Clyde E. Blackard

COMPARISONS OF PLACEBO, PYRIDOXINE, AND TOPICAL THIOTEPA IN PREVENTING RECURRENCE OF STAGE I BLADDER CANCER*

Animal studies have shown that metabolites of tryptophan can cause bladder cancer, and human observations reveal an appreciable incidence of abnormalities of tryptophan metabolism in patients with bladder cancer. It has been suggested that pyridoxine (vitamin B6) may correct this abnormality and prevent recurrences of superficial bladder cancers. Intravesical instillation of thiotepa has been used for more than fifteen years in the treatment of superficial bladder cancer, but no controlled trials have been done. We report here a prospective clinical trial of 121 patients with Stage I bladder cancer randomized to placebo, pyridoxine, or intravesical thiotepa. The percentages of patients with recurrences over the period of study were 60.4, 46.9, and 47.4 for the three groups, respectively, and did not differ significantly. However, if patients having recurrences during the first ten months or followed up less than ten months were excluded, pyridoxine was significantly better than placebo (P = 0.03). Thiotepa significantly reduced the recurrence rate compared with placebo (P = 0.016) or pyridoxine (P = 0.015). These results suggest that a new trial of pyridoxine should be undertaken in which the tryptophan metabolites are measured and that further study of intravesical instillation of chemotherapeutic agents is warranted.

Incidence of cardiovascular disease and death in patients receiving diethylstilbestrol for carcinoma of the prostate

Patients treated with a 5.0‐mg daily dose of diethylstilbestrol (DES) had an increased incidence of fatal and non‐fatal cardiovascular disease when compared to placebo in all stages of prostatic cancer (p < 0.025). The pretreatment cardiovascular status of estrogen‐treated patients was generally better than those treated with placebo. Therapy with DES 5.0 mg did not increase survival of Stage III or IV patients significantly when compared to placebo. The decrease in cancer mortality associated with the 5.0‐mg dose of DES was offset by an increase in deaths from cardiovascular causes. Early endocrine treatment of patients with asymptomatic Stage III carcinoma is not indicated. Endocrine therapy should be started early only in Stage IV patients. When DES is preferred, it should be administered in a dose lower than 5.0 mg. Complications of estrogen therapy may be due to an increased incidence of thromboembolism.

Orchiectomy for advanced prostatic carcinoma A reevaluation

Abstract The efficacy of four treatments, placebo, orchiectomy plus placebo, estrogen (diethylstilbestrol 5.0 mg. daily), and orchiectomy plus estrogen, was evaluated in 1,903 Stage III and IV prostatic cancer patients by comparing (1) survival curves, (2) causes of death, (3) clinical response, (4) development of metastases in Stage III patients, and (5) incidence of treatment change. Survival curves did not differ significantly for the four treatment groups except in Stage III, in which orchiectomy plus estrogen was worse than placebo, or orchiectomy plus placebo. There were significantly more cancer deaths in the two nonestrogen groups in both stages. Otherwise, there were no appreciable differences between the three hormonal treatments. We conclude that estrogen is more effective than orchiectomy in preventing cancer deaths, and the addition of orchiectomy to estrogen does not offer a clear-cut advantage over either treatment alone. Therefore, if treatment becomes necessary because of cancer symptoms, initial treatment with estrogen is preferred.

A critical analysis of tumor morphology and hormone treatments in the untreated and estrogen‐treated responsive and refractory human prostatic carcinoma

This study was done to compare the ultrastructural features of prostatic cancer cells in both untreated and estrogen‐treated responsive and refractory patients. Analysis of previously untreated and estrogen‐treated carcinomas showed that the tumors possessed well‐ and poorly‐differentiated acini, and invasive cells. Malignant acini contained numerous columnar (secretory) cells in untreated, but few in treated individuals. Two distinct types of basal cells were observed in untreated and treated acini: type I (light) and type II (dark) cells. In both untreated and treated tumors, type I cells were characterized by having round nuclei with many small aggregates of euchromatin, large nucleoli, and electron‐lucent nucleoplasm. The type II cells had highly pleomorphic nuclei, folded nuclear envelope—sometimes deficient in localized areas, euchromatin, many small aggregates of heterochromatin, large pleomorphic nucleoli, and relatively electron‐opaque nucleoplasm. In some sections, both types of basal cells penetrated through the acinar basal lamina and became invasive. Prostatic carcinomas which were or subsequently became refractory to estrogens showed more abundant type II basal cells than responsive patients. It is postulated that the type II basal cells as well as some type I basal cells are endocrine unresponsive from the outset. Furthermore the tumor possesses a heterogeneous population of cancer cells. While androgen‐dependent tumor cells such as columnar cells may be destroyed by endocrine therapy, these endocrine unresponsive cells continue to proliferate, metastasize, and kill the patient. Therefore, we suggest that patient with advanced prostatic carcinoma initially may be given endocrine therapy to reduce tumor burden caused by endocrine‐sensitive cells. In addition, early treatment with chemotherapy or radiation may be used to destroy unresponsive endocrine‐insensitive cells, before these cells lines have a chance to proliferate and to develop into refractory carcinoma. Cancer 40:2836‐2850, 1977.

