Papillary Transitional Cell Carcinoma Research Articles

COMPLICATIONS OF TRANSPERITONEAL RADICAL NEPHRECTOMY, A SINGLE CENTRE EXPERIENCE

Abstract Objective: To share our experience regarding compli-cations of transperitoneal radical nephrectomy. Material and Methods: After approval from ethical committee a retrospective study was conducted exten-ding from January 2012 to January 2014 to identify clinical characteristics of renal cell carcinomas, stag-ing of RCC, per operative and early post operative complications of transperitoneal radical nephrectomy. The study included all renal cancer patients presented to Sheikh Zayed Hospital Lahore with in this specified period. Detailed history and physical examination was performed. Haematological and radiological investi-gations including abdominopelvic ultrasonography, CT scan abdomen and pelvis were performed to stage the renal tumour. High resolution CT chest was per-formed where indicated. Radical nephrectomy perfor-med through transabdominal approach and outcomes measured in terms of pre and post operative complicat-ions. Results: There were total of 50 cases. The male to female ratio was 3:2. Mean age of patients was 52.38 (18 - 93) years. Most common clinical presentation was gross haematuria(66%).The mean tumour size was 8.34 (3 - 24) cm. Operative findings in 40 patients (80%) were tumor limited to Gerota's fascia and in 6 (12%) there was tumour involvement of renal vein or IVC. In 2 patients (4%) Lymphadenectomy was per-formed. Total operative time ranged between 120 to 180 minutes. Intra-operative splenic injury was seen in 2 (4%), while aortic injury was observed in one (2%) patient. Post operatively one (2%) developed pulmo-nary embolism, 2 (4%) chest infection while 2(4%) developed wound infection and 3 patients (6%) req-uired blood transfusion. Tumour histology was clear cell in (84%), papillary transitional cell carcinoma (12%) and oncocytoma contributed 4%. Conclusion: Transperitoneal approach for radical nephrectomy is safe with minimal peroperative and early post-operative complications. It is also safe whe-re tumour thrombus extends into IVC, as it provides good exposure of vessels. Key Words: Renal cell carcinoma, Radical nephrec-tomy, Complications.

Analysis of TMEM174 gene expression in various renal cancer types by RNA in situ hybridization.

Transmembrane protein 174 (TMEM174) mRNA is easily detectable in human kidney tissues and activates AP-1 and promotes 293T cell proliferation. In the present study, RNA in situ hybridization was used to detect TMEM174 gene expression in various malignant renal cancer and normal renal tissues. The results showed that TMEM174 exhibits differential expression in renal tissues, with a high positive rate of expression in squamous cell carcinoma with necrosis, papillary renal cell carcinoma and transitional cell carcinoma, and a low positive rate of expression in clear cell carcinoma, interstitial nephritis, undifferentiated carcinoma, retroperitoneal metastatic clear cell carcinoma, adrenal gland metastatic clear cell carcinoma, pelvic cavity metastatic chromophobe carcinoma, severe atypical hyperplasia of transitional epithelium and hyperplasia. Extremely weak expression was exhibited in collecting duct carcinoma, Wilms’ tumor, chronic pyelonephritis, acute pyelonephritis, cancer adjacent normal renal tissue and normal renal tissue. In conclusion, the TMEM174 gene exhibited high expression levels in certain renal carcinomas, which may indicate that TMEM174 may have a significant role in the development and progression of these renal carcinomas.

Duration and intensity of tobacco smoking and the risk of papillary and non-papillary transitional cell carcinoma of the bladder.

To evaluate the impact of tobacco smoking on specific histological subtypes of transitional cell carcinoma of the bladder (TCC). Between 2003 and 2009, we conducted a hospital-based case-control study in Italy, enrolling 531 incident TCC cases and 524 cancer-free matched patients. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were estimated through multiple logistic regression models. Compared to never smokers, TCC risk was threefold higher in former smokers (95% CI 2.07-4.18) and more than sixfold higher in current smokers (95% CI 4.54-9.85). TCC risk steadily increased with increasing intensity (OR for ≥25 cigarettes/day 8.75; 95% CI 3.40-22.55) and duration of smoking (OR for ≥50years 5.46; 95% CI 2.60-11.49). No heterogeneity emerged between papillary and non-papillary TCCs for smoking intensity and duration, but the risk for those who had smoked for ≥50years was twice for non-papillary TCC (OR 10.88) compared with papillary one (OR 4.76). Among current smokers, the risk for a 10-year increase in duration grew across strata of intensity (p-trend=0.046). Conversely, the risk for a 5-cigarette/day increase in smoking intensity was quite steady across strata of duration (p-trend=0.18). Study results suggested that duration of smoking outweighs intensity in determining TCC risk, with limited differences across histological subtypes. Elimination of tobacco smoking may prevent about 65% of TCCs.

