Carl M. Pinsky

Long-Term Effect of Intravesical Bacillus Calmette-Guerin on Flat Carcinoma in Situ of the Bladder

Intravesical bacillus Calmette-Guerin is effective therapy for multifocal carcinoma in situ of the bladder. The duration of this favorable response and its effect on disease progression are the subject of this report. Between March 1978 and July 1981, 47 patients with diffuse, often symptomatic, carcinoma in situ were treated with intravesical bacillus Calmette-Guerin and followed every 3 to 4 months with cystoendoscopy, biopsy and urine cytology for 3 to 6 years. All patients had had prior or concurrent superficial papillary tumors controlled initially by transurethral resection and fulguration 2 to 3 weeks before bacillus Calmette-Guerin treatment. Of the 47 patients 23 were entered into a randomized study, and received intravesical and percutaneous bacillus Calmette-Guerin. Another 24 patients with carcinoma in situ were treated with intravesical bacillus Calmette-Guerin alone. Bacillus Calmette-Guerin (Pasteur strain) was given intravesically (120 mg. in 50 ml. saline) weekly for 6 weeks. Of the 47 patients 32 (68 per cent) are free of disease (negative urine cytology, cystoendoscopy and biopsy): 15 (65 per cent) after combined bacillus Calmette-Guerin for a median duration of 51 months (range 37 to 75 months) and 17 (71 per cent) after intravesical bacillus Calmette-Guerin alone for a median of 45 months (range 36 to 53 months). Of the 23 patients in the randomized study 4 (17 per cent) have required cystectomy for local progression of disease compared to 17 of 26 controls (65 per cent) who were randomized to transurethral resection and fulguration alone. Cystectomy was performed 3 to 27 months after bacillus Calmette-Guerin treatment and in 3 patients tumor was localized to the prostate gland (no tumor found within the bladder). These data indicate that intravesical bacillus Calmette-Guerin is capable of producing long-term remissions of carcinoma in situ in high risk patients and may prevent or delay progression of disease necessitating cystectomy.

Experience with intravesical bacillus calmette-guèrin therapy of superficial bladder tumors☆

Between March, 1978, and July, 1981, 86 patients with polychronotopic superficial papillary bladder tumors and concurrent carcinoma in situ were randomized to receive either transurethral resection alone (43) or TUR plus BCG (43). The results indicate that BCG is not only active in preventing recurrences of new tumors but also effective for the diffuse, flat carcinoma in situ.

Effect of intravesical bacillus calmette-guerin (BCG) on carcinoma in situ of the bladder

Development of invasive bladder cancer is a definite risk in patients with flat carcinoma in situ (CIS) associated with multifocal concurrent superficial papillary tumors. In a prior prospective randomized trial, the authors showed that intravesical BCG reduces local tumor recurrences and prolongs the disease free interval in patients with recurrent, papillary bladder tumors treated by transurethral resection (TUR) and/or fulguration. In this study, BCG was administered intravesically, 120 mg in 50 ml saline and percutaneously, 5 × 107 viable organisms, weekly for 6 weeks. The current study was conducted to determine the impact of this regimen in patients with flat in situ carcinoma. Of the first 69 patients entered, 41 (59%) had multiple (2) lesions of flat CIS associated with papillary tumors: 17/34 (50%) in the TUR + BCG group and 24/35 (69%) in the TUR alone group. Complete regression of CIS documented by negative bladder biopsy and negative urine cytology results was seen in 11/17 (65%) of the BCG treated patients for a median duration of 18 months (range, 12–30 months) and in 2/24 (8%) patients in the TUR alone group for a median duration of 3 months (P < 0.01). In situ carcinoma failed to respond to intravesical BCG in seven patients, three of whom required cystectomy for local progression of disease. In two of these three patients, cystectomy was performed for CIS involving the prostatic ducts and no tumor was found in the bladder specimen. This suggested that the response of in situ cancer required that the epithelium be adequately exposed to BCG, and that intravesical BCG + TUR may potentially reverse the insidious natural history of carcinoma in situ compared with a control group treated with endoscopic destruction alone.