Disseminated Intravascular Coagulation in the Urologic Patient

Gram-negative septicemia and metastatic prostatic cancer are frequent causes of disseminated intravascular coagulation. The clinical manifestations of this condition as well as the laboratory data vary considerably, depending on the patients compensatory mechanisms in relation to the magnitude and duration of the thromboplastin or endotoxin release. Treatment centers primarily on correcting the underlying disorder. Secondly, deficient clotting factors and platelets should be replaced in the appropriate patient. Heparinization is often unnecessary. The use of drugs that inhibit the protective fibrinolytic mechanism is contraindicated in disseminated intravascular coagulation.

Analysis of Fixation Effects on Immunohistochemical Localization of Prostatic Specific Antigen in Human Prostate

We studied human prostatic specific antigen (PSA) localization in human prostate to investigate the possibility that the previously reported variations in the intensity of antigen staining were due to fixation and embedding methods. We have evaluated the effects of physical and several chemical fixatives on prostate samples obtained immediately after prostatectomies and radical cystectomies. Our analysis of fixation effects and immunohistochemical staining of polyclonal antibody to PSA indicates that the formalin fixation and paraffin embedding methods used previously did provide optimum localization of the antigen and the variations in the intensity of PSA staining could not be attributed to the methodology. Although PSA staining was relatively uniform in the lower grade neoplastic tumors, the higher grade, moderately to poorly differentiated tumors showed intense-through-weak PSA localization or no PSA staining suggesting that PSA staining intensity was not uniformly related to tumor differentiation.

The in vitro localization of H3 estradiol in human prostatic carcinoma. An electron microscopic autoradiographic study

The in vitro localization of H3 estradiol in human prostatic carcinoma was studied in five patients who had not been treated with hormones previously. The isotope was incorporated into the basal and invasive cells but rarely in the differentiated ones of carcinomatous acini. In basal and invasive cells, the grains were localized on the nuclear membranes and associated condensed heterochromatin, and on some mitochondria. The binding of estradiol in prostatic tissues appeared covalent and nonreversible in our preparative techniques for autoradiography. It is tentatively suggested that cytoplasmic binding of estradiol in mitochondria may be associated with the nucleic‐acid‐protein complex found with the organelle membranes. The nuclear binding of the hormone appears associated with the protein portion of the heterochromatin material. Furthermore, the in vitro study has shown that estrogen directly affects some of the prostatic cancer cells within two hours, but the extent of changes in the tumor cells remains undetermined.

Use of vacuum tumescence device for impotence secondary to venous leakage.

The causes and treatment of venogenic impotence are still controversial. From September 1989 to April 1991, 317 men complaining of impotence were evaluated in our Erectile Dysfunction Clinic. Seventy patients were suspected of having venous leakage, and all men had dynamic cavernosography performed. Forty-seven of these 70 men (67%) had venous leakage, and a vacuum tumescence device was recommended as initial treatment for all of them. A questionnaire was later mailed to all 47 patients. A response to the questionnaire was obtained from 45 men (96%). Twenty-nine patients had purchased a vacuum tumescence device (Osbon ErecAid). A satisfactory result was obtained in 20 patients (69%) with venous leakage. Since the use of the vacuum tumescence device is relatively safe and noninvasive, and the results are as good as or better than venous ligation, we recommend its use as the initial treatment of venogenic impotence until a consistently reliable treatment for this condition is found.

Prophylactic Antibiotics in Transurethral Prostatectomy

In a prospective randomized study involving 90 uninfected patients undergoing transurethral prostatectomy it was found that routine postoperative use of prophylactic cephalosporins had no beneficial effect on the incidence of fever, hospital stay or major complications. Patients receiving cephalosporins had a significantly lower incidence of postoperative bacteriuria immediately after catheter removal and 1 month postoperatively.

Freeze-fracture observations on the membranes and junctions in human prostatic carcinoma and benign prostatic hypertrophy.

In human prostatic carcinomatous acini, the columnar cells possessed a loosely organized meshwork of ridges and grooves and many isolated, short, and disorganized strands of tight junctions, unlike those of benign prostatic hypertrophy (BPH), where the tight junctional ridges and grooves were numerous and compact. Desmosomes were more irregular in size, shape and distribution in cancerous cells than in BPH. Our observation indicated that the junctional complexes were altered and defective in cancerous cells and probably facilitated migration of some acinar cells into the stroma. In addition, we have also shown that the membranes including the intramembranous particles of Golgi complexes, mitochondria, secretory granules and vacuoles, lipofuscin granules and nuclei, were essentially similar in cancerous and BPH columar cells.