Jonathan Fleischmann

Interleukin-2 Immunotherapy Followed by Resection of Residual Renal Cell Carcinoma

We administered 10 (E5) units per kg. interleukin-2, 3 times daily, with or without lymphokine-activated killer cells, to 10 patients with metastatic renal cell carcinoma. All patients had metastases to the lung, and 3 of 5 patients who had previously undergone nephrectomy had metastases to the renal fossa. Of the 9 patients who completed at least 1 course of therapy 3 had complete regression of disease outside the abdomen, including 2 who were rendered disease-free after subsequent cytoreductive surgery (nephrectomy in 1 and resection of the renal fossa recurrence in 1). Viable tumor comprised less than 1% of each surgical specimen. Our results support the view that initial treatment with interleukin-2 immunotherapy, followed by abdominal cytoreductive surgery if the peripheral metastases have regressed, may be preferable to the practice of performing abdominal cytoreductive surgery before administering interleukin-2 immunotherapy for patients with widely metastatic renal cell carcinoma.

Urinary interleukins in patients receiving intravesical Bacillus Calmette-Guerin therapy for superficial bladder cancer.

Intravesical administration of Bacillus Calmette‐Guerin (BCG) causes a localized cell‐mediated immune response. The intensity of this inflammatory response may be gauged by measuring the levels of both interleukin‐2 (IL‐2) and an inhibitor of interleukin‐2 (IL‐2‐IN) activity in the urine during the hours after a BCG instillation. The levels of urinary IL‐2 and IL‐2‐IN in the sixth week of BCG therapy predicted the subsequent clinical course in a group of 25 patients (P < 0.01). Measurement of urinary IL‐2 and IL‐2‐IN activity may be used to identify accurately those patients likely to develop a tumor recurrence, thereby sparing them the risk associated with inadequately treated bladder cancer. Since IL‐2 and IL‐2‐IN are competitive with respect to biologic activity, and since relatively high urinary levels of either IL‐2 or IL‐2‐IN activity correlated with a favorable clinical course, the authors conclude that the presence of bioactive IL‐2 in urine is not required for the prevention of recurrent superficial bladder cancer.

Endocrine Therapy for Bladder Outlet Obstruction from Carcinoma of the Prostate

The optimum treatment of bladder outlet obstruction from prostatic cancer is controversial. Although transurethral resection of the prostate may provide immediate relief of the obstruction, there are attendant surgical and anesthetic risks, as well as accumulating clinical evidence to suggest that transurethral resection of the prostate may cause tumor dissemination and diminish patient survival. Orchiectomy, which can be performed safely with local anesthesia, provides definitive endocrine therapy and has been used at our institution in preference to transurethral resection to relieve bladder outlet obstruction from carcinoma of the prostate. There were 35 patients between 51 and 96 years old in urinary retention from carcinoma of the prostate. Patients were treated with orchiectomy and suprapubic or urethral catheter drainage, and subsequently were given voiding trials. If a patient failed to void satisfactorily within 60 days transurethral resection of the prostate was performed. Over-all, 24 of 35 patients (68.6 per cent) were relieved of bladder outlet obstruction by orchiectomy alone. Neither tumor stage nor grade correlated significantly with the response to orchiectomy. We conclude that transurethral resection of the prostate may be held in reserve for patients who do not respond to endocrine therapy or those who do not wish to risk sexual impotence.

Clinical and Immunological Response to Nifedipine for the Treatment of Interstitial Cystitis

Nifedipine is a calcium channel antagonist known to inhibit smooth muscle contraction and cell-mediated immunity. The clinical and local immune response to nifedipine was investigated in an open trial with 10 female interstitial cystitis patients, whose disease was diagnosed according to the consensus criteria developed in 1987 at a National Institutes of Health workshop. To evaluate the symptoms and clinical response of the patients objectively we scored the symptoms of frequency, urgency, nocturia, dysuria and suprapubic pain on a scale of 0 to 2. Nifedipine was administered as a single daily dose determined by a dose-titration test. Urinary interleukin-2 inhibitor activity, a marker of cell-mediated inflammation, was measured using a murine interleukin-2 dependent cell line. Before nifedipine therapy the symptom scores (total of the 5 symptoms) ranged between 5 and 9, and after 2 months they ranged between 0 and 6. Of the 9 patients followed for at least 4 months only 1 failed to have a significant clinical improvement, 5 showed at least a 50% decrease in symptom scores and 3 were asymptomatic. Drug side effects were minimal. Urinary interleukin-2 inhibitor activity before nifedipine therapy confirmed the presence of cell-mediated inflammation. After 4 months of therapy interleukin-2 inhibitor activity was normal in 7 of 9 patients regardless of the severity of symptoms, which indicated that nifedipine exerted an immunosuppressive effect. Although our data suggest that nifedipine is an efficacious, well tolerated, convenient oral medication for the treatment of interstitial cystitis, the true value of nifedipine for patients with this disease must be determined by a prospective, randomized trial of nifedipine versus placebo.

