Biomedical subjects
J Sheinfeld
Publications and source records attributed to J Sheinfeld.
Urinary reconstruction and diversion.
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Results of a multicenter trial using the BTA test to monitor for and diagnose recurrent bladder cancer.
OBJECTIVES: We compare the Bard BTA (bladder tumor antigen) test to voided cytology studies in patients undergoing surveillance cystoscopy for recurrent bladder cancer. MATERIALS AND METHODS: A prospective, blinded, multicenter trial was performed. RESULTS: A total of 499 patients underwent 1,014 cystoscopic examinations and tumor was identified in 151. The bladder tumor antigen test was more sensitive than cytology studies in detecting recurrent cancer (p < 0.001), being positive in 61 cases versus 25 for cytology. The trial in healthy volunteers and nonurological patients estimates bladder tumor antigen test specificity to be 95.9%. CONCLUSIONS: The bladder tumor antigen test is a simple, rapid and inexpensive adjunct to cystoscopy, and the results are equivalent or superior to those of voided cytology as performed in this trial.
Etoposide and cisplatin adjuvant therapy for patients with pathologic stage II germ cell tumors.
PURPOSE: Two options cure nearly all patients with pathologic stage II nonseminomatous germ cell tumors (NSGCTs): two cycles of adjuvant chemotherapy with cisplatin, vinblastine, and bleomycin (PVB) or cisplatin, vinblastine, bleomycin, cyclophosphamide, and dactinomycin (VAB-6); or close observation with full treatment at relapse. Two cycles of etoposide plus cisplatin (EP) were given to selected patients with pathologic stage II NSGCT and high-volume nodal metastases. PATIENTS AND METHODS: All patients had pathologic stage II NSGCT with one or more of the following features found at retroperitoneal lymph node dissection (RPLND), suggesting a greater than 50% likelihood of relapse after observation alone: (1) any lymph node involved by tumor greater than 2 cm (stage N2b); (2) > or = six nodes involved with tumor (stage N2b); and (3) extranodal extension (stage N3). Two cycles of therapy were given at 21-day intervals; each cycle consisted of etoposide 100 mg/m2 plus cisplatin 20 mg/m2 per day given on days 1 to 5. RESULTS: Fifty patients were treated with two cycles of EP. Treatment was well tolerated; five patients (10%) were admitted for nadir fever and none had grade II or greater neurologic, renal, or pulmonary toxicity. All 50 patients are alive and relapse-free at a median follow-up time of 35 months (range, 12 to 72). The follow-up duration has been > or = 2 years for 42 patients. CONCLUSION: A treatment program that consists of two cycles of EP is effective in preventing relapses in patients with completely resected pathologic stage N2b and N3 NSGCT. The likelihood of relapse without adjuvant cisplatin-containing chemotherapy in this group has been shown to be greater than 50%. As has been demonstrated in patients with disseminated germ cell tumor (GCT), EP can be considered a therapeutic option in the adjuvant setting for completely resected N2b and N3 NSGCT.
The role of pelvic lymphadenectomy and radical cystectomy for lymph node positive bladder cancer. The Memorial Sloan-Kettering Cancer Center experience.
BACKGROUND: The impact of pelvic lymph node dissection (PLND) on the survival of patients with lymph node positive bladder cancer is controversial. METHODS: The authors retrospectively analyzed the long term and disease free survival among 140 patients with lymph node positive disease having radical cystectomy and bilateral PLND at the Memorial Sloan-Kettering Cancer Center between 1980 and 1988. They also sought to identify prognostic variables for recurrence and survival. RESULTS: Of the 140 patients, 36 (25.7%) were found to be tumor free, with 22 (15.7%) followed longer than 5 years. Regression analysis identified P-category as the only prognostic parameter influencing survival. Patients with tumors confined to the bladder (< or = P3a) had a 52.6% 5-year survival rate compared with 23.4% among those with extravesical (> or = P3b) tumors. N-category was a significant predictor for recurrence but not survival. CONCLUSIONS: As judged from this analysis, radical cystectomy and a systematic PLND alone can provide favorable outcome in some patients with regional nodal metastases from bladder cancer. The survival advantage is most pronounced in patients with low stage primary tumors. Stage migration and patient selection may have biased these findings.
