Transitional Cell Carcinoma Of The Bladder Research Articles

Synchronous and multiple transitional cell carcinoma of the bladder and urachal cyst

Incomplete involution of the allantoic duct can result in different pathological forms of urachus which can give rise to inflammation or late malignant changes. Among urachal tumors, adenocarcinoma is most frequent, although other histological types can also be found. The synchronous presentation of a urachal transitional cell tumor, along with recurrent superficial bladder tumors has not been reported previously. We are reporting a 49-year-old male patient in whom transitional cell carcinoma of a urachal cyst was found with recurrent, multiple bladder tumors. The diagnosis of urachal cyst tumor was established according to ultrasonography and computed tomography. Most of the bladder tumors were resected transurethrally while open surgical excision of the urachal cyst with en bloc resection of the bladder dome was performed. Recurrent bladder tumors were afterwards treated with Bacillus Calmette Guerin (BCG) instillations. A year after surgery the patient has no signs of local recurrence or distant metastases of transitional cell carcinoma.

Radical Cystectomy for Carcinoma of the Bladder: 2,720 Consecutive Cases 5 Years Later

We performed a critical analysis of the results of radical cystectomy for invasive bladder carcinoma treated at 1 center. Between 1970 and 2000, 2,090 men and 630 women with invasive bladder cancer were treated with 1-stage radical cystectomy and urinary diversion. Followup ranged from 0 to 34.2 years with a mean of 5.5 +/- 5.7. Survival data were correlated to patient and tumor characteristics using univariate and multivariate analysis. Postoperative mortality was 2.6%. Squamous tumors accounted for 49.4% of cases, transitional cell carcinoma for 36.4% and adenocarcinoma for 9.6%. Regional lymph nodes were involved in 20.4% of cases. The 5 and 10-year disease-free survival rates were 55.5% and 50.03%, respectively. Evidence was provided that tumor stage, histological grade and lymph node status are the only independent variables which affect survival probability. Contemporary cystectomy can be performed with minimal mortality. Radical cystectomy for organ confined disease is followed by good therapeutic results and enhances the possibilities for functional restoration. With stage progression there is a stepwise reduction in survival probability. The radical operation can provide disease-free survival for an important subgroup of node positive cases (27.3%). Additional therapy is needed to improve the oncological outcome for advanced locoregional disease.

Presentation, location, and overall survival of pelvic recurrence after radical cystectomy for transitional cell carcinoma of the bladder: Dhar NB, Jones JS, Reuther AM, Dreicer R, Campbell SC, Sanii K, Klein EA, Section of Urologic Oncology, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH.

To evaluate the presentation, location, and overall survival of pelvic recurrence after radical cystectomy (RC) for transitional cell carcinoma (TCC) of the bladder. We reviewed a consecutive series of 130 patients who had a limited bilateral pelvic lymph node dissection (PLND) and RC between 1987 and 2000, and who later developed pelvic recurrence. All patients were staged N0M0 before RC and no patient received neoadjuvant radio/chemotherapy. The boundaries of the limited PLND were the pelvic side-wall between the genitofemoral and obturator nerves, and the bifurcation of iliac vessels to the circumflex iliac vein. Pelvic recurrence was defined as a radiographic soft-tissue density of ≥2 cm below the bifurcation of the aorta. Kaplan-Meier and Cox proportional hazards analyses were used to determine if imaging or symptomatic presentation, age, pT stage, and pN status were predictive of overall survival. The median (range) time from RC to pelvic recurrence was 7.3 (1.2–55.4) months. No patients had concomitant distant metastasis. Of the patients, 61.5% were diagnosed with pelvic recurrence because of symptoms, and 38.5% by surveillance computed tomography (CT). Of the 130 patients, 128 died, with a median survival from the time of pelvic recurrence of 4.9 (0.1–129.3) months. The median overall survival time for pelvic recurrence diagnosed with CT was 21.6 months, vs. 10.6 months for symptomatic presentations ( P < 0.001). In the uni- and multivariate models, type of presentation (CT vs. symptomatic) and pT stage were predictors of overall survival, while age and pN status were not. The prognosis of patients with pelvic recurrence after RC for TCC is poor even with subsequent therapy, emphasizing the need for optimum local control at the time of initial treatment.