Metformin inhibits urothelial tumorigenesis in the UPII-mutant Ha-ras transgenic mouse model

Background Bladder cancer occurs mainly in older people and is expensive to manage. As the population continues to age, bladder cancer may remain to be a major public health burden. Therefore, we hypothesized that an agent, like metformin, with anti-aging property could have preventive activity against the development and progression of human urinary bladder cancer. Materials and methods The UPII mutant Ha-ras transgenic mouse model mimics human papillary transitional urothelial cell carcinoma and exhibits enhanced mTOR activity in tumor tissues. Homozygous UPII mutant Ha-ras transgenic mice were identified through genotyping using the Southern blotting method. Genotyped Ha-ras mice were then fed orally with normal drinking water or 0.1% or 0.05% metformin in drinking water starting at 6 weeks of age and ending at 6 months of age. Death rate, body weight, tumor burden, and proliferative and apoptotic indices at the end of treatments will be evaluated by pathological and statistical analyses. Results About 62% of male, homozygous mutant Ha-ras transgenic mice which drank normal water died of urinary tract obstruction and hydronephrosis within 6 months of age, while only about 11% or 15% of mice which drank 0.1% or 0.05% metformin containing water died. Drinking metformin dramatically increased the survival of mutant Ha-ras tumor bearing mice by 51 to 47% (Ps<0.01). Metformin drinking also significantly decreased the mean bladder weights of male, homozygous mutant Ha-ras transgenic mice by up to 62%. Histological analysis of H&E stained bladder sections from metformin treated mice demonstrated more differentiated tumors compared to those in control groups. The in vivo mechanisms of metformin’s action are associated with anti-proliferation, reduction of phospho-mTOR and 4E-BP1 expression and induction of TSC2 expression in bladder tissues. Conclusions Our results demonstrated strong in vivo anti-urothelial tumorigenesis activity of metformin drinking in the UPIImutant H-ras model via inhibition of the mTOR pathway. These results suggested the potential of metformin in preventing recurrence of clinical bladder cancer and in improving quality of life for patients.

A Rare Case of Nephrogenic Adenoma Mimicking Bladder Neoplasm

A 37-year old female, 6 months post renal transplant with no other co-morbid features presented with haematuria since one week. Cystoscopy was planned and a therapeutic procedure of transurethral resection is based on clinical impression of papillary transitional cell carcinoma (TCC). Histopathology showed nephrogenic adenoma. Antibiotic course was given for three weeks. Cystoscopy and ultrasound surveillance showed no evidence of recurrence over the last 18 months. Here is a rare case of nephrogenic adenoma occurred after transplant, which was initially confused for bladder malignancy. Although nephrogenic adenomas may resemble certain types of urologic malignancies, their histology is distinctive and varies little from lesion to lesion, so that once an entity is considered; an accurate pathologic diagnosis is rarely a problem. This case report discusses about presentation and management of a case of nephrogenic adenoma features that differentiate it from bladder malignancy.

P53-stabilizing Agent CP-31398 Prevents Growth and Invasion of Urothelial Cancer of the Bladder in Transgenic UPII-SV40T Mice

The high prevalence of bladder cancer and its recurrence make it an important target for chemoprevention. About half of invasive urothelial tumors have mutations in p53. We determined the chemopreventive efficacy of a p53-stabilizing agent, CP-31398, in a transgenic UPII-SV40T mouse model of bladder transitional cell carcinoma (TCC) that strongly resembles human TCC. After genotyping, six-week-old UPII-SV40T mice (n = 30/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm of CP-31398 for 34 weeks. Progression of bladder cancer growth was monitored by magnetic resonance imaging. At 40 weeks of age, all mice were killed; urinary bladders were collected to determine weights, tumor incidence, and histopathology. There was a significant increase in bladder weights of transgenic versus wild-type mice (male: 140.2 mg vs 27.3 mg, P < .0001; female: 34.2 mg vs 14.8 mg, P < .0001). A significant decrease in the bladder tumor weights (by 68.6–80.2%, P < .0001 in males and by 36.9–55.3%, P < .0001 in females) was observed in CP-31398-treated mice. Invasive papillary TCC incidence was 100% in transgenic mice fed control diet. Both male and female mice exposed to CP-31398 showed inhibition of invasive TCC. CP-31398 (300 ppm) completely blocked invasion in female mice. Molecular analysis of the bladder tumors showed an increase in apoptosis markers (p53, p21, Bax, and Annexin V) with a decrease in vascular endothelial growth factor in transgenic mice fed CP-31398. These results suggest that p53-modulating agents can serve as potential chemopreventive agents for bladder TCC.

Abstract 3690: p53 stabilizing agent CP-31398 prevents urinary bladder tumor growth and invasion in transgenic UPII-SV40T mice.

Abstract The United States will have approximately 73,510 new cases of bladder cancer in 2012 with 14,880 deaths. More than 50% of the invasive (lamina and muscularis) bladder tumors have mutations in p53 and/or pRB. p53 appears to play a major role in the etiology of human bladder cancer, particularly in the high grade invasive type. Structural and functional defects in p53 are found in majority of human transitional cell carcinomas (TCC). The high prevalence of bladder cancer and the frequency of tumor recurrence make it an important target for chemoprevention. In UPII-SV40T transgenic mice, induced bladder TCC bears strong resemblance to that of human TCC in phenotype and in the mode of progression. In the present study, we determined the chemopreventive efficacy of a p53 stabilizing agent, CP-31398, using transgenic UPII-SV40T mouse model. After genotyping, six-week old UPII-SV40T mice (n=32/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm CP-31398 for ∼34 weeks. Progression of bladder cancer was monitored by MRI imaging. At 40 weeks of age, all mice were euthanized; urinary bladders were collected to determine weights, tumor incidence and multiplicity; and histopathology. There was a significant increase in bladder weights of transgenic vs. wild type mice (male 140.2 mg vs. 27.3 mg, p&amp;lt;0.0001; female 34.2 mg vs, 14.8 mg p&amp;lt;0.0001, respectively). A significant decrease in the tumor growth as evidenced by decreased bladder weights (by 52-65%, p&amp;lt;0.000 in males; by 32 %, p&amp;lt;0.001 in females) was observed in CP-31398 treated mice. Invasive papillary TCC incidence was 100 % in transgenic mice fed with control diet. The mice exposed to 150 and 300 ppm CP-31398 showed dose dependent inhibition (29%, p&amp;lt;0.01; 57%, p&amp;lt;0.005) of invasive TCC with 28% and 53% carcinoma In situ, respectively, suggesting suppression of invasive tumor growth. Kidney abnormalities like ureter obstruction and nephrohydrosis were observed in almost all control mice but significantly less frequent in CP-31398-fed mice. Molecular analysis of the bladder tumors showed an increase in apoptosis markers (p53, p21, Bax) with a decrease in angiogenic markers (CD31 and VEGF) in transgenic mice fed with CP-31398. These results suggest that p53 modulating agents can serve as potential chemopreventive for bladder TCC. (Supported in part by NCI-CN53300) Citation Format: Venkateshwar Madka, Yuting Zhang, Qian Li, Altaf Mohammed, Stan Lightfoot, Wu Re Xue, Levy Kopelovich, Chinthalapally V. Rao. p53 stabilizing agent CP-31398 prevents urinary bladder tumor growth and invasion in transgenic UPII-SV40T mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3690. doi:10.1158/1538-7445.AM2013-3690

Antiangiogenic Agents, Chemotherapy, and the Treatment of Metastatic Transitional Cell Carcinoma

