David E. Mckay

The Gonadotropin Response of Men with Varicoceles to Gonadotropin-Releasing Hormone*†

The serum gonadotropin and testosterone responses to 100 micrograms of intravenously administered gonadotropin-releasing hormone (GnRH) were studied, over 180 minutes, in four groups of men: severely oligospermic men with varicoceles and sperm densities less than 10 million/ml, men with varicoceles and sperm densities greater than 10 million/ml, severely oligospermic men without varicoceles, and men of normal fertility. Each group had similar preinjection gonadotropin and testosterone levels. Following the injection of GnRH, the severely oligospermic men with varicoceles had excessive increases in luteinizing hormone and follicle-stimulating hormone levels and a slower return to preinjection values as compared with the other three groups. The responses of the other groups were not different from each other. There was not a consistent increase in testosterone levels in any group during the period of the study. These results suggest that severely oligospermic men with varicoceles have a pantesticular defect in testosterone synthesis and spermatogenesis which can be demonstrated by their response to GnRH.

The gonadotropin response of men with varicoceles to a four-hour infusion of gonadotropin-releasing hormone * †

The serum gonadotropin, testosterone, and estradiol responses to a 4-hour intravenous infusion of gonadotropin-releasing hormone (GnRH) were studied in four groups of men: severely oligospermic men with varicoceles and sperm densities less than 1 X 10(7)/ml, men with varicoceles and sperm densities between 1.1 X 10(7) and 3 X 10(7)/ml, men with varicoceles and sperm densities greater than 3 X 10(7)/ml, and men of normal fertility. Each group had similar preinfusion luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol levels. Both the severely oligospermic men and the men with sperm densities between 1.1 X 10(7)/ml and 3 X 10(7)/ml had excessive gonadotropin responses to the GnRH infusion. The gonadotropin responses of the men with sperm densities greater than 3 X 10(7)/ml were not different from normal. These results demonstrate that men with varicoceles and sperm densities less than 3 X 10(7)/ml have an altered integrity of their hypothalamic-pituitary-testicular axes, which can be demonstrated by their responses to GnRH.

Embryonal rhabdomyosarcoma of the prostate. An ultrastructural study

An ultrastructural study of an embryonal rhabdomyosarcoma arising from the prostate of a 9‐year‐old boy is reported. Cross striations in neoplastic cells were difficult to find under the light microscope. The electron microscope, however, revealed large cells with poorly formed but easily recognizable myofibrils. There were numerous small cells devoid of myofilaments in the vicinity as well. Their cytoplasmic contents were of two types: one type had abundant free ribosomes while the other had rough endoplasmic reticulum and Golgi apparatus. Irrespective of type, the small cells were associated either with the large cells containing myofilaments or with collagen fibrils. From their disposition and ultrastructural characteristics, it was difficult to determine which type of the small cells represented the precursor of the large cells containing myofibrils and which belonged to the stromal component of the neoplasm.

Intra-Arterial Cisplatin for Bladder Cancer

Cisplatin (25 to 120 mg. per m.2) was injected into the internal iliac arteries of 33 patients with locally advanced bladder cancer. Of the patients 9 were inevaluable for response to the cisplatin, since they began radiotherapy to the bladder before course 2 of cisplatin as part of a preplanned therapeutic approach. One patient received the treatment as postoperative adjuvant therapy, 1 did not return for followup and 1 with metastatic disease did not undergo repeat cystoscopy. Of 21 evaluable patients 3 (14 per cent) achieved complete remission, 12 (57 per cent) achieved partial remission, 2 (14 per cent) were stable and 4 (19 per cent) failed. The response rate was higher in patients receiving 100 to 120 mg. per m.2 per course than in patients receiving lower doses (all except 1 of whom received 60 or less mg. per m.2 per course) (86 versus 64 per cent) and it was higher in patients without prior radiotherapy or chemotherapy. The response rate in patients with previously untreated invasive transitional cell carcinoma was 88 per cent. Of the 33 patients 21 were alive at last followup, with a median duration of followup of 32 weeks. Toxicity was dose-related and local neurotoxicity was excessive at cisplatin doses of 100 to 120 mg. per m.2. Diabetic patients were particularly prone to have neurotoxicity. Other toxicity generally was not severe and consisted of ototoxicity, nephrotoxicity, myelosuppression, nausea, vomiting and diarrhea. Even elderly patients and patients with cardiac disease tolerated the treatment well. We plan to proceed with further intra-arterial cisplatin studies in which all patients except those more than 80 years old will be treated with an intra-arterial cisplatin dose of 90 mg. per m.2 per course combined with radiotherapy with or without cystectomy.

Intra-Arterial Cisplatin Treatment of Unresectable or Medically Inoperable Invasive Carcinoma of the Bladder

Five patients between 72 and 82 years old received 5 to 6 treatments of 50 to 75 mg. per m.2 cisplatin by bilateral internal iliac artery infusion for unirradiated invasive transitional cell carcinoma of the bladder. Of the patients 3 also were diabetics and 1 had congestive heart failure. Treatment was tolerated extremely well, although most courses were associated with moderate to severe nausea and vomiting lasting several hours. Of 4 evaluable patients 3 achieved complete remission and 1 achieved a good partial remission. An additional 55-year-old woman with a large invasive bladder carcinoma fixed to surrounding structures was treated with 4 courses of 100 mg. per m.2 intra-arterial cisplatin. This patient had a marked decrease in tumor size, permitting surgical resection of all known residual tumor. A 49-year-old patient with large pelvic lymph node metastases from a squamous cell carcinoma of the bladder achieved only minimal decrease in tumor size after 3 courses of 100 mg. per m.2 intra-arterial cisplatin. We conclude that intra-arterial cisplatin can be highly effective for localized invasive bladder cancer even when relatively low doses are used. With proper care the regimen can be used safely and effectively in elderly patients with medical contraindications to an operation.

Phase I and Pharmacology Study of Intravesical Mitoxantrone for Recurrent Superficial Bladder Tumors

A phase 1 study of intravesical mitoxantrone was done in patients with superficial bladder tumors recurrent after previous intravesical therapy. Mitoxantrone (5 to 10.5 mg.) was instilled in the bladder via catheter and was left in situ for 2 hours. Each patient received 6 treatments at 1-week intervals. Pharmacology studies were conducted in a subset of consenting patients. Dysuria, urinary frequency and hematuria were dose-limiting at 10 to 10.5 mg., the dose recommended for our phase 2 studies. One patient treated with 7.5 mg. mitoxantrone had bladder contracture after severe bladder injury caused by the drug. The interval free of recurrence increased in 5 of 8 patients treated with 10 to 10.5 mg. mitoxantrone and in 6 of 19 treated at lower dose levels. One patient who had residual evaluable tumor in the bladder at treatment experienced a complete remission for 16 months. Only 1 of 18 patients who underwent pharmacology studies had any mitoxantrone detectable in the blood after intravesical administration. This patient had severe irritative symptoms at treatment. No systemic toxicity was noted in any patient. Of the mitoxantrone instilled into the bladder 33 to 100% (mean 75%) was recovered in the specimen voided at the end of treatment. In summary, intravesical mitoxantrone is reasonably well tolerated and should be studied further at a dose of 10 mg. per week for 6 weeks. Caution should be exercised, since bladder contracture was seen in 1 patient. Systemic absorption and toxicity are negligible.