Flow cytometry was used to detect and quantify expression of a urothelial differentiation antigen (Om5) and nuclear DNA in exfoliated epithelial cells of the urinary bladder from 15 patients with ...nonpapillary carcinoma in situ during and after intravesical therapy with Bacillus Calmette-Guérin (BCG). Before BCG treatment exfoliated cells reacting with the mouse monoclonal antibody Om5 were found in 13 cases. Following treatment Om5 positive cells were still present in 9 cases but 4 patients who had had Om5 positive cells prior to BCG therapy no longer had detectable antigen-positive cells after therapy. Thus intravesical BCG therapy can alter detection of a urothelial differentiation antigen in exfoliated bladder epithelial cells. It is not certain whether this antigen or other differentiation antigens measured by flow cytometry will advance our present techniques for assessing effects of therapy on carcinoma in situ and other bladder tumors. However, five of nine patients showing persistence of Om5 positive cells after therapy were found to have recurrent tumor by biopsy and two others had positive cytology (median follow-up, 13 months). None of the four without detectable antigen-positive cells after therapy had clinical evidence of tumor by cystoscopy, biopsy, or cytology (median follow-up, 12 months). It now appears feasible and desirable to initiate clinical investigations of this and other differentiation antigens in combination with DNA by flow cytometry of bladder irrigation specimens.
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-Hodgkin's 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 approximately 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.
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.
Background. Previous studies in the literature have suggested that radiolabeled F(ab′)2 fragments might be superior to whole immunoglobulin G (IgG) for imaging and therapy of cancer because of their ...greater penetration in tumors. To test this hypothesis, the authors compared tumor and normal tissue uptake along with plasma clearance of 125I‐labeled monoclonal antibody (MoAb) IMMU‐4 whole IgG with its 131I‐labeled F(ab′)2 fragment.
Methods. Five patients with either liver metastases from colorectal cancer (n = 4) or intact primary tumors (n = 1) received a combination of 125I‐IMMU‐4 IgG (2 mCi/1 mg) plus131I‐IMMU‐4 F(ab′)2 (10 mCi/1 mg) as a single 1‐hour intravenous infusion on day 1. Serial blood samples were taken for up to 72 hours postinfusion to determine plasma clearance of each MoAb. On days 3–9, patients underwent exploratory laparotomy in which biopsies of tumor as well as normal tissues (liver, normal colon, lymph node, and blood) were obtained. Tissues were weighed and counted in a gamma counter, and the percent of injected dose per kilogram (%ID/kg) of each antibody, along with the radiolocalization index (RI), was computed (RI = %ID/kg tumor. %ID/kg normal tissue).
Results. Tumor uptake of both antibodies (2.3 ± 0.53 %ID/kg) was significantly higher than that of normal tissues (0.56 ± 0.12; P < 0.001), except for blood (2.8 ± 0.83), resulting in an RI ≥ 3. There were no significant differences in uptake (%ID/g) between F(ab′)2 and IgG (Fab′2 = 2.0 ± 0.57; IgG = 2.6 ± 0.94). The mean ± SD of plasma T½ was slightly shorter for F(ab′)2 (28.8 ± 7.2 hours) than for IgG (45.9 ± 16.7; P = 0.08).
Conclusion. In short, the biodistribution and pharmacokinetics of IMMU‐4 F(ab′)2 were comparable to those of IMMU‐4‐IgG. Cancer 1994; 73:850–7.
Background. Radioimmunodetection of cancer using monoclonal antibody fragments offers certain potential advantages over that with whole monoclonal antibodies, including the ability to image early ...(i.e., to provide images at an early time after injection of the radio‐antibody) while minimizing the incidence of human anti‐mouse antibody response. This paper reports a prospective trial comparing radioimmunodetection with IMMU‐4 (a murine anti‐CEA monoclonal antibody) 99mTc‐labeled Fab′ fragments to conventional imaging in 35 colorectal cancer patients.
Methods. All patients were investigated by conventional diagnostic methods (CDM) within 4 weeks of radioimmunodetection. Surgical corroboration of findings was obtained in 26 patients (15 with evidence of disease on CDM CDM+ and 11 with abnormal serum CEA CDM‐ as the only evidence for recurrence). After 1 mg IMMU‐4 99mTc‐Fab′ was injected (19.3 mCi on average), patients underwent planar/SPECT radioimmunodetection 2–5 hours later and planar radioimmunodetection 18–24 hours later. Three patients underwent a second radioimmunodetection study 16, 20 and 23 months after the first.
Results. Radioimmunodetection was superior to CDM, accurately predicting disease distribution in six nonsurgical and ten CDM+ surgical patients, and was complementary to computed tomography in two nonsurgical and two CDM+ surgical patients. Radioimmunodetection would have directed or changed management decisions in 6 of the 15 (40%) CDM+ surgical patients. Radioimmunodetection correctly identified all recurrent tumor in 8 of 11 CDM‐ surgical patients and was negative in one patient with cirrhosis and no recurrence, representing a potential clinical benefit of 82%. Analyzed on a regional basis, radioimmunodetection was found to be superior to CDM in extrahepatic abdomen and pelvis imaging and was complementary to (although not as accurate as) CDM in the liver. Human anti‐mouse antibody did not develop in any of the patients, including three who were injected twice.
Conclusions: IMMU‐4 99mTc‐Fab′ radioimmunodetection shows promise as a clinically useful diagnostic tool in patients with colorectal cancer, detecting disease often missed by conventional imaging. IMMU‐4 99mTc‐Fab′ may prove useful for serial radioimmunodetection studies, because human anti‐mouse antibody response does not appear to be a problem with this radioimmunoconjugate. It also has the advantage of permitting same‐day imaging. Cancer 1994 73:836–45.
This summary of results with local BRM administration has been brief because the number of clinical situations in which this approach is applicable is quite limited. On the other hand, when applied ...in an appropriate patient population, clinical responses are frequent. In addition, detailed study of the effector cells and cytokines that appear in responding patients may yield information concerning the mechanism of action when BRM therapy is effective. Finally, comparison of the results from clinical trials with the results in experimental animals may help to further elucidate the mechanism by which BRMs exert antitumor effects.
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.
Seventeen patients with Stage II malignant melanoma were treated with vaccines prepared from three allogeneic melanoma cell lines in an attempt to induce a humoral immune response against melanoma ...cell surface antigens. The patients were free of detectable melanoma at the time of vaccination. Vaccines were prepared from three melanoma cell lines that expressed highly restricted melanocyte differentiation antigens. One of these cell lines also expressed an antigen found only on this particular line. The antigens were initially identified by antibodies in autologous serum; they were thus known to be recognized by the human immune system. In addition, two of the cell lines expressed HLA‐A, ‐B, ‐C, and ‐DR antigens; no HLA antigens were detectable on the third line. The vaccines were administered sequentially by subcutaneous injection, mixed with bacillus Calmette‐Guerin (BCG) or Corynebacterium parvum. The patients' sera were tested for antibodies against cell surface antigens of the vaccine cells in protein A assays and immune adherence assays, and the specificity of observed reactions was defined by absorption tests. Antibodies against alloantigens of the vaccine cells developed in 16 patients and in 15 patients, against antigens related to fetal calf serum in the culture medium. The magnitude of the antibody response to alloantigens varied considerably, with no difference between patients who received BCG or C. parvum with their vaccines. Antibodies against the restricted melanocyte differentiation antigens or the unique melanoma antigen expressed by the vaccine cells were not detected.
Chest radiographs are routinely employed in clinical practice. Radiographic findings that are abnormal suspicious (AS) for lung cancer occur commonly. The majority of AS radiographic abnormalities ...are not cancer. This study identifies predictors of true positive (TP) AS and presents models for estimating the probability of lung cancer.
This is a prospective cohort study nested in the randomized National Cancer Institute's Prostate Lung Colorectal Ovarian Cancer Screening Trial (PLCO). First-time AS screens in the screening arm of the PLCO were studied. Associations between nonradiographic and radiographic factors, and TP AS were evaluated by multiple logistic regression.
The PLCO intervention arm had 77,465 individuals, of whom 12,314 were AS and of these 232 (1.9%) had lung cancer (were TP). Important independent predictors of TP were older age, lower education, greater pack years and duration smoking history, body mass index <30, family history of lung cancer, lung nodule, lung mass, unilateral mediastinal or hilar lymphadenopathy, lung infiltrate, and upper/middle chest AS location. The model including these variables had a receiver operator characteristic area under the curve (ROC AUC) of 86.4%. This model excluding the smoking variables had an ROC AUC of 77.1% and excluding all nonradiographic variables had an ROC AUC of 73.3% (p < 0.0001 for all these model differences). Smoking and nonsmoking nonradiographic variables significantly added to prediction.
This study identifies important nonradiographic and radiographic predictors of lung cancer, and presents an accurate model for estimating the probability of lung cancer in individuals with suspicious radiographs. These findings may be of value for screening, research, and patient and clinician decision-making.
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