A consecutive series of 111 hemilaryngectomies performed for previously untreated invasive epidermoid carcinoma was analyzed. Serial step sections in a longitudinal plane were available for re-examination and re-evaluation of the surgical margins in each case. Clinical follow-up on every patient was current through 1972. Thirty-nine patients had cancer involvement of a margin in the hemilaryngectomy specimen. None of these patients received any immediate therapy but were followed only. Seven of these patients (18 percent) subsequently developed a biopsy proven local recurrence. Four of the 72 patients (6 percent) with uninvolved margins developed a local recurrence. The site of the positive margin in the specimen was compared with the clinical site of recurrence. The seven local recurrences in patients with positive margins were treated with full course irradiation or total laryngectomy. All of these patients are alive and free of cancer or have died of other causes without evidence of cancer. Of the four local recurrences in patients with negative margins one died of cancer; two are living and well, and one died of other causes. This study provides evidence to support the conservative management of those hemilaryngectomy patients who have involved margins in the resection specimen. No immediate treatment is required. Careful follow-up is indicated with 18 percent chance of clinical recurrence. These biopsy proven recurrences can then be successfully treated with total laryngectomy or full course irradiation. Utilizing this approach none of the 39 patients with involved margins died of cancer in the 5 to 12-year follow-up period.

S-phase fractions of breast carcinomas. Relationships to morphology, estrogen and progesterone receptors, and early recurrence.

Analysis of the S-phase fractions (SPF) measured by in vitro thymidine labeling, morphological appearances, and estrogen receptor (ER) assays of primary invasive breast carcinomas demonstrated several interrelationships. Lobular, mucinous, tubular, and adenocystic carcinomas consistently had low SPF and were usually positive for ER. The same was true for the carcinomas of no special histologic type [the not otherwise specified (NOS) group of E. R. Fisher including "infiltrating ductal" and undifferentiated carcinomas] with minimal anaplasia. Medullary, atypical medullary, and morphologically unclassifiable carcinomas with marked nuclear anaplasia nearly always had high SPF and were usually negative for ER. High SPF was associated with advanced stages of carcinoma initially or with early recurrence following mastectomy.

Tritiated thymidine labeling index of benign and malignant human breast epithelium.

38 specimens of benign breast tissue from young women and 92 primary breast carcinomas were evaluated for tritiated thymidine ([3H]TdR) labeling index (TLI) by in vitro pulse labeling. The TLI on nonneoplastic, terminal breast ducts was significantly higher during the latter half than during the first half of the menstrual cycle (P less than 0.001), and a geometric mean TLI of 1.5 during the latter half of the cycle is consistent with approximately 47% turnover of these cells during the menstrual cycle. Ducts of fibroadenomas showed similar menstrual variation TLI. The range of TLI observed in the carcinomas was 0.04-18.6, arithmetic mean 3.7, geometric mean 2.1. The TLI of carcinomas was not significantly correlated with size of the tumor, but tended to be higher in women less than 50 yr old than in women older than 50 yr (P less than 0.05), and in the presence of two or more metastatic axillary lymph nodes than when fewer than two nodes were involved (P less than 0.02).

In vitro determination of tritiated thymidine labeling index (LI). Evaluation of a method utilizing hyperbaric oxygen and observations on the LI of human mammary carcinoma.

A simple method for incubation of tissue specimens with tritiated thymidine under 3 atm oxygen tension gave an in vitro labeling index (LI) that corresponded closely with LI's determined by injection of tritiated thymidine in vivo. The LI of tumors was not affected by storage at room temperature for up to 135 minutes. The mean LI for 39 human mammary carcinomas was 3.8, but the distribution was skewed to the right, and the most frequently observed LI's were between 2 and 3. Larger carcinomas had significantly larger LI's than smaller tumors, which suggests that the larger tumors were faster-growing at the time of observation than the smaller tumors. The capacity of the larger tumors to maintain a relatively rapid growth rate may account for their large size. The data suggested, but did not prove, that a high LI was associated with more frequent metastasis to axillary lymph nodes.