A 69-year-old man with a 100 pack-year history of smoking developed gross hematuria. His medical history included hypertension, a silent myocardial infarction, and a cerebrovascular accident complicated by seizures. Cystoscopy and biopsy showed a 4-cm mass at the right ureteral orifice positive for a high-grade papillary transitional cell carcinoma (TCC) with muscularis propria invasion (Fig 1). The computed tomography (CT)/positron emission tomography (PET) scan of the chest, abdomen, and pelvis showed hydronephrosis and hydroureter with marked cortical thinning and multiple bilateral PET-avid pulmonary nodules, with the largest in the left upper lung measuring 3.0 × 2.5 cm (Figs 2A, 3A), biopsy of which showed invasive high-grade urothelial carcinoma. The patient consented to join a clinical trial for metastatic TCC (USON [US Oncology Network study] 06040) involving treatment with gemcitabine, cisplatin, and sunitinib (GCS) 37.5 mg per day. Four days later, he experienced a 10-day hospitalization for acute pancreatitis and neutropenia. Sunitinib was discontinued, and he completed four additional cycles of GC. CT/PET showed that the right ureteral mass and all lung nodules had regressed or disappeared (Figs 2B, 3B). The largest remaining lung nodule at 1.4 cm showed no metabolic activity. He underwent a radical cystoprostatectomy and right nephroureterectomy, disclosing residual high-grade urothelial carcinoma infiltrating the full thickness of the ureteral wall. There was carcinoma in situ of the bladder, and 42 nodes were negative for cancer. The surgery was followed by a small, uncomplicated myocardial infarction. A scheduled left thoracotomy to remove the remaining nodule was cancelled. No additional chemotherapy was administered, and the patient remains free of recurrence 2 years from initiation of chemotherapy. The 1.4-cm nodule has calcified and remains stable and metabolically inactive. He has no sequelae of chemotherapy or surgery, with a creatinine level of 1.35 mg/dL.

Secondary nonmonosymptomatic enuresis diurna as the first manifestation of transitional cell papillary carcinoma of the bladder in a 14-year-old girl

A 14-year-old girl presented with secondary nonmonosymptomatic enuresis diurna and urge incontinence. The patient had no history of medical, psychological or behavioral problems. Systemic physical and neurological examinations and laboratory investigations revealed no abnormality. An ultrasound showed an intravesical tumor that was subsequently excised. Histopathology revealed transitional cell papillary bladder carcinoma of low-grade malignancy. All previously reported cases have presented with the symptoms of gross hematuria or urinary tract infection. To our knowledge, this case represents the first childhood case of transitional cell carcinoma of the bladder presenting with secondary nonmonosymptomatic enuresis diurna and urge incontinence. Additionally, our experience with the above case suggests that the investigation of secondary enuresis symptoms should be thorough and include a cystoscopic examination.

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Aim The clinical behavior of the human urinary bladder papillary transitional cell carcinoma (TCC) probably results from a complex interaction between carcinogenic insults and host resistance during the patient’s life. While the main recognized risk factor is smoking, little information exists about the susceptibility to TCC development. The human leukocyte antigen E (HLA-E) molecule plays an important role both as a modulator of natural killer (NK) cell activity by interacting with CD94-NKG2A receptor in the innate immunity pathway and as an antigen-presenting molecule triggering a specific immune response, thus it may influence tumor immune surveillance. The aim of this study was to explore a possible influence of five HLA-E variation sites, one in exon 2 at position 424 (rs1059510), three at exon 3 in the positions 756 (rs1264457), 887 (rs41560815) and 906 (rs41562314) and one in exon 4 at the position 1691 (rs17875370), on the susceptibility to urinary bladder TCC development and progression in Brazilian subjects. Methods These variation sites were evaluated by means of direct sequencing of PCR products using an ABI3100 Genetic Analyzer. On this bases, 105 healthy donors and 73 patients with historical of TCC, both from Ribeirao Preto City, Southeast Brazil, were evaluated for the variation sites described above. Results Only two of the five variation sites evaluated were polymorphic in an admixed population such as Brazilians, i.e., positions +424 and +756. Considering these, the allele and genotype distributions in patients and controls were very similar and no significant difference was detected, even when patients were compared as a whole or stratified into high and low grade tumor patients. Conclusions In conclusion, although previous associations have been described evolving neighboring genes such as HLA-A and HLA-G, the HLA-G locus seems to be not associated with TCC susceptibility and/or progression to aggressive tumors.

E-cadherin expression as a prognostic factor in transitional cell carcinoma of the bladder after transurethral resection.