Bladder cancer: advances in biology and treatment.
Integrating systemic chemotherapy in the treatment of patients with invasive bladder cancer is essential to improve survival because the majority of deaths are from systemic relapse. However, as experience with invasive tumors evolves, it is clear that treatment recommendations need to be tailored to an individual patient based on metastatic risk and, ideally, sensitivity to treatment. For those with tumors that do not extend through the bladder wall, standard therapy remains radical surgery. Nevertheless, encouraging results are being reported with increasing frequency using strategies designed to preserve bladder function through a variety of means. Crucial to the recommendation of a specific approach for an individual is improving our ability to define prognosis prior to initiating treatment. Patients with a high risk of systemic recurrence generally require chemotherapy, although the optimal route of integration, pre vs. post-operatively, remains controversial. In those patients who require it, chemotherapy can be administered more safely with the concomitant administration of hematopoietic growth factors. These factors alone, however, are unlikely to improve overall survival. Crucial to the latter effort will be the identification of more active agents, improving our understanding of intrinsic and acquired resistance to chemotherapy, and better delivery of the chemotherapeutic agents currently available. Of equal importance, is the enrollment of patients in clinical trials. These can include large scale randomized comparisons with using a survival end-point, as well as new therapies in high risk populations. The latter would include patients with advanced T3b, T4 and N+ disease, with a high risk of metastatic failure, and low complete response proportions to presently available regimens.
Positive urinary cytology following a complete response to intravesical bacillus Calmette-Guerin therapy: pattern of recurrence.
The pattern of disease recurrence was examined in 75 patients with clinically undetectable positive urinary cytology results following a complete response to intravesical bacillus Calmette-Guerin (BCG) therapy for superficial bladder cancer. A complete response was defined as negative cystoscopy and biopsy findings, urine cytology and flow cytometry (when available) for at least 1 year following therapy. Urinary cytology was positive in the absence of clinical disease at a median of 25 months (range 12 to 96) after BCG administration. Clinically recognizable disease (defined by a positive biopsy or visible papillary tumor) developed at a median of 6 months (range 2 to 60) after positive cytology was detected in 62 patients (83%), while 13 (17%) had persistently positive cytology results without an obvious source at a median of 6 months (range 2 to 29). The bladder was the single most common site of recurrence, with 39 recurrences developing in 36 patients (58%, 3 of whom had recurrent cancer after a complete response to each of 2 separate courses of BCG): 30 (77%) were superficial (stages Ta in 2, Tis in 25, Tis/T1 in 2 and T1 in 1) and 9 (23%) were invasive (stage T2+). Median interval to the detection of bladder recurrence following a positive cytology result was 6 months (range 2 to 50). Upper urinary tract disease developed at a median of 7 months (range 2 to 41) in 11 patients (18%), while 7 (11%) had a prostatic recurrence at a median of 5 months (range 2 to 60). There were 9 synchronous bladder and prostate (5) or upper tract (4) recurrences in 8 patients (13%) at a median of 22 months (range 2 to 40) in the former group and 15.5 months (range 3 to 20) in the latter group. Overall, of 75 sites of recurrence in 62 patients 48 (64%) were in the bladder, 15 (20%) in the upper urinary tract and 12 (16%) in the prostate. High risk patients with superficial bladder cancer who have clinically unconfirmed positive urinary cytology results following a complete response to intravesical BCG therapy require aggressive evaluation of intravesical and extravesical sites to detect the presence of persistent or progressive in situ or invasive disease.
Association of P53 nuclear overexpression and tumor progression in carcinoma in situ of the bladder.
We investigated the prevalence and clinical relevance of p53 nuclear overexpression, as detected by antibody PAb1801 and immunohistochemistry, in 33 patients with carcinoma in situ of the bladder. Median followup was 124 months. Disease progressed in 16 patients (48%) during followup. The association between p53 nuclear overexpression and tumor progression was assessed by multivariate analysis, controlling for possible confounding variables, such as patient age and sex, presence of associated stage Ta bladder tumor and adjuvant bacillus Calmette-Guerin therapy. Patients were stratified into 2 groups according to the per cent of tumor cells displaying p53 nuclear overexpression: group 1-18 with less than 20% tumor cells positive and group 2-15 with 20% or more tumor cells positive. Disease progressed in 3 patients (16.7%) in group 1 and in 13 (86.7%) in group 2 (p < 0.0001). Detection of p53 nuclear overexpression in 20% or more tumor cells was the only independent marker of tumor progression in univariate and multivariate analyses (p = 0.004, adjusted relative risk 8.6, 95% confidence interval 2 to 40). Death specifically from bladder cancer was also associated with this altered pattern of p53 expression (p = 0.01, Fisher's exact test). We conclude that p53 nuclear overexpression is an early event in bladder cancer, occurring in 48% of cases of carcinoma in situ of the bladder. Our results also suggest that p53 nuclear overexpression offers significant clinical information and may be a useful tool in the selection of therapy for patients with carcinoma in situ of the bladder.
Nonseminomatous germ cell tumors of the testis: current concepts and controversies.
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Experience with neoadjuvant diethylstilboestrol and radical prostatectomy in patients with locally advanced prostate cancer.
OBJECTIVE: To report our experience with neoadjuvant endocrine therapy and radical retropubic prostatectomy (RRP) in patients with locally advanced prostate cancer. PATIENTS AND METHODS: Fifty-five patients with prostatic adenocarcinoma (18 clinical stage B2/3, 27 clinical stage C, and 10 clinical stage D0) were treated with diethylstilboestrol (DES) 3 mg/d (median time 12 weeks, range 5-36) followed by pelvic lymph node dissection and planned RRP. Clinical response was monitored bi-weekly with serum prostate-specific antigen (PSA), serum acid phosphatase and digital rectal examination. RESULTS: The median pre-treatment serum PSA was 20.4 ng/ml (range 1.2-620). The median post-treatment, pre-operative serum PSA was 0.4 ng/ml. Twenty-seven (49%), 41 (75%) and 54 (98%) patients had serum PSA levels that were undetectable, < 1.0 ng/ml and < 4.0 ng/ml respectively. In 15 patients, transrectal ultrasound measurement of prostatic volume changes was performed, and all demonstrated prostate volume reduction (median reduction 35%, range 18-45). All 55 patients underwent pelvic lymphadenectomy, with 47 (85%) undergoing RRP. Of the eight patients not undergoing RRP, three had negative lymph nodes but prostate resection was not deemed feasible and five had nodal metastases as determined by frozen section analysis. Final pathological stage revealed the following distribution: organ confined tumours, 18 (33%); capsular perforation with negative surgical margins, seminal vesicles and lymph nodes, seven (13%); seminal vesicle and/or margin involvement with negative lymph nodes, 18 (33%); lymph node metastases, 12 (22%). Neither pre-therapy serum PSA nor serum PSA response was predictive of final pathological stage. With a median follow-up interval of 26 months (range 12-49), 21 patients (38%) have undetectable serum PSA without adjuvant therapy. CONCLUSIONS: Our results indicate that despite clinical evidence suggestive of downstaging, the majority of patients with locally advanced prostatic carcinoma managed with neoadjuvant DES and RRP continue to have pathological evidence of extraprostatic carcinoma.
Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression.
BACKGROUND: Approximately one third of the patients with superficially infiltrative transitional cell (T1-TNM pathological staging system) bladder carcinoma who are treated with transurethral resection alone have disease progression. Despite precise pathologic staging and grading, clinical outcome in these patients is not predictable. Recent reports reveal that mutations of the p53 tumor suppressor gene (also known as TP53) occur commonly in bladder cancers. PURPOSE: The aim of this study was to investigate the hypothesis that altered patterns of expression of the protein product(s) of the mutated p53 tumor suppressor gene are associated with tumor progression in patients with T1 bladder cancer. METHODS: We examined deparaffinized tumor tissue specimens from transurethral resection in 43 patients with T1 bladder cancer who had not received adjuvant therapy. Nuclear overexpression of p53 protein was detected by immunohistochemical analysis using the mouse monoclonal antibody PAb1801, which stains both wild-type and mutant p53 proteins. The data were then correlated with the following conventional prognostic variables: age, sex, histologic presence of associated carcinoma in situ, and vascular invasion of tumor. Disease progression rates per 100 person-years were calculated. RESULTS: Median follow-up was 119 months. None of the urothelial and stromal cells from normal bladder specimens showed nuclear overexpression of p53 protein, but patients with T1 bladder tumors could be stratified into two groups with different patterns of staining for p53 protein. Eighteen patients (42%) had no more than 20% tumor cells with positive nuclear staining (group A), while the remaining 25 patients (58%) had 20% or more tumor cells with nuclear immunoreactivity (group B). Patients in group B had a significantly lower progression-free interval (P < .001). Disease progression rates were 20.5% per year for group B and 2.5% for group A. CONCLUSION: These results suggest that T1 bladder cancers exhibiting nuclear overexpression of p53 protein have a higher probability of disease progression. This study also suggests that p53 overexpression is an important prognostic factor in these patients and may be useful in selecting appropriate therapy. IMPLICATIONS: Large prospective studies are needed to confirm these results and to evaluate nuclear overexpression of p53 protein as a prognostic marker in bladder cancer.
