Robert D. Mills

Pelvic lymph node metastases from bladder cancer: outcome in 83 patients after radical cystectomy and pelvic lymphadenectomy.

PURPOSE We evaluate the outcome in patients with node positive bladder cancer with particular reference to the effect of individual characteristics of positive nodes on survival after meticulous pelvic lymphadenectomy at cystectomy. MATERIALS AND METHODS This prospective analysis contains 452 cases of bladder cancer staged preoperatively as N0M0, managed with pelvic lymphadenectomy and cystectomy between 1984 and 1997. A total of 83 (18%) patients with histologically confirmed node positive disease are included in our study. RESULTS The median overall survival of patients with positive nodes was 20 months. Median 5-year survival was 29%. Patients who survived were found with positive nodes at each site in the pelvis. The median survival of 57 patients with less than 5 positive nodes was 27 months, compared with 15 months for 26 with 5 nodes or more (log-rank test p = 0.0027). Median survival of 26 patients with no lymph node capsule perforation was 93 months, compared with 16 months for 57 with capsule perforation (p = 0.0004). The median survival of 18 patients with a maximum diameter of lymph node metastasis up to 0.5 cm. was 64 months, compared with 16 months for 65 with nodal metastasis greater than 0.5 cm. (p = 0.024). Contralateral positive nodes were found in 16 of 39 (41%) patients with unilateral bladder cancer. CONCLUSIONS Long-term survival is possible with node positive bladder cancer. Those patients with few as well as smaller and, therefore, unsuspected nodal metastases, and those without lymph node capsule perforation have the best results after removal of pelvic metastatic nodal disease. Because patients who survive may be found regardless of the site of pelvic nodal metastases, meticulous bilateral pelvic lymphadenectomy is warranted in all patients at the time of attempted curative cystectomy for bladder cancer, particularly if there is no clinical evidence of nodal involvement.

METABOLIC CONSEQUENCES OF CONTINENT URINARY DIVERSION

PURPOSE Continent diversion, in particular orthotopic bladder substitution, is a well accepted form of urinary diversion. However, potential metabolic consequences in the early postoperative period as well as long term remain a serious problem. MATERIALS AND METHODS We review the possible complications associated with removing bowel and incorporating it in the urinary tract. RESULTS Metabolic complications following continent urinary diversion are common. In the majority of cases, and with correct patient selection and education, problems may be minimized with use of an appropriate bowel segment and early intervention. CONCLUSIONS Careful patient selection and vigilant followup are essential for good long-term results in patients undergoing continent urinary diversion.

ICUD-EAU International Consultation on Bladder Cancer 2012: Urinary diversion.

CONTEXT A summary of the 2nd International Consultation on Bladder Cancer recommendations on the reconstructive options after radical cystectomy (RC), their outcomes, and their complications. OBJECTIVE To review the literature regarding indications, surgical details, postoperative care, complications, functional outcomes, as well as quality-of-life measures of patients with different forms of urinary diversion (UD). EVIDENCE ACQUISITION An English-language literature review of data published between 1970 and 2012 on patients with UD following RC for bladder cancer was undertaken. No randomized controlled studies comparing conduit diversion with neobladder or continent cutaneous diversion have been performed. Consequently, almost all studies used in this report are of level 3 evidence. Therefore, the recommendations given here are grade C only, meaning expert opinion delivered without a formal analysis. EVIDENCE SYNTHESIS Indications and patient selection criteria have significantly changed over the past 2 decades. Renal function impairment is primarily caused by obstruction. Complications such as stone formation, urine outflow, and obstruction at any level must be recognized early and treated. In patients with orthotopic bladder substitution, daytime and nocturnal continence is achieved in 85-90% and 60-80%, respectively. Continence is inferior in elderly patients with orthotopic reconstruction. Urinary retention remains significant in female patients, ranging from 7% to 50%. CONCLUSIONS RC and subsequent UD have been assessed as the most difficult surgical procedure in urology. Significant disparity on how the surgical complications were reported makes it impossible to compare postoperative morbidity results. Complications rates overall following RC and UD are significant, and when strict reporting criteria are incorporated, they are much higher than previously published. Fortunately, most complications are minor (Clavien grade 1 or 2). Complications can occur up to 20 yr after surgery, emphasizing the need for lifelong monitoring. Evidence suggests an association between surgical volume and outcome in RC; the challenge of optimum care for elderly patients with comorbidities is best mastered at high-volume hospitals by high-volume surgeons. Preoperative patient information, patient selection, surgical techniques, and careful postoperative follow-up are the cornerstones to achieve good long-term results.

