Thomas Paiss

THE ILEAL NEOBLADDER: COMPLICATIONS AND FUNCTIONAL RESULTS IN 363 PATIENTS AFTER 11 YEARS OF FOLLOWUP

PURPOSE Since 1986 orthotopic lower urinary tract reconstruction using the ileal neobladder has been our diversion of choice in patients of both sexes undergoing cystectomy. We report on experience and functional results of the first 363 men 11 years after this procedure. MATERIALS AND METHODS Complications were assessed, tabulated, subdivided into early (3 months or less postoperatively) and late types, and further categorized with respect to relationship to neobladder construction. Continence and voiding pattern were individually evaluated via a detailed patient questionnaire. RESULTS Perioperative death occurred in 11 patients (3%). Neobladder related early and late complications occurred in 56 (15.4%) and 85 (23.4%) of the 363 patients, respectively. Neobladder related early and late abdominal reoperation rates were 0.3 and 4.4%, respectively. Perioperative neobladder unrelated early complications were observed in 122 patients (33.6%) and 44 (12.1%) required operative treatment. Late postoperative complications unrelated to the neobladder occurred in 45 patients (12.4%) and 19 required open surgical revision. Of 290 evaluable patients 96.1% void spontaneously, 3.9% perform clean intermittent catheterization in some form and 1.7% perform regular intermittent catheterization. Daytime and nighttime continence was reported as good by 95.9% and satisfactory by 95% of the patients. Unacceptable daytime continence requiring more than 1 pad per day occurred in only 4.1% of the patients and only 5% are wetting more than 1 pad a night. CONCLUSIONS The ileal neobladder produces good functional results and can be constructed with acceptable complications. Our data suggest that although it is not a complication-free procedure, we advocate its use when possible.

Predisposing Gene for Early-Onset Prostate Cancer, Localized on Chromosome 1q42.2-43

There is genetic predisposition associated with >=10% of all cancer of the prostate (CaP). By means of a genomewide search on a selection of 47 French and German families, parametric and nonparametric linkage (NPL) analysis allowed identification of a locus, on chromosome 1q42.2-43, carrying a putative predisposing gene for CaP (PCaP). The primary localization was confirmed with several markers, by use of three different genetic models. We obtained a maximum two-point LOD score of 2.7 with marker D1S2785. Multipoint parametric and NPL analysis yielded maximum HLOD and NPL scores of 2.2 and 3.1, respectively, with an associated P value of . 001. Homogeneity analysis with multipoint LOD scores gave an estimate of the proportion of families with linkage to this locus of 50%, with a likelihood ratio of 157/1 in favor of heterogeneity. Furthermore, the 9/47 families with early-onset CaP at age <60 years gave multipoint LOD and NPL scores of 3.31 and 3.32, respectively, with P = .001.

THE ILEAL NEOBLADDER IN WOMEN: 9 YEARS OF EXPERIENCE WITH 18 PATIENTS

PURPOSE We present our surgical and functional experience with orthotopic bladder replacement in women. MATERIALS AND METHODS Since 1986, 18 women have undergone lower urinary tract reconstruction with an ileal neobladder. A nerve sparing cystectomy is done, and reservoirs are connected to the proximal urethra or urethrovesical junction. A total of 13 patients was available for complete followup as of March 1995. RESULTS There were no perioperative deaths and few early complications. The only 2 failures were a neobladder vaginal fistula and these cases, which were converted to a conduit, are excluded from this study. Late complications requiring rehospitalization or reoperation in 2 patients included urethroileal stenosis that had to be dilated without further sequelae and bilateral ureteroileal stenosis that was treated endoscopically. At 3 months postoperatively excellent continence was achieved in 8 patients, while 2 had grade 1 stress incontinence and 3 were hypercontinent. As of March 1995 only 4 patients voided to completion while 9 required intermittent catheterization (continuously in 5 and twice daily for residual urine in 4). We were unable to demonstrate a functional difference of the various resection lines located at the proximal urethra or urethrovesical junction. CONCLUSIONS Urethral support and nerve sparing cystectomy plus the ileal neobladder as a reservoir guarantee excellent continence in all patients. Despite our efforts, we have been unable to demonstrate any advantage of the nerve and urethral support sparing cystectomy technique as far as micturition is concerned. The development of hypercontinence in 70% of the patients with time demonstrates that our current understanding of the functional and anatomical basics of the voiding process is too limited to allow bladder replacement with a perfect functional result in all female patients. Our long-term experience, which is different from initial reports, justifies creation of an ileal neobladder in select female patients as long as they accept a 70% risk of clean intermittent catheterization in the long term. Overall patient satisfaction, including sexual life, is exceptional. However, disappointment is considerable when clean intermittent catheterization is required after periods of successful voiding per urethram.

