Neoadjuvant chemotherapy for bladder cancer: the MSKCC experience.
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Aged↗
Biomedical subjects
W R Fair
Publications and source records attributed to W R Fair.
Expression of transforming growth factor alpha and epidermal growth factor receptor messenger RNA in neoplastic and nonneoplastic human kidney tissue.
Using Northern blot analysis, we have demonstrated that mRNA for transforming growth factor alpha (TGF-alpha) was expressed in five malignant kidney tissue specimens but was not detected in their autologous nonneoplastic homologues. In addition, the expression of epidermal growth factor (EGF) receptor mRNA in these malignant tissues was 2- to 3-fold greater than in nontransformed tissues. In two cases examined using immunohistochemistry, we were able to correlate the increased expression of the mRNA with an increase in protein expression. Since TGF-alpha is known to bind to the EGF receptor, the finding of an increased expression of both TGF-alpha and EGF receptor mRNA in kidney tumor tissue suggests that interaction between TGF-alpha and the EGF receptor may play a role in promoting transformation and/or proliferation of kidney neoplasms, perhaps by an autocrine mechanism.
Blotting, Northern↗
Effect of coumarin on the normal rat prostate and on the R-3327H prostatic adenocarcinoma.
Coumarin, the parent compound of warfarin, has been observed to stimulate macrophages, increase phagocytosis, and induce changes in lymphocyte-mitogen responsiveness in cancer patients. Coumarin has been reported to have antitumor activity in human melanomas and renal cancer when used in conjunction with the H-2 antagonist, cimetidine. We have observed that coumarin has antiprostatic activity in rats. When coumarin was given to mature rats at a dose of 40 mg/kg, a significant decrease in the size of the prostate, seminal vesicles, and testes was observed. Testosterone levels were unchanged or slightly elevated, consistent with an antiandrogenic-like activity. Similarly, coumarin significantly inhibited the androgen-induced increase in prostatic size when administered to castrated rats receiving testosterone. Coumarin given to rats bearing the R-3327H androgen-sensitive, prostate-derived tumor decreased the size of the primary tumor. The effect was greater than that produced by castration. Coumarin is worthy of further consideration as an agent for use in controlling the normal and abnormal growth of the prostate.
Adenocarcinoma↗
Association of the Lewis blood-group phenotype with recurrent urinary tract infections in women.
Blood-group antigens are found on the surface of urothelial cells and may affect bacterial adherence and thereby the susceptibility to urinary tract infection. We determined the ABO, P, and Lewis blood-group phenotypes in 49 white women with histories of recurrent urinary tract infections and compared them with those found in 49 healthy control women without recurrent urinary tract infections. There was no significant difference between the two groups in the distribution of the ABO or P phenotypes. The distribution of Lewis blood-group phenotypes among control women was similar to that in the general population: secretor phenotype (Le(a-b+)), 74 percent; nonsecretor phenotype (Le(a+b-)), 18 percent; and recessive phenotype (Le(a-b-)), 8 percent. The following distribution was noted among the women with recurrent urinary tract infections: secretor phenotype, 45 percent; nonsecretor phenotype, 29 percent; and recessive phenotype, 26 percent (P = 0.002). When the women with nonsecretor and recessive phenotypes were combined and considered collectively, the odds ratio (an estimate of relative risk of recurrent urinary tract infection) for those without the secretor phenotype was 3.4 (95 percent confidence interval, 1.5 to 7.9). We conclude that there is an increased frequency of the Lewis blood-group nonsecretor (Le(a+b-] and recessive (Le(a-b-] phenotypes among women with recurrent urinary tract infections.
Adult↗
Blood group-related antigens in human kidney: modulation of Lewis determinants in renal cell carcinoma.
