Biology of BCG response in non-muscle invasive bladder cancer - 2021 IBCN Updates Part III.

Bacillus Calmette-Guerin (BCG) remains the only FDA-approved first-line therapy in patients with high-risk non-muscle invasive bladder cancer. Recurrences, even after adequate BCG therapy, are common and the efficacy of second-line therapies remains modest. Therefore, early identification of patients likely to recur and treatment after recurrence remain critical unmet needs in the clinical care of bladder cancer patients. To address these deficits, a better understanding of the mechanisms of resistance to BCG-therapy is needed. The virtual update of the International Bladder Cancer Network (IBCN) on the biology of response to BCG focused on potential mechanisms and markers of resistance to intravesical BCG therapy. The insights from this meeting will be highlighted and put into context of previously reported mechanisms of resistance to BCG in this review.

Prevention strategies for prostate cancer.

Through the last decade consideration of the role of vitamins and minerals in primary prevention of genitourinary tumors has dramatically changed. Despite all efforts efficacy of a specific compound has not been proven, so far. In consequence, recommendations for a use of vitamins or other supplements with the intention of prostate cancer prevention should be avoided today. In contrast, there is some evidence that life style modification might be helpful: recent investigations suggest that smoking may be involved in prostate cancer carcinogenesis. In addition, there is evidence that moderate food consumption, reduction of dairy products and an Asian or Mediterranean diet might not only prevent prostate cancer but also harbors additional beneficial effects on general health. This move from single compounds to more complex diets can be considered as a change of paradigm in prostate cancer prevention and could be the starting point of future epidemiological research. Disappointing findings with regards to nutritional cancer prevention contrast with a solid evidence concerning the efficacy of chemoprevention using 5a-reductase inhibitors: Long-term use of Finasteride and Dutasteride significantly reduces prostate cancer detection. Further candidate drugs are under investigation. However, translation of these findings into urological practice remains a matter of controversial discussion.

[Intraoperative frozen section diagnosis of the genitourinary tract]. / Intraoperative Schnellschnittdiagnostik des Urogenitaltrakts.

Up to now intraoperative frozen section, diagnosis has been of limited utility in urologic oncology. In the future, it may become more important due to a significant increase in the number of nerve-sparing operations performed for prostate cancer. Accuracy and benefit of intraoperative frozen sections depend both on a good communication between surgeons and pathologists as well as on a strict assessment of the need for surgery in the individual patient. In order to optimize cost-efficiency and to reduce the associated risks the indications for intraoperative frozen sections must be rigorously appraised. This report outlines clinically relevant indications for intraoperative frozen section diagnosis in tumors of the urinary tract, kidneys, prostate, testis and penis according to the most recent guidelines. The diagnostic scope and problems of this method are also discussed.

[Rational follow-up of non-muscle invasive bladder cancer]. / Rationale Nachsorge des nicht-muskelinvasiven Harnblasenkarzinoms.

BACKGROUND: Follow-up for non-muscle invasive bladder cancer (NMIBC) is a challenge for urologists that has not been finally resolved. The intensity of follow-up is based on the recurrence and progression behavior of the tumor as well as the patient's individual situation. MATERIALS AND METHODS: The following article focuses on the current data situation, the valid German S3 guideline and the available instruments for the detection of relapses and progression, taking into account tumor stages and degree of malignancy. RESULTS: Urethrocystoscopy, imaging and urine cytology are generally recommended, but the recommendations appear to be too extensive in the case of so-called intermediate risk profiles. Depending on the situation, urine markers could optimize follow-up, although results from prospective randomized studies are still pending. CONCLUSIONS: The current follow-up of NMIBC is invasive, carries the risk of side effects and increases costs. In the absence of scientific evidence, recommendations for follow-up for NMIBC are naturally based on expert opinion. In the opinion of the authors, overdiagnosis is currently taking place particularly in patients with an intermediate risk profile. The first prospective, marker-based studies are ongoing and will be helpful in the near future to improve the data situation relevant to urological practice.

[Chemoprevention of prostate cancer. Current status]. / Chemoprävention des Prostatakarzinoms. Stand der Dinge.

Fueled by the results from recently published large interventional trials the topic of chemoprevention of prostate cancer has increasingly attracted the interest of practicing urologists. In this analysis the term"chemoprevention" comprises all agents not included in regular food intake. If possible, the results from interventional studies were considered. Today, it must be accepted as evidence-based that chemoprevention of prostate cancer by 5alpha-reductase inhibition using finasteride is possible. Furthermore, there is increasing evidence that selective estrogen receptor modulators (SERMs) may also have preventive potential. Prospective interventional trials investigating these substances are currently underway. Considering the high incidence and the fact that the diagnosis of prostate cancer has serious impact on the future life of the respective individuals further scientific evaluation of chemoprevention of prostate cancer is mandatory.

[The Prostate Cancer Prevention Trial (PCPT). Relevance for clinical practice]. / Das "Prostate Cancer Prevention Trial" (PCPT). Die Bedeutung für den klinischen Alltag.

The Prostate Cancer Prevention Trial (PCPT) has been the first interventional trial directly aimed at the prevention of prostate cancer. A total of 18,882 men over 55 years with a PSA serum level less than 3.0 ng/ml were randomized to receive either the 5-alpha-reductase inhibitor finasteride 5 mg/day or placebo for 7 years. Despite a 25% reduction of prostate cancers in the treatment arm the results were discussed controversially. This criticism was mainly due to the observation of significantly more high-grade cancers in the finasteride group. Meanwhile, results of extensive follow-up analyses have been published suggesting that this finding is most likely due to optimized tumor detection in smaller glands. Further work-up demonstrated that PSA diagnosis and the histopathological examination were not compromised by finasteride. Furthermore, in addition to a decrease of prostate cancer the amount of prostatic intraepithelial dysplasia (PIN) was also reduced under finasteride. Future research must now aim at defining high-risk groups specifically profiting from chemoprevention with a 5-alpha-reductase inhibitor.

Hypomethylation of L1 LINE sequences prevailing in human urothelial carcinoma.

Alterations of DNA methylation were investigated in 6 urothelial carcinoma cell lines and 13 tumor tissues. The methylation of L1 LINE sequences was diminished in all cell lines (by 26 +/- 5%; range, 11-49%) and in most tumors (by 21 +/- 5%; range, 0-60%) compared to normal bladder mucosa. Hypermethylation of the calcitonin gene CpG island was restricted to cell lines and was not found in primary tumors, suggesting it had arisen during culture. In single-cell clones of a urothelial carcinoma cell line, both hypomethylation of L1 sequences and hypermethylation of the calcitonin gene persisted, indicating that they coexist within one cell. DNA methyltransferase expression did not correlate with the methylation status of the cell lines, but rather with histone H3 expression. Accordingly, it was down-regulated in quiescent cells. Aberrant expression of DNA methyltransferase is therefore not likely the cause for altered methylation patterns in urothelial carcinoma. L1 LINE hypomethylation seems to prevail in urothelial carcinoma and in this tumor might be useful for diagnostic or prognostic purposes.

Predisposition towards urolithiasis associated with the NQO1 null-allele.

The distribution of two alleles of the NQO1 gene encoding NADP(H):quinone oxidoreductase was studied in 140 urolithiasis patients and 271 control individuals. The minor allele encoding a protein lacking quinone reductase activity was significantly more frequent (q = 0.214) among these patients than in control individuals (P = 0.135) indicating an increased risk for kidney stone formation among heterozygotes (odds ratio 1.83, confidence interval 1.17-2.86) and homozygotes for the null-allele (odds ratio 2.97, confidence interval 0.78-11.33). Since NADP(H):quinone oxidoreductase is thought to participate in activation of vitamin K for protein gamma-carboxylation, decreased activity of the enzyme in heterozygotes or in null-allele homozygotes may disturb the post-translational modification of urinary calcium-binding proteins protective against kidney stone formation. The NQO1 null-allele might therefore be a determinant in enhanced risk of urolithiasis.

Increased frequency of a null-allele for NAD(P)H: quinone oxidoreductase in patients with urological malignancies.

The NQO1 locus on chromosome 16q2.2 encodes NAD(P)H:quinone oxidoreductase, an enzyme implicated in detoxication and protection against redox cycling. Two alleles have been identified in the human population, the rarer one, termed the null-allele, coding for a nonfunctional enzyme. Since lack of NQOR activity has been suggested to increase susceptibility to certain cancers, the distribution of the two alleles was determined by polymerase chain reaction-restriction fragment length polymorphism analysis in patients with renal cell carcinoma (n = 131) and urothelial carcinoma (n = 99) compared with a normal population (n = 260). Allele distribution in the normal population followed a Hardy-Weinberg distribution with frequencies of 0.867 for the major allele and 0.133 for the null-allele. Increased frequencies of the null-allele were found in the tumour patient groups (0.191 and 0.182, respectively) due to an increased number of both homo- and heterozygotes. The odds ratios for homozygous null-allele vs. wild-type genotypes were 1.7 and 3.6 for renal cell carcinoma and urothelial carcinoma, respectively. These data are compatible with the assumption that diminished activity of NQOR in some individuals increases susceptibility to certain cancers.

WAF1/p21 regulates proliferation, but does not mediate p53-dependent apoptosis in urothelial carcinoma cell lines.

The WAF1/p21 gene product is an inhibitor of cyclin-dependent kinases which can be induced by the tumor suppressor p53 and mediate some of its effects, or function in p53-independent pathways of cell cycle regulation. Although a potential tumor suppressor gene, WAF1/p21 is expressed in bladder cancer. To elucidate the function of p21 in tumor cells we have investigated in urothelial carcinoma cell lines: i) WAF1/p21 mRNA and protein expression, ii) the biological effects of p21 overexpression or down-regulation and (iii) whether p21 can be induced by p53. WAF1/p21 mRNA levels examined in four cell lines were comparable to bladder mucosa. One cell line, HT1376, failed to express p21 protein due to a frame shift mutation. Overexpression of WAF1/p21 cDNA inhibited clone formation in three cell lines, whereas transfection with antisense WAF1 increased clone sizes and numbers. WAF1 sense clones showed diminished cell proliferation compared to the parental cell line. Apoptosis- induced wild-type p53 was not inhibited by overexpression of antisense WAF1/p21. In a cell clone derived from line VMCub1 by stable transfection with wild-type p53 under the control of a metallothionein promotor, p21 was induced along with p53 upon activation of the promoter with zinc chloride. This induction was accompanied by a decrease in cell proliferation but by little apoptosis. These data suggest that p21 inhibits proliferation in a p53-dependent or independent manner but does not mediate p53-induced apoptosis in urothelial carcinoma cells.

High-intensity focused ultrasound (HIFU) in the treatment of benign prostatic hyperplasia (BPH).

Transurethral resection of the prostate (TURP) and open adenectomy are regarded the golden standard in the management of patients with symptomatic benign prostatic hyperplasia (BPH). Various alternative treatment forms (microwaves, laser, radiofrequency, focused ultrasound) have been introduced recently. They all aim at reduction of morbidity related to TURP keeping a comparable efficacy at the same time. Since December 1992, 50 patients with BPH have been treated by high intensity focused ultrasound (HIFU-P) at our department. Six weeks following HIFU-P mean Qmax improved from 5.7 ml/s to 11.6 ml/s. Post voiding residual volume (RV) dropped from 215 ml to 100 ml, the International Prostate Symptom Score (IPSS) from 19.8 to 9.9. Both, IPSS and RV further improved during the following weeks. Follow-up data one year after treatment demonstrate that results remained stable in the majority of patients. Urinary tract infections were observed in 3 patients, macrohematospermia in all and macrohematuria (caused by the suprapubic catheter) requiring blood transfusion in 1 patient.

Accuracy of imaging modalities in staging the local extent of prostate cancer.

In this study, none of the evaluated clinical staging methods was found to predict reliably the presence or absence of extracapsular growth of histologically proved carcinoma of the prostate. In this respect, digital rectal examination, transrectal ultrasound, CT, and MR imaging cannot contribute to treatment decisions in localized prostate cancer. Further studies are under way to determine the value of 7.5-MHz scanners in transrectal ultrasound and high-resolution surface coils in MR imaging.

Filter immunocytology: methodologic evaluation of a new assay for the diagnosis of urothelial cancer.

OBJECTIVE: Several investigators have demonstrated the high sensitivity of immunocytology in the diagnosis of transitional cell carcinoma (TCC). A new technique, designated "filter immunocytology" (FLIC), simplifies the technique of quantitative immunocytology, considerable decreases assay time and increases the percentage of assessable specimens. STUDY DESIGN: Voided urine samples were obtained from 89 patients without evidence of TCC and from 91 patients with histologically proven TCC. The cells were transferred onto a polycarbonate membrane. Immunostaining was performed using monoclonal antibody. Due ABC 3, directed against a differentiation antigen on urothelial cells. Specimens containing > 35% positive urothelial cells were regarded as abnormal. RESULTS: Of 153 specimens 180 (85%) were assessable. The investigation of 76 specimens from control patients and 77 from patients with TCC yielded a specificity of 86% and a sensitivity of 75%, respectively. Sensitivity did not correlate with tumor grade. Despite high interobserver and intrapatient variations regarding the amount of antigen-positive cells, a concordant attribution to either "normal" or "abnormal" was made in > 95% of cases. Intraobserver variation was small and did not influence the test result. CONCLUSION: These results suggest that FLIC assay may be a valuable adjunct to conventional cytology. A careful prospective investigation appears to be worthwhile to further define the indications for this technique.

