Norman Futter

Increased prevalence and analysis of risk factors for indinavir nephrolithiasis.

PURPOSE Indinavir is a protease inhibitor used for treating HIV-1. The drug is lithogenic and was thought to cause a 3% incidence of kidney stones. We evaluated a cohort of patients positive for HIV on indinavir to determine the incidence of indinavir nephrolithiasis and identify risk factors for indinavir stone formation. MATERIALS AND METHODS Our cohort study of the prevalence of indinavir nephrolithiasis included 155 patients with HIV for 5,732 patient-weeks. The same cohort was then used for a retrospective chart review to assess patient age, weight, duration of drug use, time to stone formation, CD4 count, creatinine, alanine transaminase, and urinary pH and specific gravity as risk factors for stone formation. RESULTS We estimated the cumulative incidence of indinavir stone formation by the Kaplan-Meier product limit estimator method. At 78 weeks 43.2% of patients had stones (95% confidence interval [CI] 0.292 to 0.543). Increasing age was the only variable that was a statistically significant predictor of indinavair urolithiasis (relative risk 0.955, 95% CI 0.918 to 0.993, p = 0.0159). The mean duration plus or minus standard deviation of indinavir use was statistically the same in each group (42.5 +/- 27. 2 and 40.3 +/- 27.1 weeks in those without and with stones, respectively) despite the observed mean time to stone formation of 23.0 +/- 19.8 weeks. CONCLUSIONS The clinical prevalence of indinavir nephrolithiasis is much greater than initially reported. Nephrolithiasis during indinavir use does not appear to induce patients to withdraw from the drug.

Diagnosis of Renal Malacoplakia by Fine Needle Aspiration Cytology

BACKGROUND Malacoplakia is a rare chronic inflammatory disease first described by von Hansemann in 1901. L. Michaelis and M. Gutmann published the first report in 1902, describing the characteristic round intracellular and extracellular inclusions, or Michaelis-Gutmann bodies. Renal malacoplakia is a form of chronic tubulointerstitial nephritis the clinical and radiologic findings of which are often suggestive of a neoplasm. Renal malacoplakia may be related to megalocytic interstitial nephritis and xanthogranulomatous pyelonephritis. CASE A 67-year-old male presented with acute left loin pain suggestive of uretery colic. The past medical history was unremarkable and physical examination within normal limits. Renal ultrasound and computed tomography showed a 3.5-cm, cystic mass with a thickened, irregular wall located centrally within the left renal sinus. The size of the left kidney was 11.5 cm. A renal arteriogram provided no evidence of a vascular mass of any type. Fine needle aspiration (FNA) revealed many large, foamy, granular macrophages with large, eccentric nuclei and prominent nucleoli containing round inclusions that exhibited a laminated appearance, consistent with the structure of Michaelis-Gutmann bodies. Many were also present extracellularly. CONCLUSION To our knowledge this is the first case of renal malacoplakia diagnosed by fine needle aspiration. This case demonstrates the value of FNA in determining the nature of a radiologically nonspecific lesion. It highlights the value of FNA as a substitute for or preliminary method before more invasive procedures in the diagnosis of a treatable disease entity.

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.

Mitomycin-C and metronidazole in the treatment of advanced renal-cell carcinoma

Fifteen patients with advanced renal-cell carcinoma were treated with the combination of mitomycin-C 14–20 mg/m2 i.v. every 7 weeks and metronidazole 1,500 mg/m2 p.o. 12 and 1 h before and 6 and 24 h after the mitomycin-C. Of 12 patients evaluable for response, three (25%) responded with partial remissions. Myelosuppression did not appear to be increased over that seen with mitomycin-C alone. Pulmonary toxicity occurred in three patients and was fatal in two. The incidence of pulmonary toxicity was probably increased over that seen with mitomycin-C alone. Renal toxicity was also seen. Based on this small study, it was our feeling that this dose-schedule of metronidazole did not appear to result in enough of an augmentation of the efficacy of mitomycin-C against renal-cell carcinoma to justify the incidence of serious toxicity.

Phase II study of lonidamine in metastatic prostatic carcinoma.

Consenting patients with evaluable metastatic prostate cancer, creatinine < 200 micromoles/L, bilirubin < 30 micromoles/L, ECOG performance status 0 2 , and ~ one prior chemotherapy regimen were eligible. Lonidamine 50 mg/m ~ was given orally on day 1, then escalated over one week to 300 mg/m2/day (in 3 divided doses). Further dose escalations were possible in some patients. Other hormones were stopped prior to starting lonidamine. Patient status, blood counts, creatinine, liver enzymes, and (in a subset of patients) serum testosterone, FSH, and LH were monitored once every 2 to 4 weeks. Response consisted of _> 4 weeks of a combination of all of: no new lesions, no increase in size of any old lesions, normalization of acid phosphatase levels, no worsening of tumor-related symptoms or performance status, no weight loss of > 10%, plus at least one of recalcification of _> 1 osteolytic metastases, or decrease by > 50% of measurable/evaluable tumor size or of intensity or area of uptake on bone scan. Stability consisted of _> 12 weeks with a combination of all of no new lesions, no increase in size of any lesion by > 25%, reduction in acid phosphatase level, no worsening of bone metastases, and no deterioration by > 10% in weight or performance status.