Low incidence of perioperative chemotherapy for Stage III bladder cancer 1998 to 2003: A report from the National Cancer Data Base: David KA, Milowsky MI, Ritchey J, Carroll PR, Nanus DM, Department of Medicine, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY.

Purpose Studies of perioperative chemotherapy for muscle invasive bladder cancer have shown a survival benefit with combined modality therapy. We reviewed chemotherapy use in patients with Stage III transitional cell carcinoma of the bladder from 1998 to 2003 to evaluate perioperative chemotherapy treatment patterns. Materials and Methods The National Cancer Data Base collected data on approximately 60% of all newly diagnosed bladder cancer cases in the United States from 1998 to 2003. We queried the National Cancer Data Base for all treatment of male and female patients 18 years old or older with bladder transitional cell carcinoma diagnosed between 1998 and 2003. A total of 224,060 bladder transitional cell carcinoma records were reviewed. Perioperative chemotherapy was defined as chemotherapy given within 4 months before and 4 months after surgery. Of 11,339 cases of Stage III bladder cancer treatment, analysis was possible for 7,161. Results Treatment patterns were analyzed in 7,161 patients with Stage III bladder transitional cell carcinoma. Perioperative chemotherapy was administered to 11.6% of patients with Stage III bladder transitional cell carcinoma with 10.4% receiving adjuvant chemotherapy and 1.2% receiving neoadjuvant chemotherapy. When comparing perioperative chemotherapy use by diagnosis year in 1998 and 2003, a small statistically significant increase was observed using the Pearson's χ2 test with Bonferroni correction (P Conclusions Perioperative chemotherapy is underused in the management of surgically resectable Stage III transitional cell carcinoma of the bladder. This finding may reflect a delay in implementing the results of recently reported randomized trials, a low incidence of referrals by urologists for chemotherapy and/or confidence in salvage chemotherapy as an equivalent alternative. Further follow-up will determine if this treatment pattern changes in the future.

The efficiency of excretory urography to detect upper urinary tract tumors after cystectomy for urothelial cancer: Meissner C, Giannarini G, Schumacher MC, Thoeny H, Studer UE, Burkhard FC, Department of Urology and Institute of Diagnostic Radiology, University of Bern, Bern, Switzerland.

Purpose We determined the efficiency of routine excretory urography for detecting tumor recurrence in the upper urinary tract after cystectomy and urinary diversion for bladder cancer. Materials and Methods We evaluated 322 patients who underwent cystectomy and urinary diversion, and had undergone routine followup, including regular excretory urography 1, 2, 3, 5, 7, and 10 years after cystectomy. Results Upper urinary tract recurrence was found in 15 of the 322 patients (4.7%) patients. Eight of 15 cases were detected by routine excretory urography, resulting in a low efficiency of 0.75% (8 of 1,064 studies) for this method. The remaining 7 recurrences were detected as a result of symptoms such as macrohematuria or flank pain occurring between routine follow-up examinations. Patients were at up to 10 times higher risk for recurrence in the upper urinary tract if they had positive distal ureteral resection margins or a history of upper urinary tract tumors. Although the incidence of recurrence in the upper urinary tract increased 1.8-fold in patients with pTa/pT1 tumors, it remained relatively low at 8.4%. Conclusions The incidence of recurrence in the upper urinary tract a median of 49 months (range 12 to 220) after cystectomy for transitional cell carcinoma was 4.7%. Because only-half of these cases were detected by routine excretory urography, this should be limited to patients at high risk with a history of upper urinary tract tumors or positive ureteral margins. In the future, other techniques, e.g., cytology of voided urine or new markers, should be evaluated to replace excretory urography for routine follow-up of patients after cystectomy for transitional cell carcinoma of the bladder.