[Indications and follow-up of total pelvic exenteration]. / Indikationsstellung und Verlauf bei der totalen pelvinen Exenteration.

From 1988 to 1996 we performed 18 total pelvic exenterations in patients with an average age of 59.8 years who could be followed up for a mean 29.8 months. In 10 cases a recurrent tumor of the pelvic viscera and 7 times a primary carcinoma of the rectum, bladder or prostate were treated. In 1 patient a radiogenic fistula led to this operation. Intestinal continuity could be reconstructed in 7 cases. Following cystectomy, urinary diversion was accomplished in half of the cases by an ileal conduit. Due to septic multiorgan failure 2 patients died postoperatively (hospital mortality rate 11%). In 82% a complete resection (R0) was possible. Subsequently 5 patients (29%) developed tumor recurrence. Distant metastases were observed in 3 patients, 8-9 months after surgery. So far 10 further patients have died. Their mean survival time was 28.9 months (range 5-99 months). The remaining 6 patients are still alive between 22 and 36 months postoperatively. Despite the extent of this kind of major surgery, which also requires multidisciplinary cooperation, and the psychosocial problems resulting from two permanent stomas, total pelvic exenteration should be regarded as an adequate alternative in the treatment plan in selected patients with locally advanced or recurrent pelvic disease.

[Prognostic factors for predicting the success of immunotherapy in metastatic renal cell carcinoma]. / Prognostiche Faktoren zur Vorhersage des Erfolges einer Immuntherapie beim metastasierten Nierenzellkarzinom.

Only approximately 20% of the patients with metastatic renal cell carcinoma who undergo systemic immunotherapy will respond to this form of treatment. Appropriate selection of patients could exclude many who will not benefit from immunotherapy from a toxic and expensive treatment. Several factors predicting the outcome of immunotherapy have been reported so far. These predictors can be classified into (1) patient-related factors, (2) tumour-related factors and (3) alterations of the immune system during immunotherapy. Performance status and the interval between tumour nephrectomy and metastasization are the most important patient-related factors. Liver metastases are apparently an unfavourable tumour-related prognostic factor. Various alterations of the immune system during immunotherapy are significantly linked with the outcome of the treatment. In consequence, the prospective investigation of prognostic factors within clinical trials appears to be mandatory.

[High energy focused ultrasound in treatment of benign prostatic hyperplasia]. / Hochenergetischer fokussierter Ultraschall (HIFU) in der Behandlung der benignen Prostatahyperplasie.

Transurethral resection of the prostate (TURP) and open adenectomy are regarded the "golden standard" in the treatment of benign prostate hyperplasia (BPH). Various alternative treatment forms (microwaves, laser, radio frequency, focused ultrasound) have been introduced recently. They are all aimed at reducing the morbidity related to TURP while achieving comparable efficacy at the same time. Since December 1992, 35 patients with BPH have been treated with high-intensity focused ultrasound (HIFU-P) in our department. By 6 weeks after HIFU-P, mean Qmax had improved from 6.5 ml/s to 12.1 ml/s. Residual volume dropped from 207 ml to 95 ml, IPSS from 20.1 to 9.7. Both subjective as well as objective improvements remained stable after 3 and 6 months. Urinary tract infections were observed in 3 patients, macrohemato-spermia in all, and macrohematuria (caused by the suprapubic catheter) requiring blood transfusion in 1 patient.

[Immunotherapy of superficial bladder cancer]. / Immuntherapie des oberflächlichen Harnblasenkarzinoms.

Because patients with superficial bladder cancer are in a high-risk group where tumor progression is concerned, topical therapeutic strategies are necessary to prevent tumor recurrence and tumor progression. Based on experimental studies and several case reports, during the last two decades immunotherapy for superficial bladder cancer has been developed. The effects of topical instillation of bacillus Calmette-Guerin (BCG) has been carefully investigated in numerous clinical trials. Especially patients with carcinoma in situ appear to benefit from BCG therapy. Other types of local immunotherapy, e.g., instillation of interferons, interleukins, and keyhole limpet hemocyanin have been found to have fewer side effects than BDG. These new approaches are currently under clinical investigation.