Pelvic Lymph Node Status as Predictor of Extracapsular Tumor Extension in Clinical Stage B Prostatic Cancer

To examine the accuracy of normal pelvic lymph node status in identifying patients with clinical stage B prostatic cancer not having extracapsular tumor extension we reviewed 63 consecutive patients (39 stage B1 and 24 stage B2) treated with radical prostatectomy. Ten per cent of the patients with stage B1 lesions (tumor involving 1 lobe) and 38 per cent with stage B2 lesions (tumor involving both lobes) had extracapsular extension. Extracapsular tumor extension was more common in patients with larger, less differentiated lesions. The results suggest that a negative pelvic lymphadenectomy does not exclude with a high degree of confidence extracapsular tumor extension in patients with clinical stage B2 prostatic cancer.

Fibronectin Expression on Surgical Specimens Correlated with the Response to Intravesical Bacillus Calmette-Guerin Therapy

Attachment of bacillus Calmette-Guerin (BCG) organisms to the bladder during intravesical therapy is thought to be mediated exclusively by the glycoprotein fibronectin, which is expressed variably on epithelial surfaces and on basement membranes. We examined the relationship between the degree of fibronectin expressed on surgical specimens obtained from 50 candidates for BCG therapy and the subsequent clinical response. Immunoperoxidase staining for fibronectin was performed on tumor, nonadjacent normal mucosa and basement membrane tissues, and the intensity of the staining was scored on a scale of 0 to 3+ (control 2+). In the absence of recurrence at quarterly surveillance cystoscopy, a course of Tice BCG therapy consisted of 6 weekly and 12 monthly instillations. Recurrence of noninvasive tumor prompted a second BCG course. Followup ranged from 24 to 66 months (median 40 months). Of the 50 patients (11 with carcinoma in situ) disease progression occurred in 9 (none with carcinoma in situ). Compared to the results for tumors or for basement membranes, the degree of fibronectin expression on normal mucosa was well correlated with the clinical response (r = 0.59, p < 0.001 by Kendall Tau B). Routine assessment of fibronectin expression on the normal mucosa associated with superficial bladder cancer may be useful for predicting the clinical response to BCG therapy.

Lack of value of radioimmunoassay for prostatic acid phosphatase as a screening test for prostatic cancer in patients with obstructive prostatic hyperplasia.

We examined the incidence of prostatic cancer in patients with an elevated radioimmunoassay for prostatic acid phosphatase and clinical benign prostatic hyperplasia on digital rectal examination. Of 295 patients screened with prostatic acid phosphatase tests 17 fulfilled the criteria of having an elevated prostatic acid phosphatase, clinically benign prostate and histological examination of the prostatectomy specimen. None of the 17 patients had histological evidence of prostatic cancer. The results confirm the predictions of mathematical models that prostatic acid phosphatase is of no practical value as a screening test for prostatic cancer in patients with clinical benign prostatic hyperplasia.

Embryonal Rhabdomyosarcoma of the Genitourinary Organs

We report on 14 patients with embryonal rhabdomyosarcoma of the genitourinary organs treated with combined modality therapy. Six patients with paratesticular lesions are free of tumor 7 to 72 months (mean 44) after diagnosis, while 6 of 8 with pelvic lesions are free of tumor 18 to 132 months (mean 61) following diagnosis. Two patients died of metastases. Over-all, 2-year survival free of relapse was obtained in 9 of 11 patients (81 per cent). Of 4 patients with pelvic lesions who were treated with primary radiation-chemotherapy without exenteration 3 were managed successfully but 1 required urinary diversion for vesical fibrosis. Current concepts in the management of embryonal rhabdomyosarcoma are discussed.

Renal Cell Carcinoma and the Clonogenic Assay

The clonogenic assay is an in vitro chemosensitivity test performed on tumor specimens and has had limited success in predicting or confirming patient response to chemotherapy. We investigated this assay system, using a 1-hour method, in 37 renal cell carcinoma specimens to determine its clinical usefulness. These specimens also were graded independently by a pathologist with respect to cell type, mitotic figures and degree of differentiation. Only 22 specimens formed at least 50 colonies per 500,000 cells plated and few specimens displayed any chemosensitivities. Marked variations of colony counts among duplicate controls or drug-treated samples demonstrated further the unreliability of the assay. Of several factors responsible for the poor performance of the assay the 2 outstanding problems were losses of clear cells in variable amounts (unique to renal cell carcinoma), and the inability to generate and maintain single cell suspensions. Pathologic correlations confirmed that predominantly clear cell carcinomas did not form colonies as well as granular cell carcinomas. Owing to these problems in its present form the clonogenic assay is not useful clinically and is unsuited particularly for renal cell carcinoma.

Urinary interleukin-2 inhibition in patients with cystitis

An inhibitor of interleukin-2 activity (IL-2-IN) is present in the urine of most patients during the acute phase of untreated bacterial cystitis (UTI). We measured urinary IL-2-IN activity in 30 adults with uncomplicated UTIs and followed the patients for an additional 6 months. Urinary IL-2-IN activity ranged between 0 and 1.97 units/mg urine creatinine (U/mg u.c.). Relatively low levels of IL-2-IN (less than 0.5 U/mg u.c.) correlated with a prior history of recurrent UTIs (p less than 0.01), and also were predictive of a subsequent UTI during the 6 month follow-up, regardless of the prior medical history (p less than 0.01). Measurement of urinary IL-2-IN during the untreated phase of a UTI may prove helpful for directing antibiotic prophylaxis against subsequent UTIs.