Seven mouse monoclonal antibodies and the lectin Ulex europaeus, detecting blood group related antigens of the ABH and Lewis systems, have been used to determine the immunophenotype of human renal cell carcinomas. Immunohistochemical analyses have demonstrated that these antigenic systems are differentially expressed by distinct normal cell types and domains of the human nephron. In the present study we analyzed the immunophenotype of 29 primary and 15 metastatic renal carcinomas by the immunoperoxidase method. Blood type was known in all of the cases and secretor status in nine cases. ABH specificities were not detected in tumor cells of the primary tumors studied, although two of the metastases showed heterogeneous expression of H and A antigens, respectively. Lewisx (Lex) determinant was detected in 76% of primary renal cell carcinomas; however, Lex was only expressed by occasional cells in 20% of the metastatic tumors analyzed. Lewisa (Lea) was detected with a heterogeneous pattern of expression in 31% of the primary and 26% of the metastatic renal tumors studied. Lewisy (Ley) antigen expression was found in 17% of the primary and 20% of the metastatic tumors analyzed. Detection of precursor type 1 structure was observed in 28% of primary and 20% of metastatic renal cell carcinomas. The present study suggests the histogenesis of renal cell carcinoma in the proximal nephron, based on the expression of Lex and Lea antigens. It also shows: (a) an apparent deletion, downregulation or structural modification of Lex determinant in most of the metastatic tumors; (b) undetectable levels of ABH specificities in tumor cells of primary renal cell carcinoma; and (c) enhanced expression and/or neosynthesis of precursor type 1 structure and Ley determinant in some renal cell carcinomas.
ABO Blood-Group System↗
Initial evaluation of a new epithelial antigen (T16) for bivariate flow cytometry of bladder irrigation specimens.
Bivariate flow cytometry (FCM) was used to study immunofluorescent T16 mouse monoclonal antibody (Mab) binding simultaneously with propidium iodide DNA measurements in bladder irrigation specimens from 30 patients with a history of bladder cancer. Aliquots of the same samples were stained with acridine orange (AO) and examined by conventional FCM. T16 Mab is believed to be specific for epithelial cells in this type of specimen and stained from 13% of the cells in a patient with cystitis to 95% of the cells in a patient with an atypical papilloma. In combination with DNA measurements, this antibody increased the sensitivity of FCM in patients with severe cystitis and relatively small numbers of tumor cells, but the diagnostic specificity may be decreased and the criteria established for interpreting univariate flow cytometry may have to be re-evaluated and modified.
Antibodies, Monoclonal↗
Detection of bladder carcinoma in females by flow cytometry and cytology.
The sensitivity of bladder wash flow cytometry (BWFCM), voided urinary cytology (VUC), and cytology of catheterized urine obtained at the time of cystoscopy (CUC) were reviewed on all women evaluated for bladder cancer at Memorial Sloan-Kettering Cancer Center between June 1985 and December 1986. This comprised sixty-four episodes of pathologically proven bladder cancer in 48 women. Considering positive and suspicious results jointly the sensitivities of BWFCM, CUC and 3 VUC were 75%, 64% and 56%, respectively. If only positive results were considered (i.e., suspicious results considered as negative), the sensitivities of BWFCM, CUC and 3 VUC were 64%, 31% and 32%, respectively. The sensitivities of these tests are less than for a predominantly male population, presumably related to the presence of squamous epithelium and greater frequency of pyuria. However, bladder wash flow cytometry and conventional cytology are still a very valuable addition to cystoscopic examination, and the combination of BWFCM with conventional cytology is more sensitive than either procedure alone.
Adult↗
Superficial bladder cancer treated with bacillus Calmette-Guerin: a multivariate analysis of factors affecting tumor progression.