Toxicity of intravesical BCG and its management in patients with superficial bladder tumors

Toxicity of bacillus Calmette‐Guerin (BCG) Pasteur strain, given in a dose of 120 mg once a week for 6 weeks, was retrospectively evaluated in a study of 107 patients with recurrent superficial bladder cancer. Only six patients had no symptoms of toxicity. Severe cystitis (ten patients) was most likely to occur in those with decreased bladder compliance before treatment. Systemic symptoms resembling those of influenza (flu) were severe in six patients. Potentially serious complications occurred in six patients. Overall, toxic reactions were mild and self limited, and toxicity often could be easily managed by a reduction in the BCG dose (17 patients), temporary interruption of treatment (five patients), or cessation (four patients). Late occurrence of bladder granulomas (32 patients) and cystoscopic appearance of significant cystitis (55 patients) did not correlate with posttreatment voiding symptoms, and these changes were temporary and confined to the first 6 months after treatment. There were no cases of late bladder contracture, and none of the patients free of voiding symptoms before treatment had such symptoms afterward. Extravesical granulomas were observed in 37 patients and were the cause of obstruction of the urinary tract in nine. Pretreatment skin reactivity did not correlate with toxicity, and concurrent percutaneous administration of BCG had no effect on toxicity. BCG has a cumulative effect, so increased toxicity is to be expected during long‐term administration. BCG toxicity is primarily a response of the cell‐mediated immune system, and transient local or systemic infection appears to be important. This fact suggests that immunosuppression is a relative contraindication to BCG use.

Clinical evaluation of tumor targeting with a high-affinity, anticarcinoembryonic-antigen-specific, murine monoclonal antibody, MN-14

Background. The authors previously reported that an anticarcinoembryonic antigen antibody against a carcinoembryonic antigen (CEA)‐specific epitope is preferred for clinical investigations. They developed a second generation, CEA‐specific murine monoclonal antibody (MoAb), MN‐14 (IMMU‐14), that has a tenfold higher affinity. This report summarizes the initial clinical experience with the new MoAb.

Comparison of multiple in vivo and in vitro parameters in untreated patients with Hodgkin's disease

Multiple in vivo and in vitro immune parameters were used to examine 52 untreated patients with Hodgkins disease in all stages. A significant number (p < 0.01) of patients in all stages demonstrated abnormalities in DNCB sensitization, peripheral blood lymphocyte response to phytohemagglutination, absolute lymphocyte count, absolute number of T cells (as measured by spontaneous rosette formation with sheep erythrocytes), and absolute number of B cells (as measured by immunofluorescence with polyvalent antiserum). The number of T and B cells fell progressively with each stage, but the proportion of T to B cells remained constant. Cutaneous anergy was found in Stages III and IV. Depressed circulating immunoglobulins were found in a few patients in all stages. Neither the total lymphocyte number nor the number of T and B cells correlated with the measures of lymphocyte function (skin test reactivity, DNCB sensitization, mitogen response, or immunoglobulin levels). This study suggests that selective abnormalities in the immune system exist even in early Hodgkins disease, involving the absolute number of circulating T and B lymphocytes and T‐lymphocyte function. The study fails, however, to define a consistent pattern of immune defects as characteristic of Hodgkins Disease.

Multivariate analysis of T-cell functional defects and circulating serum factors in Hodgkin's disease.

A comprehensive immunologic and serologic analysis was performed on 31 untreated patients with Hodgkins disease. Immune evaluations stressed T‐cell functional activity and included traditional parameters (PHA responsiveness and delayed hypersensitivity skin reactivity), as well as newer functional assays (T‐cell colony formation, chemotaxis, spontaneous and antibody‐dependent cytotoxicity, and concanavalin A‐induced suppressor cell activity (CISA)). Serum factors included ferritin, prostaglandins, zinc, copper, immune complexes, and thymic hormone activity. Every patient exhibited at least one T‐cell or serum abnormality. The greatest percentage of patients exhibited T‐cell defects in chemotaxis (85%), colony formation (81%), and PHA reactivity (64%). Immune defects were more common with advanced disease but were not related to absolute T‐cell or monocyte count, skin test anergy, or abnormalities of Tμ/Tγ cell proportions. Linear relationships were identified among abnormalities in the three assays employing mononuclear cells (PHA, colony formation, CISA) which may have reflected the inhibitory influence of monocytes present in the mononuclear cell preparations. Low serum zinc correlated with marked impairment of T‐cell chemotaxis. Elevated prostaglandins were associated with high PHA reactivity and with depressed colony formation. Our results indicate that many complex factors, including intrinsic T‐cell defects, contribute to the impaired immunity associated with Hodgkins disease.

TREATMENT OF BOWEN'S DISEASE WITH TOPICAL DINITROCHLOROBENZENE AND 5-FLUOROURACIL

“Bowens disease” is a clinical and histologic diagnosis describing the lesions (single or multiple) of cutaneous in situ squamous cell carcinoma. The case of a 54‐year‐old man with 60 such intra‐epidermal carcinomas, and a history of arsenic ingestion, is presented. The patient was sensitized to dinitrochlorobenzene (DNCB), and his lesions were treated with a topical DNCB preparation. All lesions disappeared completely (demonstrated by biopsy of several sites) except for a large (12 × 7 cm) tumor on the flank which partially resolved. Total regression of this lesion was achieved by adding topical 5‐fluorouracil (5‐FU) therapy. This case demonstrates that the inflammatory reaction induced by DNCB (as evidenced by erythema and by a dense inflammatory cell infiltrate in biopsied areas of treated lesions) can lead to regression of extensive in situ epidermoid carcinoma, and that combined therapy with DNCB and 5‐FU can be more effective than DNCB alone. Both agents in appropriate concentrations led to selective destruction of neoplastic tissue with no effect on adjacent normal skin. No systemic toxicity was observed.

Lymphoma imaging with a new technetium-99m labelled antibody, LL2

The lesion detection capability of a new technetium-99m labelled B-cell lymphoma monoclonal antibody (MoAb) imaging agent, LL2, was evaluated in 8 patients with non-Hodgkins lymphoma and 1 patient with chronic lymphocytic leukaemia. The MoAb kit consists of a 1-vial, 1-mg Fab′ form of LL2 ready for instant labelling with technetium. The patients were injected with ∼ 925 MBq (25 mCi) of 99mTc-LL2 Fab′ (1 mg), and planar and single photon emission tomography (SPET) studies were performed at 3–4 h post injection and at 24 h. There was no evidence of thyroid or stomach activity up to 24 h. Uniform splenic uptake was seen in all patients. Two non-lymphoma patients were also administered with the same agent and demonstrated a similar splenic distribution; therefore, splenic targeting was not scored as tumour-specific. A total of 29 from 48 tumour sites were detected by scintigraphy, including tumours of various grades and histological types. Excluding 1 patient who had a large tumour burden of over 500 g, 29 of 33 lesions were detected. One patient was free of disease at the time of the study and had a negative scan. Another patient showed excellent targeting of gallium-negative sites in the liver and bone. The bone involvement was not known prior to the antibody study and was subsequently confirmed by a bone scan. Additional sites of MoAb localization could not be followed in this group, since most patients went on to radioimmunotherapy immediately following the 99mTc-LL2 study. However, these initial results suggest that this new 99mTc-labelled antibody imaging kit should be further investigated for its potential role in the staging and follow-up of lymphoma patients.

Immunologic reactivity and prognosis in breast cancer.

The relationship of immune reactivity to the stage of disease and to prognosis within stages was studied in 202 women with breast cancer. Patients were staged according to the following system: those with primary operable breast cancer were classified according to the presence or absence of regional lymph node metastases; those with advanced breast cancer were classified according to the predominant site of metastases: (1) those with skin, soft tissue, or nodal metastases, (2) those with bone metastases, and (3) those with visceral organ metastases. A significant linear trend of decreasing DNCB reactivity was seen with increasing extent of disease (P < 0.01). The results of other tests of immune reactivity, including intradermal skin tests with microbial antigens, and, in patients with advanced breast cancer only, absolute lymphocyte counts, lymphocyte proliferative responses to mitogens and microbial antigens, serum immunoglobulin levels, and T and B‐cell counts, did not change significantly with increasing extent of disease. No significant difference in recurrence distributions was seen when all primary operable breast cancer patients with positive and negative DNCB responses were compared. However, when the presence or absence of lymph node involvement was taken into account, a trend to earlier recurrence for DNCB‐positive patients was seen (P = 0.03). When the survival distributions for all DNCB‐positive and‐negative patients were compared, the DNCB‐positive patients showed a significantly longer survival (P < 0.01). However, when the survival distributions for DNCB‐positive and‐negative patients with either primary operable or advanced breast cancer were compared separately, significant differences were not seen. Other tests of immune function, including intradermal skin tests with microbial antigens, absolute lymphocyte counts, and lymphocyte responses to mitogens in vitro, were not useful in distinguishing prognostically favorable groups among patients with advanced disease. Advanced breast cancer patients who were given an adequate trial of combination chemotherapy showed no difference in response rate or survival when DNCB‐positive and‐negative patients were compared. We conclude that, although DNCB reactivity is progressively impaired in patients with increasing tumor burden and correlates with survival in breast cancer patients in general, in our experience such tests do not provide prognostically important information above that given by careful clinical and pathologic staging.