[Reconstructive surgery of the efferent urinary tract in pelvic exenteration of gynecological tumors]. / Rekonstruktive Chirurgie der ableitenden Harnwege bei exenterativer Resektion gynäkologischer Tumoren.

In locally advanced or recurrent tumors of the female genital tract anterior or total exenteration may be mandatory in case of tumor invasion into the lower urinary tract or if a second course of radiation therapy is not feasible. The management of resection and reconstruction of the affected lower urinary tract has to be well integrated into the gynecological therapeutic concept. In 11/32 patients the reconstruction of the partially resected lower urinary tract was feasible with preservation of a functionally intact urinary bladder. Urinary diversion following pelvic exenteration was achieved in 13/17 patients with a continent urinary reservoir and in 4/17 patients with an ileal conduit. Operative reinterventions were needed only in patients with continent urinary diversion in 5 cases. All these patients had a past history of primary radiation therapy of their gynecological tumor. In the remaining other 11 patients with a history of primary radiation therapy no complications occurred. 9 of 32 patients survived the operative procedure 40.8 (25-57) month with no evidence of recurrent tumor. Continent urinary diversion represents an excellent therapeutic option for replacement of function lost due to exenterative pelvic surgery. Stringent selection of patients is mandatory to consider the presented therapeutic concept a reasonable tool in the management of the described clinical situations.

[A study of the quantitative dual-parameter flow cytometry analyses of cellular antigens on transitional cells for the diagnosis of bladder cancer].

To establish a quantitative dual-parameter flow cytometry (FCM) analysis of cell surface antigens, possible obstacles caused by contaminated leucocytes in a specimen and staining and measuring conditions were investigated using human bladder cancer cell lines, 5637, T24 and SW1710. The first monoclonal antibody (MoAb) used to select urothelial cells in a specimen was applied with the second MoAb used to discriminate between normal and transformed urothelial cells. MoAbs Due AUT 2 and CD45 appeared to be suitable for the selection of urothelial cells, while Due ABC 3 and Due ABC 5 were applied to detect transformed cells. Tumor cell-leucocyte suspension was simultaneously stained with combinations of these MoAbs. The results demonstrated that Due AUT 2 and CD45 effectively eliminated contaminated leucocytes by means of positive and negative selection of the urothelial cells, respectively. Based on these experiments, dual-parameter FCM analyses of bladder washing from 5 patients with bladder cancer were performed using MoAbs Due AUT 2 and Due ABC 3. The results indicated that by dual-parameter FCM distinct antigenic features of transitional cells could be investigated even if considerable amounts of contaminated leucocytes were present. The clinical impact of this approach is a subject of ongoing trials.

Use of markers in defining urothelial premalignant and malignant conditions.

Markers have revealed the presence of phenotypically abnormal areas in histologically benign urothelium in bladders containing transitional cell carcinomas. This finding strongly suggests that at least some bladder cancers are associated with changes in the field and that markers can detect these lesions before they reach a grossly malignant stage. Markers have been used clinically for the detection of cancer in patients who are under regular surveillance for recurrence of bladder cancer. Much less information is available regarding the use of markers to detect bladder cancer without a prior history of the disease and for the prediction of which tumors are biologically more aggressive. However, ongoing clinical trials are addressing the latter issue. The type of specimen and its preparation will determine what type of markers can be analyzed. Although marker performance is based upon sensitivity and specificity, the prevalence of bladder cancer in the population being tested will dramatically affect the positive predictive value of an assay. Markers with high positive predictive value are indicators for interventions, such as biopsy, while markers with high negative specific values are useful for avoiding interventions. Cytology is used to detect occult high-grade neoplasms such as carcinoma in situ. While not yet clinically validated, tests with high negative predictive value could be used to decrease the frequency of cystoscopic evaluation. Markers must be validated by testing them prospectively using previously defined cut-off values. Furthermore, markers that will be used to alter treatment should be tested prospectively to determine the safety and cost-effectiveness of this strategy. Recommendations for future work include: (1) evaluation of markers in patients with dysplasia defined by the current pathologic classification; (2) evaluation of markers as indicators of tumor recurrence; (3) evaluation of markers as indicators of tumor progression; and (4) evaluation of markers in chemoprevention studies.