The role of carbonic anhydrase IX as a molecular marker for transitional cell carcinoma of the bladder

The role of carbonic anhydrase IX as a molecular marker for transitional cell carcinoma of the bladder

Laparoscopic radical cystectomy for 43 patients with invasive bladder carcinoma

To report initial experience with laparoscopic radical cystectomy in 43 patients with invasive bladder carcinoma. From December 2003 to October 2006, 29 men and 14 women underwent laparoscopic radical cystectomy with extracorporeal-assisted urinary diversion for transitional cell carcinoma of the bladder (n=40), adenocarcinoma (n=2) and squamous cell arcinoma (n=1). We report the specific technical details and present initial results of our series. The mean operative time of laparoscopic radical cystectomy with pelvic lymph node dissection was 195.4 min, the mean blood loss 273.7 ml, and the transfusion rate 6.9%. Two procedures converted to open techniques. Lymphadenectomy detected lymph node metastasis in three patients. We demonstrate that the combination of laparoscopic radical cystectomy and extracorporeal urinary diversion is possible and remains a safe, feasible, and repeatable surgical technique. The laparoscopic surgery with extracorporeal urinary reconstruction is emerging as a viable alternative to open radical cystectomy while characterized by less trauma, short recovery time and low complications. Intermediate oncologic outcomes are encouraging and comparable to those of open series. To determine the oncologic outcome long-time follow-up will be necessary.

Age‐adjusted Charlson comorbidity score is associated with treatment decisions and clinical outcomes for patients undergoing radical cystectomy for bladder cancer

By using the age-adjusted Charlson comorbidity index (ACCI), the authors characterized the impact of age and comorbidity on disease progression and overall survival after radical cystectomy (RC) for transitional cell carcinoma of the bladder. Also evaluated was whether ACCI was associated with clinicopathologic and treatment characteristics. The authors evaluated 1121 patients treated by RC for transitional cell carcinoma of the bladder at a single institution (1990-2004). Logistic regression was used to determine the relation between ACCI and clinical features. They evaluated the association between ACCI and overall and progression-free survival by using multivariate survival-time models with pathologic stage and nodal status as covariates. ACCI scores increased during the study period (P = .009). Extravesical disease was present in 43% of patients with ACCI <or=2, 49% with ACCI 3-5, and 56% with ACCI >5 (P = .051). Despite their higher prevalence of extravesical disease, patients with higher ACCI were less likely to have lymph-node dissection (odds ratio, 0.55 and 0.35, respectively, for ACCI 3-5 and >5 vs <or=2; P = .005), and when it was performed, fewer lymph nodes were evaluated (P < .0005). Patients with higher ACCI were also less likely to have postoperative chemotherapy (odds ratio, 0.70 and 0.66, respectively, for ACCI 3-5 and >5 vs <or=2; P = .04). Higher ACCI was significantly associated with lower overall (P < .005) but not recurrence-free (P = .17) survival after RC. Age and comorbidity among patients who underwent RC at a cancer referral hospital increased with time. Both age and comorbidity were associated with treatment selection and survival and should, therefore, be considered when comparing outcomes after RC.

Investigations in the molecular events of Transitional Cell Carcinoma of the Bladder

Problem Statement: Transitional Cell Carcinoma (TCC) of the bladder is a significant health problem worldwide. The molecular mechanisms of tumor development and progression are complicated but likely involve the interaction of tumor suppressor genes, oncogenes, cell cycle regulatory proteins and other factors. Hence this study tries to explore the role of p53, bcl-2, c-myc and Ki-67 in TCC of the bladder in correlation with different clinicopathological criteria which are tumor grade, muscle invasion by the tumor and disease presentation, primary or recurrent tumor. Approach: Thirty patients with TCC of the bladder were involved in the period from March 2007 - May 2008. Tumors were diagnosed by histopathology and compared with 20 control subjects. The expressions of p53, bcl-2, c-myc and Ki-67 proteins were investigated by immunohistochemistry (IHC). Results: Increased expression of p53 and bcl-2 was associated with tumor grade and muscle invasion (p 0.05). C-myc expression was only associated with muscle invasion (p<0.05). Ki-67 was associated with tumor grade, muscle invasion and tumor presentation (p<0.05). The correlation among these cell cycle proteins was generally significantly positive except for the correlation between bcl-2 and c-myc was poor. Conclusions: There was a significant oncogenic role of p53 and bcl-2 on TCC in terms of muscle invasion and tumor grade. C-myc was associated only with tumor invasiveness and Ki-67 proved to act as a reliable prognostic factor of TCC. This could highlight the hot targets of TCC anti-cancer therapy and the reliable targets for disease prognosis.

The accuracy of sentinel node biopsy after primary systemic therapy is comparable with the results of sentinel node biopsy in breast cancer patients with primary surgery

Objectives. To evaluate microstaging by means of quantifying the depth of invasion of the subepithelial connective tissue in pT1 transitional cell carcinoma (TCC) of the bladder for its additional prognostic value with respect to disease recurrence and progression.Methods. We reviewed the pathologic findings of a consecutive series of 124 patients with pT1 tumors entered in a prospective randomized multicenter trial comparing mitomycin C and bacillus Calmette-Guérin treatment, with at least 3 years of follow-up and clinical outcome hidden from reviewers. The depth of invasion was established by identifying submucosal tumor invasion up to, in, or beyond the muscularis mucosae or vascular plexus and classified as pT1a, pT1b, or pT1c, respectively. In addition to tumor grade, the presence of carcinoma in situ (CIS) near the primary tumor or in biopsy specimens taken from abnormal looking mucosa was taken into account. The risks of recurrence and progression were calculated using Kaplan-Meier curves and modeled with proportional hazard models.Results. pT1 subclassification was possible in more than 90% of the specimens. The 3-year risk of recurrence was not different in any of the subgroups. By contrast, the Kaplan-Meier 3-year risk for progression was 6%, 33%, and 55% for pT1a, pT1b (hazard ratio [HR] 5.51), and pT1c (HR 12.35) tumors, respectively (log-rank test P < 0.001). The Kaplan-Meier 3-year risk of progression was 9% versus 39% (HR 5.62) for the absence or presence of CIS in the tumor (P = 0.001) and 8% versus 49% (HR 6.72) for CIS in biopsy specimens (P < 0.001). Tumor grade had no statistically significant prognostic value with respect to progression, nor had tumor volume or multifocality. The combination of the parameters (pT1c and CIS) increased the risk of progression by a factor of 27 (P < 0.0001) compared with the absence of pT1c and CIS.Conclusions. These data show that the extent of lamina propria invasion (pT1a, pT1b, pT1c) is a clinically relevant prognostic factor for progression of pT1 TCC of the bladder. With the combination of this pT1 subclassification and the presence of CIS subgroups, distinct risks of progression can be identified that may give additional information for follow-up and treatment policies.

INSTILLATION OF MITOMYCIN C AFTER TRANSURETHRAL RESECTION OF BLADDER CANCER IMPAIRS WOUND HEALING: AN ANIMAL MODEL

Background: Mitomycin C is used in the immediate post-operative period to prevent tumor re-implantation, but it has adverse effects on the bladder. This study devised an animal model to investigate the effects of intravesical mitomycin C on wound healing. Methods and materials: A cystotomy was made in the dome of the bladder of female rats. The mucosa of the posterior wall was scratch with closed forceps. The bladder was closed and 0.2 ml of saline with or without 0.4 mg mitomycin C was instilled into the bladder transurethrally. The rats were sacrificed 30 and 60 days after the treatment and the bladder was examined grossly and microscopically. Results: The most frequent histological findings in the bladder were chronic inflammation and fibrosis. Fibrosis but not chronic inflammation was significantly associated with the exposure to MMC and it persisted even 60 days after the exposure to mitomycin C. Conclusion: Mitomycin C produces chronic fibrosis in rat bladder that is often seen in patients receiving prophylactic treatment with this drug. Transitional cell carcinoma of the bladder is the sixth most common cancer in the United States with 14,680 people expected to die of the disease in 2010 (1). Seventy to 80% of patients with bladder cancer present with superficial disease (stages Ta, T1 and carcinoma in situ, CIS). The treatment of choice for this group of patients is a transurethral resection of bladder tumor (2). Unfortunately, without an adjuvant therapy, 50%-70% of patients will recur with 20% progressing to muscle-invasive disease. Intravesical chemotherapy is used to treat T1 cancers, multifocal and high grade tumors including CIS, and recurrent TCC (3). The role of this treatment in patients with low-risk solitary tumors remains open to debate (4). Multiple agents are available to treat superficial bladder cancer. Intravesical chemotherapy is also used to decrease the rate of tumor cell implantation after transurethral resection of bladder tumor (5). Instillation of mitomycin C (MMC) has been shown to decrease the rate of tumor recurrence (6-8). Serious side-effects of this treatment have been described in the literature (9-11). However, this is an underreported problem which requires further investigation. This study designed an animal model to study the adverse effects of MMC on healing properties of an injured urothelium.

Presentation, location and overall survival of pelvic recurrence after radical cystectomy for transitional cell carcinoma of the bladder

To evaluate the presentation, location and overall survival of pelvic recurrence after radical cystectomy (RC) for transitional cell carcinoma (TCC) of the bladder. We reviewed a consecutive series of 130 patients who had a limited bilateral pelvic lymph node dissection (PLND) and RC between 1987 and 2000, and who later developed pelvic recurrence. All patients were staged N0M0 before RC and no patient received neoadjuvant radio/chemotherapy. The boundaries of the limited PLND were the pelvic side-wall between the genitofemoral and obturator nerves, and the bifurcation of iliac vessels to the circumflex iliac vein. Pelvic recurrence was defined as a radiographic soft-tissue density of > or = 2 cm below the bifurcation of the aorta. Kaplan-Meier and Cox proportional hazards analyses were used to determine if imaging or symptomatic presentation, age, pT stage, and pN status were predictive of overall survival. The median (range) time from RC to pelvic recurrence was 7.3 (1.2-55.4) months. No patients had concomitant distant metastasis. Of the patients, 61.5% were diagnosed with pelvic recurrence because of symptoms, and 38.5% by surveillance computed tomography (CT). Of the 130 patients, 128 died, with a median survival from the time of pelvic recurrence of 4.9 (0.1-129.3) months. The median overall survival time for pelvic recurrence diagnosed with CT was 21.6 months, vs 10.6 months for symptomatic presentations (P < 0.001). In the uni- and multivariate models, type of presentation (CT vs symptomatic) and pT stage were predictors of overall survival, while age and pN status were not. The prognosis of patients with pelvic recurrence after RC for TCC is poor even with subsequent therapy, emphasizing the need for optimum local control at the time of initial treatment.

Implications of p53 gene mutations on patient survival in transitional cell carcinoma of the bladder: A long-term study

Objective To determine the prognostic value of p53 gene mutations and P53 overexpression for predicting the incidence of recurrence, progression and long-term survival of patients with transitional cell carcinoma (TCC) of the bladder. Methods Prospective cohort study with 94 consecutive patients diagnosed and treated for TCC. DNA was obtained from tumor tissue to perform PCR-SSCP of p53 exons 5–9, with automatic sequencing of any mutated samples. Immunohistochemistry using anti-human P53 monoclonal antibody was also performed. Survival was analyzed and the survival curves compared (Mantel-Haenszel). Lastly, a Cox proportional hazards model was constructed. Results Mutations were found in 46.8% of samples, with 61.8% in infiltrating tumors. Exon 8 was involved in 42.3%. P53 overexpression (cutoff ≥20%) was found in 52.1%. Mean follow-up was 44.1 months; 43.6% had died by the end of this period. Mean survival was lower in patients with exon 8 mutations (38.4 months), compared with patients without this exon mutated ( P = 0.016). There were no differences in patient survival based on positive or negative immunohistochemistry (cutoff ≥20%), although survival was lower in patients with a percentage higher than 50% of antibody-stained cells ( P = 0.02). In the Cox analysis, tumor stage, pM stage, and interaction between stage ≥pT2 and mutated p53 gene were independent risk factors, with a 6.13-fold risk of death in these patients ( P = 0.019). The number of tumors, nuclear grade, pTa stage, and the interaction between GI degree and nonmutated p53 gene remained in the Cox model for superficial tumors, such that these patients had a lower risk of recurrence or progression ( P = 0.008). Conclusions Alterations in the p53 gene may be indicative of poorer prognosis and greater recurrence in patients with urothelial bladder tumor, in particular, the presence of mutations in exon 8 and a greater percentage of stained cells in the immunohistochemistry. Nevertheless, the classic prognostic factors (primarily, pTNM stage) should still be considered the most useful factors for follow-up of these patients.

Use of Bipolar Energy for Transurethral Resection of Superficial Bladder Tumors: Long-Term Results

To evaluate the long-term efficacy and safety of transurethral resection of bladder tumor (TURBT) with bipolar plasmakinetic energy. We reviewed the records of 121 patients with superficial transitional cell carcinoma of the bladder treated at our institute. Bipolar TURBT with plasmakinetic energy was performed for diagnostic and therapeutic purposes in all patients. Resected tissue was examined by a pathologist who recorded the number of tumors, tumor size, tumor shape, location, grade, invasion of the muscularis propria, and presence of muscular invasion. The operating time, length of hospital stay, blood loss, and intraoperative and postoperative complications were recorded by a urologist. Follow-up was 3 to 5.5 years after operation. The median age of the patients was 61 years; 41 patients had multiple tumors and 80 had single tumors. The mean tumor size was 1.9 cm in diameter. The tumor was located in the lateral wall of the bladder in 67 patients. The mean operative time was (25 +/- 16) minutes and the mean postoperative hospitalization period was 3 days. Three (2.5%) patients had hematuria requiring blood transfusion and 2 (1.7%) patients had bladder perforation. Adductor contraction was noted in 6 patients (4.9%), and urethral strictures occurred in 5 patients (4.1%). Transurethral resection of bladder tumors with bipolar plasmakinetic energy is safe and effective in the treatment of superficial bladder tumors.

TA T1 Low and Intermediate Transitional Cell Carcinoma of the Bladder: Recurrence Rates and the Timing of Check Cystoscopies within the First Year

Introduction: The intensity of cystoscopic follow-up in the first year for patients with superficial bladder cancer has not been clearly defined. The cystoscopic follow-up of superficial bladder cancer accounts for a considerable workload for the urologist and is also an invasive procedure with high costs. We retrospectively reviewed our experience to determine any possible criteria which can lead to reduce the frequency of check cystoscopy. Material and Methods: A retrospective study was done on 427 patients with primary stage Ta and T1 bladder cancers treated between 1998 and 2005. The pattern of recurrence in the first year was assessed and recurrence rates calculated. Results: The recurrence rate was 22% at 3 months. The recurrence rates at 6 and 9 months were 8 and 13.6% respectively. The recurrence rate at 12 months was 9.4%. For tumors with no recurrence at 3 months, the recurrence rates at 6, 9 and 12 months were 6.6, 13.4 and 8.9% respectively. With respect to stages, there was a statistically significant difference in recurrence rate stages pTa and pT1 in the first and in the third control (p = 0.001, p = 0.003) respectively. According to the recurrence rate within the first year, the difference between G1 and G2 tumors was not statistically significant regardless of the stage (p > 0.05). Conclusions: Patients with initial stage Ta or T1 grade 1 and 2 bladder cancers and negative first cystoscopy have a significantly lower recurrence rate than those with recurrence at first cystoscopy. There is a reason to change follow-up routines but in our opinion only in patients with initial low-grade carcinoma. If the third-month cystoscopy is clear, it is appropriate to perform the first check cystoscopy 1 year after initial resection.

Gynecologic-tract sparing extra peritoneal retrograde radical cystectomy with neobladder

We report on a series of female patients with transitional cell carcinoma of the bladder who underwent extraperitoneal retrograde radical cystectomy sparing the female reproductive organs with neobladder creation. 14 female patients between the ages of 45 and 72 years who underwent gynecologic-tract sparing cystectomy (GTSC) with neobladder between 1997 and 2002 were retrospectively reviewed. Our surgical technique is also described. Radical cystectomy is accomplished by a retrograde method sparing the uterus, adnexa, vagina and distal urethra. An orthotopic neobladder was constructed using small bowel or sigmoid colon, brought extraperitoneally, and anastomosed to the distal urethra. Operating time ranged from 4.5 to six hours with a mean of 5.3 hours. Ten patients were able to void satisfactorily while four required self-catheterization for complete emptying of the bladder. Seven patients were continent day and night and another 7 reported varying degrees of daytime and nighttime incontinence. One patient died of metastases and another of pelvic recurrence. There were no urethral recurrences. Patient satisfaction with the procedure was high. Gynecologic-tract sparing cystectomy with orthotopic neobladder is a viable alternative in female patients with muscle invasive traditional cell carcinoma of the bladder, providing oncological safety with improved quality of life. Our extraperitoneal technique, which is an extension of our successful experience with retrograde extraperitoneal radical cystectomy in men, minimizes intraoperative complications and simplifies the management of post-operative morbidity with the neobladder.

High Incidence of Lung Cancer After Non–Muscle-Invasive Transitional Cell Carcinoma of the Bladder: Implications for Screening Trials

PURPOSELung cancer screening trials depend on the selection of a sufficiently high-risk population. Because not all smokers develop cancer, we hypothesize that a history of tobacco-associated malignancy might more reliably predict for subsequent lung cancer. Because patients with early-stage bladder transitional cell carcinoma (TCC) often have a long survival, we considered whether they would constitute a suitable population for a screening study. PATIENTS AND METHODSPatients with Ta/is/1 N0 M0 TCC of the bladder and no history of previous cancer treated surgically between 1983 and 2002 were studied using the Surveillance, Epidemiology, and End Results (SEER) database. The incidence and cancer-specific mortality of second nonurothelial solid organ cancers was determined. The standardized incidence ratio (SIR) and 15-year actuarial incidences were determined. RESULTSFrom 1983 to 2002, 8300 patients meeting the inclusion criteria were entered into the SEER-9 Registry. Among them, the SIR for a second solid organ malignancy was 1.25 (95% CI, 1.18-1.32). The SIR was significantly increased for tumors of the lung (1.71), head and neck (1.32), and prostate (1.28). The 15-year incidence of and mortality from lung cancer were 8.8% and 8.6%, respectively. Among all nonurothelial second malignancies, lung cancers accounted for 32.5% of the incidence and 53.4% of cancer-specific deaths. Moreover, lung cancer accounted for 12.2% of overall deaths in these patients. CONCLUSIONS: Patients with non–muscle-invasive bladder TCC suffer a high incidence of mortality from lung cancer and might constitute a suitable population for a lung screening trial. Other tobacco-related health events might add to smoking history in identifying high-risk populations.