Biological markers of prognosis in transitional cell carcinoma of the bladder: current concepts.
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Management of the postchemotherapy residual mass.
The role of surgery in patients with advanced germ-cell tumors after chemotherapy has evolved substantially in the era of combined modality therapy. In evaluating patients for surgery after chemotherapy, the clinician must consider carefully the histologic type (seminoma versus nonseminomatous germ-cell tumors) of the primary tumor as well as the extent of the residual disease. Criteria designed to select patients with non-seminomatous tumors in whom the surgical histologic findings are negative are associated with substantial error. A normal radiographic evaluation in patients with nonseminomatous germ-cell tumors is not entirely predictive of negative pathology findings, and the treating physician must consider the risk of residual tumor despite a radiographic complete remission. In contrast, patients with seminoma have less potential for residual tumor, and the size of the residual disease permits more accurate selection of patients who still have malignancy. Continued research is needed to improve the sensitivity and specificity of patient selection for surgery after chemotherapy in order to limit the toxicity of curative therapy.
High-dose chemotherapy and autologous bone marrow rescue for patients with refractory germ cell tumors. Early intervention is better tolerated.
Therapy with high-dose carboplatin plus etoposide-based chemotherapy plus autologous bone marrow rescue (AUBMR) was administered to 29 patients with advanced germ cell tumors (GCT) refractory to cisplatin-based chemotherapy. Two groups of patients with refractory disease were treated. Sixteen patients had been identified as "poor risk" at diagnosis and had an inappropriately slow decline of serum tumor markers after two cycles of induction cisplatin-based therapy (Group A). In addition, 13 patients were treated who had never had a complete response (CR) or had relapses after ifosfamide-based salvage chemotherapy (Group B). Patients in Group A were treated with high-dose carboplatin etoposide, and patients in Group B received high-dose carboplatin, etoposide, and cyclophosphamide. Fifteen of 29 (52%) patients had a CR (9, Group A; 6, Group B). The patients in Group A had fewer hematologic toxic effects, and the median number of days from day 0 to a granulocyte count greater than 0.5/microliters was 16 and to a platelet count of more than 50/microliters was 15, compared with 22 days and 23 days in Group B, respectively. There were fewer episodes of culture-positive sepsis in Group A (12%) compared with Group B (26%), and the only treatment-related death occurred in Group B. Therapy with high-dose carboplatin plus etoposide-based chemotherapy plus AUBMR is effective for patients with GCT refractory to regimens of cisplatin with or without ifosfamide. Early use of high-dose chemotherapy reduces hematologic toxic effects and allows patients to start treatment in a more predictable fashion after cytoreduction, rather than when the disease is progressing rapidly.
Blood group antigens in normal and neoplastic urothelium.