DOES THE OPTION OF THE ILEAL NEOBLADDER STIMULATE PATIENT AND PHYSICIAN DECISION TOWARD EARLIER CYSTECTOMY

PURPOSE The primary goal of bladder replacement is to attempt to improve patient quality of life, not to increase survival, affect cancer prognosis or decrease renal metabolic complications. Nevertheless, we retrospectively determined whether orthotopic bladder replacement has an impact on the decision to perform cystectomy. MATERIALS AND METHODS From April 1986 to September 1994, 213 men a mean of 63 years old with stages pT2N0M0 to pT4N0M0 invasive bladder cancer were referred to our department for cystectomy. For 135 patients who underwent an ileal neobladder procedure and 78 who underwent conduit diversion median followup was 4.8 and 3.5 years, respectively. We evaluated the interval from the primary diagnosis of bladder cancer to cystectomy as well as the number of previous transurethral bladder resections. The 5-year cancer specific survival rates were calculated using the Kaplan-Meier method. The Wilcoxon and log rank tests, and the Cox proportional hazards model were used to determine statistical significance. RESULTS In the neobladder and conduit groups an average of 2.1 (range 1 to 18) and 4.1 (range 1 to 15) transurethral bladder resections was performed, respectively. Interval from the primary diagnosis to cystectomy was 11.8 months in the neobladder and 16.7 months in the conduit group. Cystectomy was performed 4.1 months after the diagnosis of invasive cancer in the neobladder group, whereas radical surgery was delayed for 15.4 months in the conduit group. Cancer specific 5-year survival rates were 76.6 and 28.35% in the neobladder and conduit groups, respectively. After stratifying according to tumor stage the 5-year survival rate was significantly higher for all disease stages in the neobladder than in the conduit group. The proportional hazards model revealed that this difference was not due to patient age at disease stages pT3bN0 and pT4N0 or by American Society of Anesthesiologists score. Independent prognostic factors for survival were diversion type and age. Delayed cystectomy was a risk factor only in advanced disease stages. CONCLUSIONS These data suggest that the ileal neobladder may decrease physician reluctance to perform cystectomy early in the disease process, increasing the survival rate. They also demonstrate that the ileal neobladder option significantly affects an earlier patient and physician decision in favor of cystectomy.

Linkage of aggressive prostate cancer to chromosome 7q31-33 in German prostate cancer families

It has been suggested that chromosome 7q32 contains genes that influence the progression of prostate cancer from latent to invasive disease. In an attempt to confirm this linkage to prostate cancer aggressiveness, 100 German prostate cancer families were genotyped using a panel of eight polymorphic markers on chromosome 7q. We used a multipoint allele sharing method based upon a likelihood ratio test implemented in GENEHUNTERPLUS v1.2 in order to calculate the nonparametric Zlr and the associated LOD scores. We applied the aggressiveness of prostate cancer given by the pathological tumour grade of each individual, and the mean age of onset of a family as covariates, and constructed two weighted models. The first (weight0–1 model) puts weights on families with at least two cases of GIII prostate cancer. The second (weight0–2 model) also adds weights to families with early and late onset cancer respectively. The unweighted analysis gave no evidence of linkage to chromosome 7q. The Zlr scores increased when including the covariates, to 2.60 (P=0.005) using the weight0–1 and to 3.02 (P=0.001) using the weight0–2 model for late onset prostate cancer. The associated LOD scores were respectively 1.47 (P=0.009) and 1.98 (P=0.002). The markers that gave most evidence for linkage were exactly in the range of the published prostate cancer aggressiveness region. Our results support a widespread relevance of this locus and suggest that aggressive and late onset prostate cancer is linked to chromosme 7q31-33 in the German population.

Chromosomal changes during progression of transitional cell carcinoma of the bladder and delineation of the amplified interval on chromosome arm 8q

The cascade of genetic alterations leading to malignant transformation has been described for adenocarcinoma of the colon but is not established for other common tumor entities. In the present study, different stages of transitional cell carcinoma (TCC) of the bladder are analyzed by comparative genomic hybridization. A dynamic pattern of the chromosomal changes during tumor progression is described. Deletion of chromosome arm 9q is the earliest genetic alteration in pTa tumors. In stage pT1 carcinomas, losses of 9q, 9p, and 11p and gain of 1q and 8q are the most common. In addition to the changes specific for earlier stages, gain of 5p and 20q becomes prominent in carcinomas stage ≥pT2. Association analysis reveals a remarkable cooccurrence of 9p deletion with gain of 5p and 20q in ≥pT2 tumors. In order to determine more precisely the size of the amplified segment and the degree of amplification on chromosome arm 8q in stage pT1 tumors, this region was analyzed by semiquantitative PCR using polymorphic microsatellite markers. These studies revealed an up to 13‐fold amplification. The common region of amplification could be narrowed down to 8q22.3 and between GAAT1A4 and D8S1834 (about 7 cM). Genes Chromosomes Cancer 23:167–174, 1998.