A multivariate analysis was performed on data from 221 patients with superficial bladder tumors (papilloma in 30, grade II to III stage Ta in 51, grade II to III stage Tis in 111 and grade II to III stage T1 in 29) who were treated with intravesical bacillus Calmette-Guerin and followed for a minimum of 24 months or until progression. The purpose of this analysis was to identify prognostic variables predictive of tumor progression defined as muscle invasion, metastasis or endoscopically uncontrolled superficial bladder carcinoma involving the bladder and/or prostatic urethra. Variables examined before bacillus Calmette-Guerin, and at 3 and 6 months after bacillus Calmette-Guerin included age, sex, race, purified protein derivative reaction, duration of disease, tumor category, tumor grade, multifocality, results of cytology, flow cytometry, cystoscopy, biopsy, prior chemotherapy and bacillus Calmette-Guerin treatment regimen. Significant variables (Cox regression analysis, p less than 0.07) for tumor progression were before bacillus Calmette-Guerin--stage T1 tumors and duration of disease less than 1 year, at 3 months after bacillus Calmette-Guerin--stage T1 tumor, duration of disease less than 1 year, positive cytology studies and multifocality, and at 6 months after bacillus Calmette-Guerin--stage T1 tumor, positive cytology and positive biopsy other than stage T1 tumors. Prognostic risk groups were best defined at 6 months after bacillus Calmette-Guerin, the probability of tumor progression thereafter being at 1, 3 and 5 years, respectively, as follows: for risk group 1 (T1 tumor)--71, 100 and 100 per cent, for risk group 2 (positive biopsy other than T1 plus positive cytology)--25, 79 and 100 per cent, for risk group 3 (either positive biopsy other than stage T1 or positive cytology studies)--18, 40 and greater than 81 per cent, and for risk group 4 (negative biopsy and negative cytology studies)--2, 11 and 26 per cent, respectively. Evaluation of patients with superficial bladder carcinoma at 6 months after intravesical bacillus Calmette-Guerin therapy identifies the probability of tumor progression. Patients at high risk for tumor progression require alternative treatment strategies, whereas low risk patients can be observed for further therapy if necessary.
BCG Vaccine↗
Intravesical bacillus Calmette-Guerin therapy for in situ transitional cell carcinoma involving the prostatic urethra.
A total of 23 patients presenting with multifocal superficial bladder cancer and concomitant in situ transitional cell carcinoma of the prostatic urethra (mucosal in 19 and ductal in 4) underwent transurethral resection and intravesical bacillus Calmette-Guerin therapy. Median followup was 51.6 months (range 6 to 105 months). Of the 23 patients 13 (48 per cent) had a complete response with a median followup of 43.7 months without recurrence. Progression of some type (local, muscle invasion or metastasis) occurred in 10 patients (44 per cent); none occurred in the prostatic urethra. Median interval free of progression was 55.7 months; 7 of 10 patients required cystectomy for progression or refractory disease in the bladder (prostate negative for transitional cell carcinoma). A trial of complete transurethral resection plus intravesical bacillus Calmette-Guerin is a viable alternative to immediate radical cystectomy for patients with mucosal and/or ductal involvement of the prostatic urethra with in situ transitional cell carcinoma.
Administration, Intravesical↗
Cytotoxicity of high energy shock waves: methodologic considerations.
In vivo and in vitro experimentation with high energy shock waves (HESW) is necessary to further our understanding of the biologic effects and potential application of this novel energy form. Factors are identified which are critical to the design and subsequent interpretation of HESW experimentation. First, the nature of the containment vessel and the presence or absence of acoustic interfaces are shown to significantly alter the outcome of cell suspension experiments. Second, the effects of HESW are shown to differ markedly for cells in suspension versus cells in tissue making comparisons between the two uncertain. Finally, the need for appropriate negative controls is demonstrated with in vivo experiments to control for the generalized toxicity which occurs when small animals are exposed to such an intense force distributed over a relatively large area. These findings affect the interpretation of previously reported work which investigated the cytotoxic potential of HESW.
Animals↗
Flow cytometry as a predictor of response and progression in patients with superficial bladder cancer treated with bacillus Calmette-Guerin.
Simultaneous bladder wash flow cytometry, voided urinary cytology and cystoscopic examinations were performed at 3-month intervals during a median of 18 months (range 5.5 to 50 months) in 65 patients receiving intravesical bacillus Calmette-Guerin treatment for superficial bladder cancer. Of the 65 patients treated 36 (56 per cent) had a complete response, 12 (18 per cent) had no response and 17 (26 per cent) had progression. Results of examinations at 6 months suggested that a negative bladder wash flow cytometry (29 of 36 patients, r equals 0.73, p less than 10(-7) is a strong predictor of response to bacillus Calmette-Guerin, comparable with cytological (r equals 0.60, p less than 10(-7) or cystoscopic (r equals 0.38, p less than 0.005) examinations alone or combined with cytology (r equals 0.74, p less than 10(-7)). At 6 months a positive bladder wash flow cytometry (r equals 0.44, p less than 0.0005) is as strong a predictor of disease progression as a positive cystoscopic examination (r equals 0.43, p less than 0.0005). The combination of bladder wash flow cytometry and voided urinary cytology is not superior to positive bladder wash flow cytometry alone. Median estimated interval to progression for these patients treated with bacillus Calmette-Guerin was 38 months. In the subgroup with positive bladder wash flow cytometry at 6 months the median interval to progression was 30 months. With a negative bladder wash flow cytometry at 6 months the probability of survival free of progression at 30 months was 85 per cent (p less than 0.01). Thus, negative bladder wash flow cytometry at 6 months is a strong predictor of response to bacillus Calmette-Guerin and also survival free of progression.
Administration, Intravesical↗
Primary carcinoma of the bulbo-membranous urethra.
Twenty-four cases of primary carcinoma of the bulbo-membranous were reviewed. While half of them had history of gonorrhea or urethral stricture, most of patients initially presenting with high grade (58%) and high stage (91%) contributed to the poor prognosis of the patients studied. Some patients with clinical localized disease were cured by radical cysto-prostatectomy, penectomy with or without emasculation and resection of inferior pubic rami following with or without preoperative irradiation. The result of radical irradiation is uniformly poor. Based on the small number of cases in this report, we could not conclude that preoperative irradiation would improve the results of excision; however, the recent introduction of neoadjnvant chemotherapy for patients with transitional cell carcinoma warrants further investigation.
Adult↗
Immunohistochemical characterization of two monoclonal antibodies, P25.48 and P25.91, which define a new prostate-specific antigen.
We have generated two new mouse monoclonal antibodies against prostate cancer. P25.48 (IgG3) and P25.91 (IgG2a) were derived from a fusion using fresh prostate cancer cells as the immunogen. Initial screening was performed by indirect immunofluorescence on frozen tissue sections of prostate cancer specimens. The specificity analysis was performed by indirect immunoperoxidase on frozen sections of normal tissues and benign and malignant prostate tissues. P25.48 and P25.91 did not react with any benign prostatic tissues (0 of 17), but reacted with a subset of the malignant prostatic tissues. Five specimens of well-differentiated carcinoma were tested and did not react with P25.48 or with P25.91. Of 16 higher grade specimens, nine reacted with both P25.48 and P25.91, one reacted with P25.48 only, and one reacted with P25.91 only. In most positive cases, the reactivity was heterogenous. P25.48 and P25.91 showed a very restricted pattern of reactivity in nonprostatic tissues. Of 50 normal specimens, only one breast specimen showed some reactivity. None of the nine fetal tissues or of the 15 malignant tissues tested reacted with these monoclonal antibodies. The pattern of reactivity of P25.48 and P25.91 suggests that they recognize the same antigen. This antigen is selectively expressed by malignant prostatic epithelium. In addition, it appears to be distinct from all other previously described prostate cancer-associated antigens.
Antibodies, Monoclonal↗
Blood group-related antigens in human urothelium: enhanced expression of precursor, LeX, and LeY determinants in urothelial carcinoma.
Seven mouse monoclonal antibodies and the lectin from Ulex europaeus, detecting blood group specificities of the ABH and Lewis systems, have been used to define the expression and/or modulation of these antigenic structures in human normal urothelium and tumors of the urinary bladder. The reagents employed recognize the following blood group related antigens: A, B, H, Lewisa (Lea), Lewisb (Leb), Lewisx (Lex), Lewisy (Ley), and type 1 precursor chain. Immunohistochemical studies have demonstrated that these antigenic systems are differentially expressed in the urothelium of secretor and nonsecretor individuals. The normal urothelium of secretors is particularly rich in ABH blood group antigens as well as Leb and Ley specificities. Nonsecretors, however, either lack or show decreased and patchy expression of H, Leb, and Ley antigens. In general, areas affected by carcinoma in situ showed deletion of ABH, as did invasive carcinomas, as demonstrated by other investigators. This was not a universal observation, however, as variable expression of ABH antigens occurred in a few invasive tumors. Lex antigen was not expressed in normal urothelium except for occasional umbrella cells, but was demonstrated in the majority of invasive tumors, regardless of blood type and secretor status of the individuals studied. Ley determinant, which was poorly expressed in the normal urothelium of nonsecretor individuals, was found in all tumors analyzed. An accumulation of non-fucosylated precursor structure was also a feature of invasive carcinoma, particularly in secretor individuals. A panel of anti-blood group antibodies, encompassing A, B, Lex, Ley and type 1 precursor chain specificities for use in patients of known secretor status, may provide useful early markers of malignant change in the urothelium.