The ABO and Lewis blood group antigens are cell surface carbohydrate determinants formed by the sequential addition of saccharides to precursor backbone structures of membrane lipids and proteins. Suppression of normally active glycosyltransferases results in the absence of antigens that are normally expressed. ABH antigen deletion in malignant and premalignant urothelium has been extensively evaluated; it appears to correlate with significantly higher rates of tumor recurrence and disease progression. However, we have recently shown that the ABH blood group system is differentially expressed in the normal urothelium of secretors in contrast to nonsecretor individuals. The normal urothelium of nonsecretors does not express A, B or H determinants; therefore, deletion of ABH antigens can only be ascertained in secretor individuals. Although nonsecretors only comprise 22-24% of the population, this observation mandates a reevaluation of earlier studies. Deletion of A, B or H antigens is noted in carcinoma in situ (CIS), and in invasive and metastatic transitional cell carcinoma (TCC) of secretor individuals. Increased synthesis or activation of normally quiescent glycosyltransferases in bladder tumors can result in the expression of aberrant tumor-associated blood group antigens. Immunohistochemical analysis has demonstrated that Lewis X (Le(x)) is not detected in normal adult urothelium except for occasional umbrella cells. However, papillomas, CIS and TCC expressed Le(x) in 84% of cases, regardless of grade, stage, blood type or secretor status of the individual. The presence of Le(x)-positive cells in bladder lavage specimens enhanced the detection of urothelial tumor cells, correctly identifying bladder tumors in 253/293 (86%) cases compared to a 63% sensitivity for cytology alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Intervention strategies for chemoprevention of bladder cancer.
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Salvage chemotherapy for patients with germ cell tumors. The Memorial Sloan-Kettering Cancer Center experience (1979-1989).
Twenty-eight of 124 (23%) advanced germ cell tumor (GCT) patients who were treated on four successive platin-based induction regimens and who failed to achieve a durable complete response (CR) remain alive (median follow-up, 50 months). An analysis of prognostic factors for response and survival was conducted on the 94 patients who received salvage chemotherapy. Survival and/or response to salvage therapy were significantly enhanced for patients with a prior CR to induction chemotherapy, treatment with a cisplatin-based salvage regimen, a testis primary site, a normal serum human chorionic gonadotropin level, a normal serum lactate dehydrogenase level, one site of metastasis, and an Indiana Class of 6 or less. Patients with a prior incomplete response (IR) had a particularly poor prognosis (P = 0.00007) with only 4 of 52 (9%) patients alive (median follow-up, 37 months) compared with 15 of 42 (36%) patients with a prior best response of a CR (median follow-up, 35 months). The poor survival of patients who fail to achieve a durable CR to induction chemotherapy warrants the continued investigation of new salvage therapy. The identification of prognostic features may direct salvage therapy and aid in the interpretation of clinical trials of salvage regimens.
Association of type 1 blood group antigens with urinary tract infections in children with genitourinary structural abnormalities.
Bacterial adherence to carbohydrate receptors on the surface of urothelial cells is important in the pathogenesis of urinary tract infections. Blood group-related antigens, genetically determined carbohydrate structures found on the urothelial cell surface, may influence the availability of these receptors thereby affecting bacterial adherence and the susceptibility to urinary tract infections. Recent evidence indicates that the immunoanatomical distribution of type 1 blood group-related antigens in urothelium is influenced by ABO, Lewis and secretor phenotypes, women with Le(a-b-) and Le(a+b-) blood phenotypes have more than a 3-fold greater risk of recurrent urinary tract infections compared to Le(a-b+) women and epithelial cells from nonsecretors have more bacterial receptors than cells from secretors. To determine the relation between the expression of type 1 blood group-related antigens and urinary tract infections we performed an immunohistochemical analysis using a well characterized panel of monoclonal antibodies on 72 surgical specimens obtained from children who underwent correction of a structural genitourinary anomaly at the University of Rochester Medical Center from December 1983 to May 1988. Of 72 children 48 had a history of at least 1 documented urinary tract infection. The differences in the distribution of children by type 1 blood group immunophenotype in the infection and noninfection groups were highly significant (p = 0.003, Fisher's exact test). There is an increased frequency of urinary tract infections in children with genitourinary structural anomalies whose urothelium reflects the nonsecretor phenotype, that is they have minimal or undetectable levels of ABO and Leb reactivity compared to those with intense ABO and/or Leb immunoreactivity. Of 17 children with minimal or no ABO or Leb immunoreactivity 16 (94.1%) belonged to the infection group. Furthermore, 23 of 24 patients (95.8%) without a history of urinary tract infection expressed intense ABO and/or Leb immunoreactivity. It appears that the type 1 blood group-related antigen profile of urothelium influences susceptibility to urinary tract infection and it may be important in identifying patients who would benefit from prophylactic antibiotic therapy or earlier surgical intervention.