Broccoli Consumption Interacts with GSTM1 to Perturb Oncogenic Signalling Pathways in the Prostate

Background Epidemiological studies suggest that people who consume more than one portion of cruciferous vegetables per week are at lower risk of both the incidence of prostate cancer and of developing aggressive prostate cancer but there is little understanding of the underlying mechanisms. In this study, we quantify and interpret changes in global gene expression patterns in the human prostate gland before, during and after a 12 month broccoli-rich diet. Methods and Findings Volunteers were randomly assigned to either a broccoli-rich or a pea-rich diet. After six months there were no differences in gene expression between glutathione S-transferase mu 1 (GSTM1) positive and null individuals on the pea-rich diet but significant differences between GSTM1 genotypes on the broccoli-rich diet, associated with transforming growth factor beta 1 (TGFβ1) and epidermal growth factor (EGF) signalling pathways. Comparison of biopsies obtained pre and post intervention revealed more changes in gene expression occurred in individuals on a broccoli-rich diet than in those on a pea-rich diet. While there were changes in androgen signalling, regardless of diet, men on the broccoli diet had additional changes to mRNA processing, and TGFβ1, EGF and insulin signalling. We also provide evidence that sulforaphane (the isothiocyanate derived from 4-methylsuphinylbutyl glucosinolate that accumulates in broccoli) chemically interacts with TGFβ1, EGF and insulin peptides to form thioureas, and enhances TGFβ1/Smad-mediated transcription. Conclusions These findings suggest that consuming broccoli interacts with GSTM1 genotype to result in complex changes to signalling pathways associated with inflammation and carcinogenesis in the prostate. We propose that these changes may be mediated through the chemical interaction of isothiocyanates with signalling peptides in the plasma. This study provides, for the first time, experimental evidence obtained in humans to support observational studies that diets rich in cruciferous vegetables may reduce the risk of prostate cancer and other chronic disease. Trial Registration ClinicalTrials.gov NCT00535977

FEMALE ORTHOTOPIC BLADDER SUBSTITUTION: A GOOD OPERATION IN THE RIGHT CIRCUMSTANCES

PURPOSE We present the long-term results of orthotopic bladder substitution in women. MATERIALS AND METHODS We prospectively assessed 15 female patients undergoing orthotopic bladder substitution between October 1984 and April 1998. The indication for diversion was bladder carcinoma in 8 cases, gynecologic malignancy in 2 and benign disease in 5. RESULTS At a median followup of 19 months daytime and nighttime continence was 100% and 80%, respectively. All but 1 patient voided spontaneously. Two patients who were initially able to void successfully had voiding difficulties in the initial 10 months due to prominent mucosal tissue at the bladder neck. In each case this condition was successfully managed by endoscopic resection. There has been no local recurrence of bladder carcinoma. CONCLUSIONS With strict selection criteria and vigilant followup female orthotopic bladder substitution produces excellent long-term functional results comparable to those in men. However, the limits in women who require radical cystectomy for invasive bladder cancer cannot be determined from our results. Further long-term data on the local recurrence rate of invasive urothelial malignancy are needed before the true risk may be quantified accurately.

FERTILITY AND SEXUAL FUNCTION FOLLOWING ORCHIECTOMY AND 2 CYCLES OF CHEMOTHERAPY FOR STAGE I HIGH RISK NONSEMINOMATOUS GERM CELL CANCER

PURPOSE We investigate fertility and sexual function in patients following orchiectomy and adjuvant cisplatin based chemotherapy for high risk, stage I nonseminomatous germ cell tumor of the testis. MATERIALS AND METHODS Between 1985 and 1994, 59 patients with stage I nonseminomatous germ cell tumor and poor prognostic factors were treated with 2 cycles of cisplatin, vinblastine and bleomycin, or bleomycin, etoposide and cisplatin after orchiectomy. At least 32 months following treatment all patients were contacted and asked to complete a questionnaire regarding fertility and sexual activity, and to volunteer for a semen and hormonal analysis. RESULTS Of the 59 patients 49 (83%) completed the questionnaire. Before chemotherapy 18 (37%) patients had fathered children, 6 (12%) were involuntarily childless and none had a major sexual dysfunction. After treatment 11 (22%) patients fathered children, and 5 (10%) were involuntarily childless, with 4 involuntarily childless before chemotherapy. There were no significant alterations in sexual function. Semen analysis in 27 patients was normal in 23, and revealed mild oligospermia in 2 and azoospermia in 2. In 18 patients with hormone analysis median values for luteinizing hormone and free testosterone were normal but median value for follicle-stimulating hormone was slightly increased. CONCLUSIONS Two cycles of cisplatin based adjuvant chemotherapy do not seem to affect adversely fertility or sexual activity.