Role of the Nijmegen Breakage Syndrome 1 Gene in Familial and Sporadic Prostate Cancer

The Nijmegen breakage syndrome 1 (NBS1) gene, which participates in DNA double strand break repair, has been postulated to be a susceptibility factor for a number of cancers, including prostate cancer. Numerous mutations have been identified in NBS1, including the founder mutation 657del5. In this study, a number of analyses were done to determine whether mutations in NBS1 are associated with an increased risk for prostate cancer. The frequency of the 657del5 mutation in both familial prostate cancer cases (1,819 affected men among 909 families) and sporadic prostate cancer cases (1,218 affected men) collected from five centers participating in the International Consortium for Prostate Cancer Genetics were compared with that found in 697 normal controls. Seven individuals were identified to carry the mutation among the 3,037 cases screened: four in the familial group (three from one family and one from another) and three in the sporadic cases. The carrier frequency was 0.22% (2 of 909) for the probands and 0.25% (3 of 1,218) for the sporadic cases of prostate cancer. The 657del5 mutation was not detected in either the 293 unaffected members of the prostate cancer families or in the 697 control samples tested. The entire NBS1 gene was also sequenced in 20 of the youngest affected individuals from the Finnish group of familial cases to identify the presence of possible mutations in this high-risk group. One rare (D95N) and one common (E185Q) missense alteration was identified. More detailed analyses of the E185Q polymorphism, along with a third rare variant (R215W), failed to show an association with prostate cancer. Because the 657del5 mutation was absent from the control population, we are unable to determine if this alteration predisposes to prostate cancer. However, our data does suggest that mutations within NBS1, and in particular, 657del5, do not significantly contribute to the overall prostate cancer burden within our patient samples. (Cancer Epidemiol Biomarkers Prev 2006;15(5):935–8)

A genomewide linkage analysis for prostate cancer susceptibility genes in families from Germany

Prostate cancer is a complex disease with a substantial genetic contribution involved in the disease risk. Several genomewide linkage studies conducted so far have demonstrated a strong heterogeneity of susceptibility. In order to assess candidate regions that are particularly relevant for the German population, we performed a genomewide linkage search on 139 prostate cancer families. A nonparametric method (Zlr scores), using GENEHUNTERPLUS, was applied at 500 markers (panel P1400, deCODE), with an average spacing of 7.25 cM. In the entire family collection, linkage was most evident at 8p22 (Zlr=2.47, P=0.0068), close to the previously identified susceptibility gene MSR1. Further local maxima with Zlr>2 (P<0.025) were observed at 1q, 5q and 15q. In a subgroup of 47 families, which matched the Johns Hopkins criteria of hereditary prostate cancer, suggestive linkage was found on 1p31 (Zlr=3.37, P=0.00038), a previously not described candidate region. The remaining 92 pedigrees, with no strong disease history, revealed a maximum Zlr=3.15 (P=0.00082) at 8q13, possibly indicating a gene with reduced penetrance or recessive inheritance. Our results suggest pronounced locus heterogeneity of prostate cancer susceptibility in Germany. In the present study population, the MSR1 gene could play a significant role. Other conspicuous loci, like 1p31 and 8q13, need further investigation in order to verify their relevance and to identify candidate genes.

SOME TUMORS OF THE BLADDER ARE POLYCLONAL IN ORIGIN

PURPOSE Clonality assays can be used to address different questions of neoplasm development. The study of the X chromosome inactivation pattern in female patients provides a useful and most commonly used indirect approach to demonstrate the monoclonal status of a cell population. We used this approach to examine whether recurrent tumors of the bladder supposed to be of monoclonal origin derive from different, independently transformed cells or whether they arise from 1 primary tumor. MATERIALS AND METHODS We analyzed 45 archival or fresh frozen bladder tumors from 27 female patients. We assessed the X inactivation status of each tumor by a polymerase chain reaction based method after HpaII digestion. RESULTS Surprisingly 16 of the 45 tumors revealed a polyclonal pattern. The amount of undigested DNA far exceeded what was explained by contamination with normal cells, as determined on histological sections indicating that these tumors were in fact polyclonal. This polyclonal status was further confirmed by a comprehensive series of controls. CONCLUSIONS Some bladder tumors are polyclonal in origin. Our findings are at variance with earlier observations and possibilities for explanation are proposed.

Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for prostate cancer Genetics using novel sumLINK and sumLOD analyses

Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity.