The addition of chemotherapy to hormonal therapy for treatment of patients with metastatic carcinoma of the prostate.

Patients with advanced prostate carcinoma that had been stabilized by orchiectomy (ORCH) or hormone therapy for at least 3 months, were randomized to either diethylstilbestrol (DES) alone or DES plus Cytoxan or DES plus Emcyt. A total of 188 patients were randomized between July, 1976 and February, 1982 of which 161 were evaluable for objective response to treatment. Objective response rates, response duration, or survival experiences were not demonstrably different between treatment arms, either for all patients or within good or poor prognosis groups determined by initial pain or acid phosphatase level. Subjective improvements in performance status were small for each treatment. Pain relief was somewhat greater in the chemotherapy-hormone combinations than in the DES/ORCH, but the advantage was not statistically significant. Side effects were primarily nausea and vomiting and leukopenia, mostly in the DES + Cytoxan arm. The duration of stabilization prior to entry did not influence response overall, although there were opposing trends within each of the two chemotherapy arms. The premise for combining antitumor agents with hormones before hormone failure is still felt to be a more logical approach than waiting for the ultimate hormone failure, and a combination of hormones plus two antitumor agents is being evaluated in a subsequent ongoing trial where a more rigid design limits the duration of the preentry period of hormone stabilization.

Comparison of estramustine phosphate, methotrexate and cis-platinum in patients with advanced, hormone refractory prostate cancer.

In this clinical trial of men with advanced prostatic cancer no longer responsive to hormone therapy 189 were randomized to receive estramustine phosphate, methotrexate or cis-platinum. Response evaluations were done in 158 cases. Objective response rates (complete, partial or stabilization of disease) were 34 per cent for estramustine phosphate, 36 per cent for cis-platinum and 41 per cent for methotrexate. Subjective parameters indicated a substantial advantage for pain improvement with methotrexate or cis-platinum over estramustine phosphate. Probabilities of continued response indicated some advantage for methotrexate and median response durations at this time were twice as long for methotrexate (32 weeks) as for cis-platinum (16 weeks), with estramustine phosphate intermediate (23 weeks). Survival rates for the original treatment randomization groups were not different at this time. Side effects of estramustine phosphate consisted primarily of nausea and vomiting and/or anorexia but to a lesser extent than with cis-platinum. These effects were somewhat less for methotrexate, for which the major side effects were stomatitis and leukopenia, as well as hepatic toxicity reflected by elevated serum glutamic oxaloacetic transaminase levels. Other side effects of cis-platinum were less than for methotrexate (no stomatitis), except for signs of renal toxicity (elevations in blood urea nitrogen and serum creatinine), which were greater. Methotrexate had a relatively high level of activity against metastatic, progressive, hormone nonresponsive prostatic cancer, with side effects that were substantial but manageable.

The renal quantitative scintillation camera study for determination of renal function.

The renal quantitative scintillation camera study assesses glomerular filtration rate and effective renal plasma flow based upon renal uptake of 99mtechnetium-iron ascorbate and 131iodine-hippuran, respectively. The method was compared to inulin, para-aminohippuric acid and creatinine clearance studies in 7 normal subjects and 9 patients with various degrees of reduced renal function. The reproducibility of the technique was determined in 15 randomly selected pediatric patients. The values of glomerular filtration rate and effective renal plasma flow were not significantly different from those of inulin and para-aminohippuric acid studies. The reproducibility of the technique was comparable to that of inulin and para-aminohippuric acid studies. Patient acceptance of the technique is excellent and the cost is minimal. Renal morphology and excretory dynamics also are demonstrated. The technique is advocated as a clinical measure of renal function.

A comparison of estramustine phosphate versus cis-platinum alone versus estramustine phosphate plus cis-platinum in patients with advanced hormone refractory prostate cancer who had had extensive irradiation to the pelvis or lumbosacral area.

Single and combination chemotherapy was compared in a clinical trial for men with advanced, metastatic prostate cancer who had received prior pelvic irradiation and had had progression of disease despite hormonal therapy. The 149 patients were randomized to receive estramustine phosphate or cis-platinum alone or in combination. Of the 149 patients 25 (17 per cent) were excluded from the study but 124 were evaluated for response and survival. Entry variables were distributed similarly among patients in each treatment arm. There were no complete or partial responders but there were nearly twice as many patients whose disease was stabilized (33 per cent) on the combination regimen compared to estramustine phosphate (18 per cent) and about a third more than for cis-platinum (21 per cent). Analysis of survival revealed some advantage for patients on combination therapy. Major toxicities for all treatments were nausea and vomiting (62 to 88 per cent) and accompanying anorexia (72 to 95 per cent). Azotemia developed in 45 per cent of the patients receiving combination therapy. In addition an elevation in serum creatinine occurred in 22 per cent of the patients receiving combination therapy and in 17 per cent of those receiving cis-platinum alone. Myelosuppression occurred infrequently.

Quantitative renal scintillation camera studies in renal transplantation.

Renal transplant recipients and donors were studied serially with quantitative renal scintillation camera studies utilizing 131I-Hippuran and 99mTc-Iron ascorbate. This study allows for determination of effective renal plasma flow (ERPF), glomerular filtration rate (GFR), filtration fraction (FF), and predicted return in ten minutes. A drop in FF occurred with, or preceded clinical rejection; whereas, an increase in FF occurred with acute tubular necorsis (ATN) caused by preservation injury, aminoglycosides, and following acute rejection. Combined with the other parameters of renal function determined by this technique, FF alterations proved useful in the differentiation of ATN from rejection and in predicting the prognosis of renal homografts.

The incidence of contrast medium induced acute tubular necrosis following arteriography.

Twenty-one patients slated for high-dose arteriography were studied to investigate the impact of predisposing medical conditions upon contrast medium induced acute renal failure. The study suggests that predisposing medical conditions are the most important factor determining the incidence of acute renal failure and the probability, speed, and degree of recovery of renal function. Patients with diabetes mellitus incur the highest risk of contrast medium induced acute renal failure. A dose relationship is also suggested. Contrast medium doses containing more than 100 g of iodine uniformly produced acute tubular necrosis in patients with predisposing medical conditions. Conversely, contrast medium doses containing less than 80 g of iodine produced clinically manifest acute renal failure in only one of 14 patients with predisposing medical conditions. Subclinical levels of acute renal failure were recognized in a large number of patients by routine measurement of radionuclide filtration fractions, serum creatinine levels, and urine osmolality and sodium concentration.

Computed radionuclide urogram for assessing acute renal failure.

The computed radionuclide urogram is advocated as a noninvasive diagnostic method for differentiation of the most common prerenal, renal, and postrenal causes of acute renal failure. On the basis of characteristic changes in the effective renal plasma flow rate, the calculated filtration fraction, and the calculated glomerular filtration rate, prerenal conditions such as renal artery stenosis or thrombosis, renal conditions such as acute rejection or acute tubular necrosis, and postrenal conditions such as obstruction or leakage, which are the most common causes of acute renal failure, can be differentiated. In conjunction with morphologic criteria derived from sonograms, a diagnosis with acceptable confidence can be rendered in most instances. Both the computed radionuclide urogram and sonogram are noninvasive and can be used without adverse effects in the presence of azotemia and even anuria. This also makes feasible reexamination at intervals to assess effect of therapy and offer prognostic information.

Renal quantitative scintillation camera studies in the management of myelodysplasia.

The renal quantitative scintillation gamma camera study has been used in the evaluation and management of 95 children with myelodysplasia. This study has been helpful in assessing renal function. The precise information, reproducibility of results, high correlation with excretory urography and a minimal amount of irradiation exposure to the patient make this procedure an ideal technique to evaluate and follow a population that needs continuous monitoring of individual as well as total renal function.

Bacterial variants in urinary casts and renal epithelial cells.

Casts with numerous and unusually large granules were seen in the urine of a child with renal Fanconi's syndrome. When the urine sediment was sealed under a coverslip for several days, many granules changed to filamentous bacterial variants that segmented and, finally, appeared as streptococcal-like forms. When the patient's blood was cultured by a special method, bacterial variants grew consistently, and frequently reverted to parent coccal forms, although conventional cultures were negative. Variants from blood cultures had the same morphology and staining properties as granules in casts and in cystic structures found within hypertrophied renal pelvic epithelial cells. Cryptic parasitization with bacterial variants probably occurs in many nephropathies. Variants are known to produce toxins and immunogens, which could lead to mesangial and basement membrane deposits as well as to occlusive reactions in the renal microcirculation.

Determination of filtration fraction using the gamma scintillation camera.

A simple technique for determining effective renal plasma flow, filtration fraction and filtration rate is described. The determination depends upon the use of 131iodine labeled hippuran and 99mtechnetium labeled iron ascorbate or Sn diethylenetriaminepentaacetic acid. The filtration fraction is determined by dividing the corrected uptake for the technetium compound by the corrected uptake for radiohippuran. The uptake is simply determined by the 1 to 2-minute count over the kidneys with background subtraction and taking into account the amount injected. The technique is simple, quick and appears to be a useful clinical tool.

Novel bacterial structures in human blood. II. Bacterial variants as etiologic agents in idiopathic hematuria.

Novel bacterial structures have been demonstrated in lysed blood filtrates placed in special culture media from patients with idiopathic hematuria. These structures converted rapidly to gram-positive coccal (streptococcal and staphylococcal-like), coccobacillary and filamentous, bacterial forms in vitro from 96 per cent of the patients studied. Blood cultured conventionally yielded negative findings. Although structures (dense bodies) were demonstrated in normal control blood specimens (albeit in lesser numbers) few converted to classical bacteria in vitro (7 per cent). Erythromycin therapy appeared to correlate with disappearance of hematuria and inability to revert rapidly the variant forms to classical bacteria in vitro. It is suggested that continual bombardment of the blood by bacteria entering from the mouth or other sites may lead to the development of variant bacterial parasitism. In an effort to survive the deleterious host effects the organisms may convert to persisting osmotically stable variant bacterial forms (dense bodies). Development of a disease state may be conditioned by some existing or developing abnormality in the host (immunologic, physiologic and/or biochemical). Furthermore, changes (genetic?) that might take place in the organisms per se during their transition to variant forms and adaptation to life in vivo may not allow certain host environments to adapt to these new forms, possibly leading to a pathogenetic role in renal diseases whose etiologies have long been enigmas.

Flutamide therapy for carcinoma of the prostate.

In our three-year experience with the use of flutamide for the treatment of carcinoma of the prostate, 20 patients with previously untreated stage D carcinoma of the prostate were enrolled in a 12-week double-blind study. Seven patients received 1.5 gm of flutamide daily, seven patients received 0.75 gm of flutamide daily, and six patients received 1.0 mg of diethylstilbestrol daily. Two patients receiving flutamide did not complete the 12-week study. Six patients receiving flutamide and three patients receiving diethylstilbestrol had objective evidence of improvement. Of the patients receiving flutamide, 50% were alive at one year, and 43% were alive at two years. Three of the original 14 patients started on flutamide are alive at 36, 33, and 24 months. In addition, we continued clinical evaluation of flutamide as an open study, enrolling six other patients (four with stage D and two with stage C carcinoma of the prostate). All except one of these patients had received previous hormonal therapy. At present, four are still being followed up at 13, 15, 20 and 24 months, demonstrating that flutamide can give positive results to some patients whose condition is deteriorating despite diethylstilbestrol therapy.

Vasectomy in rhesus monkeys. III. Light microscopic studies of testicular morphology.

Rhesus monkeys were randomly assigned to undergo various surgical procedures. The animals were followed from one to sixty-six weeks postvasectomy, at which time they were sacrificed and their tissues prepared for light and electron microscopy. Vasectomy in the rhesus monkey, as in certain other species, appears to be a procedure not attended with widespread testicular atrophy or histologic evidence of impaired spermatogenic potential utilizing the procedures and postoperative periods studied. Why certain animals exhibited focal degenerative changes is unclear; perhaps a certain population, yet to be defined, is more sensitive to such procedures, resulting in testicular alterations. It is important that such a population and such changes be defined to predict more accurately the possibility of successful vasovasostomy and reestablishment of fertility.

Vasectomy in rhesus monkeys I. Surgical techniques and gross observations.

Vasectomy and vaso-occlusion techniques were used in 47 male rhesus monkeys to maximize and minimize the amount of sperm allowed to escape from the vas into surrounding tissues for up to seventy-two weeks postoperatively. Body weight changes and blood clinical data indicated that the general health of all the monkeys remained good. Normal seasonal changes in body weights and testicular volumes suggested that there were no disturbances to the endocrine system and that the monkeys remained responsive to seasonal environmental stimuli. Vasectomy appears to cause no short-term deleterious effects in the rhesus monkeys, based on observations made during the seventy-two weeks that these monkeys were study after vasectomy. This conclusion agrees with the findings of other investigators.

Determination of renal plasma flow using the gamma scintillation camera.

An experimental technique has been devised to determine effective renal plasma flow, using the gamma scintillation camera. This involves a computer analysis of the first 3 min of the renal histogram and does not require serum or urine collections. This technique is not sufficiently accurate to provide an exact value of plasma flow, but it can be used to provide an approximate value and hence used as a screening tool.

Novel bacterial structures in human blood: cultural isolation.

Evidence for the existence of a novel bacteriological system has been obtained from osmotically lysed and filtered human blood (membrane filters with a pore size of 0.22 micronm) placed in special culture media. These blood filtrates gave rise to ordinary bacteria for 71% of the blood specimens processed from diseased humans and for 7% of those from supposedly normal humans. Morphologically, the bacteria resembled streptococcal, staphylococcal, and gram-positive filamentous (cocco-bacillary) forms. Prior to the appearance of bacteria in the media, large and small "dense bodies" were microscopically observed but disappeared when ordinary bacteria were apparent, Cultures of of unlysed blood as conventionally performed were negative. These organisms may represent an adaptation of certain bacteria to life in the blood.

Novel bacterial structures in human blood. II. Bacterial variants as etiologic agents in idiopathic hematuria.

Novel bacterial structures have been demonstrated in lysed blood filtrates placed in special culture media from patients with idiopathic hematuria. These structures converted rapidly to gram-positive coccal (streptococcal and staphylococcal-like) coccobacillary and filamentous, bacterial forms in vitro from 96 per cent of the patients studied. Blood cultured conventionally yielded negative findings. Although structures (dense bodies) were demonstrated in normal control blood specimens (albeit in lesser numbers) few converted to classical bacteria in vitro (7 per cent). Erythromycin therapy appeared to correlate with disappearance of hematuria and inability to revert rapidly the variant froms to classical bacteria in vitro. It is suggested that continual bombardment of the blood by bacteria entering from the mouth or other sites may lead to the development of variant bacterial parasitism. In an effort to survive the deleterious host effects the organisms may convert to persisting osmotically stable variant bacterial forms (dense bodies). Development of a disease state may be conditioned by some existing or developing abnormality in the host (immunologic, physiologic and/or biochemical). Furthermore, changes (genetic?) that might take place in the organisms per se during their transition to variant forms and adaptation to life in vivo may not allow certain host environments to adapt to these new forms, possibly leading to a pathogenetic role in renal diseases whose etiologies have long been enigmas.