The dietary isothiocyanate sulforaphane modulates gene expression and alternative gene splicing in a PTEN null preclinical murine model of prostate cancer

BackgroundDietary or therapeutic interventions to counteract the loss of PTEN expression could contribute to the prevention of prostate carcinogenesis or reduce the rate of cancer progression. In this study, we investigate the interaction between sulforaphane, a dietary isothiocyanate derived from broccoli, PTEN expression and gene expression in pre malignant prostate tissue.ResultsWe initially describe heterogeneity in expression of PTEN in non-malignant prostate tissue of men deemed to be at risk of prostate cancer. We subsequently use the mouse prostate-specific PTEN deletion model, to show that sulforaphane suppresses transcriptional changes induced by PTEN deletion and induces additional changes in gene expression associated with cell cycle arrest and apoptosis in PTEN null tissue, but has no effect on transcription in wild type tissue. Comparative analyses of changes in gene expression in mouse and human prostate tissue indicate that similar changes can be induced in humans with a broccoli-rich diet. Global analyses of exon expression demonstrated that sulforaphane interacts with PTEN deletion to modulate alternative gene splicing, illustrated through a more detailed analysis of DMBT1 splicing.ConclusionTo our knowledge, this is the first report of how diet may perturb changes in transcription induced by PTEN deletion, and the effects of diet on global patterns of alternative gene splicing. The study exemplifies the complex interaction between diet, genotype and gene expression, and the multiple modes of action of small bioactive dietary components.

Five meters of H2O: The pressure at the urinary bladder neck during human ejaculation

There are no data in the literature on pressure changes in the prostatic urethra during ejaculation. In healthy men, it has always been postulated that there must be a pressure gradient in order to prevent retrograde ejaculation, but scientific proof for that is pending.

Urinary Diversion: How Experts Divert

OBJECTIVE To determine the rates of the available urinary diversion options for patients treated with radical cystectomy for bladder cancer in different settings (pioneering institutions, leading urologic oncology centers, and population based). METHODS Population-based data from the literature included all patients (n = 7608) treated in Sweden during the period 1964-2008, from Germany (n = 14,200) for the years 2008 and 2011, US patients (identified from National Inpatient Sample during 1998-2005, 35,370 patients and 2001-2008, 55,187 patients), and from Medicare (n = 22,600) for the years 1992, 1995, 1998, and 2001. After the International Consultation on Urologic Diseases-European Association of Urology International Consultation on Bladder Cancer 2012, the urinary diversion committee members disclosed data from their home institutions (n = 15,867), including the pioneering institutions and the leading urologic oncology centers. They are the coauthors of this report. RESULTS The receipt of continent urinary diversion in Sweden and the United States is <15%, whereas in the German high-volume setting, 30% of patients receive a neobladder. At leading urologic oncology centers, this rate is also 30%. At pioneering institutions up to 75% of patients receive an orthotopic reconstruction. Anal diversion is <1%. Continent cutaneous diversion is the second choice. CONCLUSION Enormous variations in urinary diversion exist for >2 decades. Increased attention in expanding the use of continent reconstruction may help to reduce these disparities for patients undergoing radical cystectomy for bladder cancer. Continent reconstruction should not be the exclusive domain of cystectomy centers. Efforts to increase rates of this complex reconstruction must concentrate on better definition of the quality-of-life impact, technique dissemination, and the centralization of radical cystectomy.

Bladder Replacement and Urinary Diversion

The use of orthotopic bladder substitution and urinary diversion has increased markedly over the last 15 years and this trend is expected to continue. Up to 50% of patients with invasive bladder cancer may be suitable candidates for orthotopic reconstruction. Medium- and long-term follow-up data indicate that the use of orthotopic bladder substitution can result in superior quality of life for patients compared with other forms of urinary diversion. Careful patient selection and vigilant follow-up are essential to maintain these good results. The principal issues surrounding the practice of orthotopic bladder substitution and urinary diversion are discussed.