Alternate Cyclin D1 mRNA Splicing Modulates p27KIP1 Binding and Cell Migration

Cyclin D1 is an important cell cycle regulator, but in cancer its overexpression also increases cellular migration mediated by p27 KIP1 stabilization and RhoA inhibition. Recently, a common polymorphism at the exon 4-intron 4 boundary of the human cyclin D1 gene within a splice donor region was associated with an altered risk of developing cancer. Altered RNA splicing caused by this polymorphism gives rise to a variant cyclin D1 isoform termed cyclin D1b, which has the same N terminus as the canonical cyclin D1a isoform but a distinct C terminus. In this study we show that these different isoforms have unique properties with regard to the cellular migration function of cyclin D1. Although they displayed little difference in transcriptional co-repression assays on idealized reporter genes, microarray cDNA expression analysis revealed differential regulation of genes, including those that influence cellular migration. Additionally, whereas cyclin D1a stabilized p27 KIP1 and inhibited RhoA-induced ROCK kinase activity, promoting cellular migration, cyclin D1b failed to stabilize p27 KIP1 or inhibit ROCK kinase activity and had no effect on migration. Our findings argue that alternate splicing is an important determinant of the function of cyclin D1 in cellular migration.

Development of a Multiplex RNA Urine Test for the Detection and Stratification of Transitional Cell Carcinoma of the Bladder

New markers that enable the percentage of transitional cell carcinomas (TCC) of the bladder that are diagnosed before invasion of the bladder muscle layers to be increased would reduce the morbidity and mortality associated with this disease. The purpose of this study was to develop a simple, accurate urine test based on mRNA markers and simple gene signatures that (a) could detect TCC before muscle invasion while maintaining high specificity in patients with hematuria or urinary tract infections and (b) identify patients most likely to have grade 3 or stage > or =T1 disease. RNA markers with high overexpression in stage Ta tumors and/or T1 to T4 tumors but low expression in blood or inflammatory cells were characterized by quantitative reverse transcription-PCR using 2 mL of voided urine from 75 TCC patients and 77 control patients with other urological diseases. A combination of the RNAs CDC2, MDK, IGFBP5, and HOXA13 detected 48%, 90%, and 100% of stage Ta, T1, and >T1 TCCs, respectively, at a specificity of 85%. Detection of Ta tumors increased to 60% for primary (non-recurrent) Ta tumors and 76% for Ta tumors > or =1 cm in diameter. Test specificity was 80% for the 20 control patients with urinary tract infections. The combination of CDC2 and HOXA13 distinguished between grade 1 to 2 TCCs and grade 3 or stage > or =T1 TCCs with approximately 80% specificity and sensitivity. Simple gene expression signatures can be used as urine markers for the accurate detection and characterization of bladder cancer.

Prognostic Value of MET, RON and Histoprognostic Factors for Urothelial Carcinoma in the Upper Urinary Tract

RON (recepteur d'origine Nantais) (Santa Cruz Technology, Santa Cruz, California) and c-met (Dako, Glostrup, Denmark) are members of the c-met proto-oncogene family. c-met encodes a receptor tyrosine kinase and has a role in oncogenesis. RON has a role in cell transformation and epithelial tumorigenesis. Over expression of the 2 genes has been demonstrated in human bladder cancer. We explored whether over expression of the 2 proteins has a role in the tumorigenesis and defined histoprognostic factors of poor clinical outcomes in patients with these tumors. We reviewed the records of 42 patients with upper urinary tract urothelial carcinoma. A total of 24 tumors were localized in the renal pelvis and 18 were in the ureter. Immunohistochemical staining for RON and c-met was performed using tissue microarrays. Patient age was 46 to 100 years (mean 70.6). Of the patients 23 (54%) died of disease. Over expression of c-met was associated with a higher risk of embolism (p = 0.0002), while over expression of RON was not significantly associated with emboli (p = 0.5). Univariate analysis showed that relapse was significantly associated with ureteral localization (p = 0.02), vascular invasion (p = 0.003), and high grade (p = 0.04) and high stage (0.02) urothelial carcinoma. The association with vascular invasion, and high grade and high stage urothelial carcinoma was also statistically significant (p <0.0001). Notably superficial tumors showed an important relapse rate (p = 0.003). Independent prognostic factors of relapse in upper urinary tract urothelial carcinoma are ureteral localization, vascular invasion, high grade and high stage. c-met seems to influence the development of vascular invasion via an unknown mechanism. Nevertheless, to our knowledge an association between c-met over expression and aggressive clinical behavior in upper urinary tract carcinomas has not been previously reported.