Subpopulations of breast carcinoma defined by S-phase fraction, morphology, and estrogen receptor content.

The S-phase fraction (SPF), defined as the number of cells per hundred that showed evidence of nuclear DNA synthesis detectable by autoradiography after in vitro incubation with tritiated thymidine, was measured in 170 primary, invasive carcinomas of the breast. Assay for estrogen receptor was performed on tissue from 129 carcinomas, and 34 were also assayed for progesterone receptor. The concentration of estradiol-17 beta was measured in the serum of 69 patients. All carcinomas were analyzed for a variety of histologic features and were classified into morphologic types. SPF were lognormally distributed and were negatively correlated with the patient's age and presence of estrogen receptor, but not with presence of progesterone receptor, size of the carcinoma, number of axillary nodal metastases, or concentration of estradiol-17 beta in serum. The SPFs of lobular, mucinous, and tubular carcinomas were consistently low (geometric mean 1.2, range 0.05 to 3.55), and the SPFs of medullary and atypical medullary carcinomas were consistently high (geometric mean 14.0, range 7.77 to 20.2), whereas carcinomas of other types (not otherwise specified) had an intermediate geometric mean (4.7) and a broad range (0.09 to 25.4). The carcinomas that were not otherwise specified could be divided into three groups with different geometric mean SPFs by nuclear morphologic criteria (1.2 for minimal atypicality, 3.5 for moderate, and 7.9 for severe). Therefore it is possible to sort breast carcinomas histologically into groups with low, intermediate, and high SPF. Correlations between SPF, estrogen receptor content, and microscopic morphology indicate the existence of distinctive subpopulations of breast carcinoma that may have epidemiologic and therapeutic importance.

Epithelialization of the lining of a breast implant capsule. Possible origins of squamous cell carcinoma associated with a breast implant capsule.

The authors described a case in which the capsule surrounding a breast implant was lined by benign squamous epithelium. A second case, in which a woman was found to have a squamous cell carcinoma in the capsule surrounding a breast implant, was also reported.

Prediction of early course of breast carcinoma by thymidine labeling.

The thymidine labeling index (TLI) was measured in vitro in 278 primary breast carcinomas. In 227 operable women treated by radical mastectomy, TLI's below the median of 4.55% carried a probability of relapse of 20% at four years, in contrast to 52% for TLI's above the median (P = 0.0001). The probability of relapse was significantly related to the TLI independent of TNM pathologic stage, axillary lymph nodal status alone, estrogen receptor (ER) content, or menopausal status. The abilities of the TLI and nodal status to predict early relapse were equally strong and independent, whereas other variables tested had less or no independent predictive capacity. The predictive value of the ER content depended largely on its relationship to the TLI, and ER was related to the probability of relapse in the below median TLI group only. The TLI can select a subgroup of node-negative patients with a relapse-expectancy of approximately 50% at four years.

Role of granulocytes and monocytes in experimental Staphylococcus epidermidis endocarditis.

The role of granulocytes and monocytes during the induction and course of Staphylococcus epidermidis endocarditis was investigated by the selective depletion of monocytes with the drug VP16-213 and of both granulocytes and monocytes with nitrogen mustard. The induction of endocarditis was influenced only by the depletion of monocytes: the 50% infective dose differed significantly, being 3.4 X 10(5) CFU in control rabbits and 3.4 X 10(4) CFU in the monocyte-depleted rabbits, whereas no significant differences were found between the latter and those depleted of both granulocytes and monocytes. Also, control rabbits injected with 10(6) or 10(7) CFU had a significantly higher incidence of sterile vegetations than did rabbits selectively depleted of granulocytes or monocytes. Compared with baseline values, mean monocyte numbers at the time of bacterial inoculation were significantly increased in control rabbits whose vegetations remained sterile, whereas this effect was not seen in rabbits whose vegetations became infected. The course of the endocarditis appeared to be significantly influenced by both granulocytes and monocytes. Comparison showed that a decrease of the same numbers of these cells per microliter of blood was accompanied for the monocytes by an approximately fourfold higher increase of the number of staphylococci in the vegetations. The correlation between the number of granulocytes and of monocytes on the one hand and the number of staphylococci in the vegetations on the other was not substantially influenced by the duration of the disease or the number of staphylococci injected to induce the endocarditis. The number injected proved to be significantly correlated with the number of staphylococci in the vegetations. In rabbits with numbers of CFU per gram of vegetation exceeding 10(7), blood cultures were usually positive. This finding applied rarely to control rabbits, but generally to drug-treated rabbits. In the latter animals a significant correlation between the number of staphylococci in the vegetations and in the circulation was found. We conclude that only monocytes have a measurable effect on the induction of Staphylococcus epidermidis endocarditis but during its course both granulocytes and monocytes keep the endocardial infection in check.

Role of granulocytes and monocytes in experimental Escherichia coli endocarditis.

The role of granulocytes and monocytes during the induction and course of Escherichia coli endocarditis was investigated in rabbits by selectively depleting monocytes from the circulation with the drug VP16-213 and granulocytes and monocytes with nitrogen mustard. For induction, the number of E. coli needed to infect the vegetations in 50% of the rabbits was significantly lower in rabbits with combined granulocytopenia and monocytopenia than in those with selective monocytopenia or in control rabbits, whereas the number of E. coli needed to infect 50% of the rabbits did not differ between the latter two. During the course of the endocarditis in endocardial vegetations, the numbers of CFU per gram of vegetation were significantly higher in the rabbits with combined granulocytopenia and monocytopenia than in the monocytopenic and control rabbits but did not differ between the latter two. The numbers of granulocytes in the circulation and the numbers of CFU per gram of vegetation showed a significant negative correlation that was not measurably influenced by the duration of the disease but was dependent on the number of E. coli injected for the induction of endocarditis. Granulocytes were found to be most effective at the lowest numbers of bacteria injected. In the circulation, too, the numbers of CFU per milliliter were significantly higher in rabbits with combined granulocytopenia and monocytopenia than in those with selective monocytopenia and control rabbits, and there was a significant negative correlation between the numbers of granulocytes and CFU per milliliter of blood. From these findings we conclude that granulocytes play a protective role during the induction and course of E. coli endocarditis in rabbits, whereas no role is demonstrable for monocytes.

Verrucous carcinoma: a light and electron microscopic, autoradiographic, and immunofluorescence study.

Verrucous carcinomas of the rectum, plantar surface of the foot, and oral cavity were studied by means of light and electron microscopy, and autoradiographic and immunofluorescent techniques. Histologic examination showed that each tumor was composed mainly of mature squamous epithelium, and each had foci of slight cellular atypia. The cells in S-phase consistently were situated near the basal layer. Immunofluorescent examination with antibasement membrane antibody showed areas of marked focal thickening and other areas where basement membrane was absent. Ultrastructural examination showed reduplicated as well as normal basal lamina. Numerous interdigitating microvilli and well developed desmosomes characterized the cells above the basal layer. A proliferative basal zone underlying a thick layer of well differentiated nonproliferating keratinocytes and reduplicated basal lamina were seen in all tumors, regardless of location. These consistent findings constitute evidence that verrucous carcinoma is a morphologic and cytokinetic entity that may occur in multiple anatomic sites.

Sweat gland differentiation in mammary adenoid cystic carcinoma.

A breast tumor is described which presented as an exophytic mass, and which by both light and electron microscopic examination had a biphasic histologic composition. In the superficial area adjacent to the epidermis, it showed tubular differentiation similar to a cutaneous tubular apocrine adenoma and salivary basal cell adenoma, and, in the deeper portion, it had the characteristic features of adenoid cystic carcinoma. Their possible interrelationships are discussed, and mammary adenoid cystic carcinoma is briefly reviewed.

Adenocarcinoma of the larynx.

Nine patients with primary adenocarcinoma of the larynx representing 0.1 per cent of 888 patients with primary laryngeal malignancy treated between 1955 and 1971 are reported. Following surgical therapy, four patients are alive without disease and five patients are dead due to their disease. Survival time was not related to histopathologic type, stage of disease, or mode of therapy. We cautiously advocate the use of the most conservative surgery feasible as the primary treatment of this poorly understood and highly fatal disease.

Role of granulocytes in experimental Streptococcus sanguis endocarditis.

We investigated the role of granulocytes during the induction and course of experimental Streptococcus sanguis endocarditis in rabbits by depleting blood granulocytes with nitrogen mustard. The induction of the endocarditis was not influenced by granulocytopenia: the 50% infectious dose was 5.4 X 10(4) colony-forming units in normal and granulocytopenic rabbits. However, granulocytopenia influenced the curse of the endocarditis, as shown by a significant increase in the number of colony-forming units per gram of vegetation (P less than 0.02) from 24 to 72 h after the injection of 10(5) colony-forming units of S. sanguis. This rise did not occur in the control rabbits. Furthermore, bacteremia was significantly higher in the granulocytopenic rabbits (P less than 0.05) during the first 48 h compared with the control rabbits. This was not because of altered clearance of the streptococcus inoculum or seeding of streptococci from extracardiac bacterial foci. We concluded that granulocytes have no measurable effect on the induction of S. sanguis endocarditis, but during the course of the endocarditis, granulocytes keep the endocardial infection in check.

Practical breast carcinoma cell kinetics: review and update.

The S-phase fraction (SP) measured by flow cytometry of DNA and the thymidine labeling index (TLI) measured autoradiographically indicate the proportion of carcinoma cells currently synthesizing DNA and reflect the rate of proliferation. The TLI and SPF are lognormally distributed. The median TLI performed to maximize precursor uptake is near 5% (5 labeled carcinoma cells per 100) the mean near 7%, and the range from less than 1% to near 40%. Corresponding values for the SPF measured by DNA flow cytometry are slightly higher when appropriate measures are taken to reduce background debris counts and other artefacts. Residual elevation of SPF above TLI may result from S-phase arrested cells. Flow cytometric histograms show that clearly aneuploid cell lines exist in 50-80% of primary breast carcinomas. Aneuploid breast carcinomas have higher mean TLI than diploid breast carcinomas, and therefore proliferate more rapidly. They also more frequently lack estrogen receptor (ER). Carcinomas with minimal nuclear anaplasia, particularly those of tubular, mucinous, infiltrating lobular and adenocystic types have low TLI and SPF, whereas carcinomas with highly anaplastic nuclei, including medullary carcinomas, have high TLI and SPF. TLI and SPF correlate inversely with ER and PgR content, have no relationship to axillary lymph nodal status, and have a weak positive correlation with tumor size and a weak negative correlation with age. High TLI predicts a high risk of early relapse after primary therapy for both node-negative and node-positive carcinomas. Carcinomas that produce brain metastases have particularly high TLI. Current evidence suggests that high SPF and aneuploidy may prove to have prognostic significance like TLI.

Hormonal receptor determination in juvenile nasopharyngeal angiofibromas.

Juvenile nasopharyngeal angiofibromas (JNA) are rare. They have been frequently treated with estrogens, either solely or as an adjuvant therapy prior to surgery or irradiation. Clinical trials have proveded no evidence to explain the objective respose to estrogens observed in some tumors. Since the mechanism of steroid hormone action is mediated via specific receptors, we analyzed 8 JNA for tumor cytosol estrogen receptors. None were positive for estrogen receptors. Additionally, all were also negative for progesterone receptors. Nasopharyngeal angiofibromas occur predominantly in adolescent boys at a time when there is a gradual change in androgen availability. Therefore, three latter angiofibromas were also analyzed for the presence of cytosol androgen receptor. Specific testosterone and dihydrotestosterone binding components in the tumor cytosol were detected. This observation raises for the first time the possibility that JNA may be an androgen-dependent tumor. Estrogen may act as an antiandrogen on these tumors, an action similar to that on prostate cancer.