Adult↗
Heparin-binding growth factor isolated from human prostatic extracts.
Prostatic tissue extracts from patients with benign prostatic hyperplasia (BPH) and prostatic carcinoma were fractionated using heparin-Sepharose chromatography. The mitogenic activity of eluted fractions on quiescent subconfluent Swiss Albino 3T3 fibroblasts was tested employing a tritiated-thymidine-incorporation assay. Two peaks of activity were consistently noted--one in the void volume and a second fraction which eluted with 1.3-1.6 M NaCl and contained the majority of the mitogenic activity. Both non-heparin- and heparin-binding fractions increased tritiated incorporation into a mouse osteoblast cell line (MC3T3), while only the heparin-binding fractions stimulated a human umbilical vein endothelial cell line (HUV). No increased uptake of thymidine was seen using a human prostatic carcinoma cell line (PC-3). Sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS/PAGE) of lyophilized active fractions showed a persistent band at 17,500 daltons. The purified protein demonstrated angiogenic properties using the chick embryo chorioallantoic membrane (CAM) assay. Western blot analysis using antibodies specific to basic fibroblast growth factor (bFGF) or acidic FGF (aFGF) demonstrated that the former, but not the latter, bound to prostatic growth factor (PrGF), and inhibited its mitogenic activity as well. It appears that PrGF shares homology with basic fibroblast growth factors.
Allantois↗
Expression of basic fibroblast growth factor mRNA in benign prostatic hyperplasia and prostatic carcinoma.
In our previous work we demonstrated that prostate-derived growth factor (PrGF) is homologous to basic fibroblast growth factor (bFGF), not acidic fibroblast growth factor (aFGF). Using Northern blot analysis we now show that the messenger RNA for bFGF but not aFGF is expressed in benign prostatic hyperplastic (BPH) tissue as well as in carcinoma of the prostate (CAP). This not only corroborates our previous results, but suggests that PrGF is produced locally and not merely stored in the prostate. The demonstration of local production of bFGF by prostate tissue may indicate that this growth factor plays a role, either alone or in conjunction with other factors, in the etiology of benign hyperplasia or prostatic cancer.
Animals↗
The effect of high energy shock waves (HESW) on human bone marrow.
The effect of High energy shock waves (HESW) on the viability and proliferation of normal human bone marrow cells was evaluated. A dose dependent increase in cytotoxicity with an increase in the number of HESW was demonstrated. In general 700 HESW immediately reduced the cell viability of bone marrow cells by 50%. The CFU-GM assay provides a method to evaluate the effect of HESW on the proliferative capacity of bone marrow. Following HESW treatment the colony forming ability of trypan blue excluding cells also felt in a dose dependent fashion, but some variation in sensitivity was noted. By comparing the sensitivity of various cells, the cells of normal human bone marrow were felt to be less sensitive to HESW effects than those of other tissue cultured cells or malignant cell lines.
Bone Marrow↗
Flow cytometry and cytology as response indicators to M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin).
We evaluated 23 patients treated with neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin for muscle invasive bladder carcinoma with serial bladder wash flow cytometry and serial urinary cytology. The sensitivities of bladder wash flow cytometry and cytology in detecting bladder cancer were 74 and 47 per cent, respectively, based on subsequent diagnosis from biopsy and cystectomy specimens. Exclusion of those cases without surface carcinoma increased the sensitivities of bladder wash flow cytometry and cytology to 93 and 60 per cent, respectively. Persistently positive bladder wash flow cytometry and cytology correctly predicted residual disease in 88 and 100 per cent, respectively. However, negative bladder wash flow cytometry and cytology after chemotherapy were not reliable indicators of disease-free status.
Antineoplastic Combined Chemotherapy Protocols↗