To analyze the role of negative versus positive immunoexpression of E-cadherin in recurrence rate of low-grade bladder tumors. A total of 180 patients with unifocal, superficial, low-grade, papillary transitional cell carcinoma of the bladder were included in this study. The E-cadherin expression was evaluated using E-cadherin antibody. The patients were followed up for 36 months. Thereafter, recurrence rate of the tumor was compared between E-cadherin positive and negative groups. Of 180 low-grade carcinomas, E-cadherin immunoexpression was negative in 101 (56%) and positive in 79 (44%) patients. The recurrence rate in negative and positive groups was 65.6% and 37.9%, respectively. Negative in comparison with positive E-cadherin expression was associated with more disease recurrence (P = .045). There is an association between decreased E-Cadherin immunoexpression and tumor recurrence in low-grade and non-muscle invasive transitional cell carcinoma of the bladder.

Beyond renal cell carcinoma: rare and unusual renal masses

The vast majority of primary renal masses represent clear cell or papillary renal cell carcinomas, angiomyolipomas, or transitional cell carcinomas. However, a number of more rare masses can also be encountered, many of which can be very difficult to differentiate from these more common entities based on their imaging features. These uncommon entities include metanephric adenoma, epithelioid angiomyolipoma, medullary renal cell carcinomas, multilocular cystic nephroma, hemangiopericytoma, hemangioma, leiomyoma, leiomyosarcoma, solitary fibrous tumor, renal plasmacytomas, and mixed epithelial and stromal tumors. In some cases, certain clinical and imaging features can allow one of these unusual entities to be placed in the differential diagnosis, including patient age, degree of tumor enhancement, presence of underlying sickle cell trait or sickle cell disease, the presence of a cystic component to the tumor, and tumor morphology. Even if a radiologist is unable to make a specific diagnosis, knowledge of these entities is important, as it allows radiologists to guide post-surgical follow-up, as well to understand the most common sites of metastatic disease.

Abstract 2569: Lyc-O-Mato causes cell cycle arrest and apoptosis in human bladder transitional carcinoma cells

Abstract Approximately two thirds of new bladder cancer cases in the United States are superficial papillary transitional cell carcinoma (TCC), the majority of which are low-grade neoplasms. Data suggest that bladder carcinogenesis is a multi-step, multi-focal (field effect) process, possibly involving the spread of pre-malignant clones-all of which are prerequisites for effective preventive and/or interventional approaches. Epidemiological data suggests an inverse relationship between serum levels of carotenoids and risk of bladder cancer which has encouraged further investigation. In this study, we evaluated the effect of Lyc-O-Mato® (a crude tomato extract containing 10% lycopene and other tomato phytonutrients viz. tocopherols, phytoene, phytofluene, beta-carotene, phospholipids and phytosterols) on human bladder cancer cell growth, cell cycle modulation, induction of apoptosis, and associated molecular alterations. Treatment of bladder cancer cell lines (T-24, high-grade TCC and TCC-SUP, high-grade invasive tumor) with Lyc-O-Mato® at doses of 1-60µM resulted in inhibition of cell growth along with a G1 arrest in T24 cells and G2/M arrest in TCCSUP cells at 24 h post-treatment. In other studies, Lyc-O-Mato® treatment strongly induced the expression of p21/waf1 and p27/kip1, and resulted in a decrease in cyclin-dependent kinases (CDKs) and cyclins involved in G1 and G2/M progression in T24 and TCC SUP cells. Lyc-O-Mato® exposure to these cells showed an increased interaction between cyclin dependent kinase inhibitors (CDKIs)-cyclin-dependent kinases (CDKs) and decrease in the interaction of cyclins and CDKs with their respective stages of the cell cycle. Furthermore, Lyc-O-Mato® treatment significantly reduced the phosphorylation of Retinoblastoma at Serine780, although no significant changes were observed in the total levels of this protein. In additional studies, Lyc-O-Mato® showed a dose- and time-dependent apoptotic death in both T24 and TCC SUP cells which was associated with significant downregulation of survivin along with the enhancement of pro-apoptotic protein, Bax. These observations provide a strong rationale for further evaluating preventive and/or intervention strategies for Lyc-O-Mato® in pre-clinical models of bladder cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2569. doi:1538-7445.AM2012-2569

Abstract 618: Rhodiola rosea L. extract, SHR-5, and metformin exhibit potent activity against bladder carcinogenesis in the UPII-mutant Ha-ras transgenic model.

Abstract The incidence of human urinary bladder cancer increases markedly with age, suggesting a mechanistic connection between aging and bladder carcinogenesis and a potential use of anti-aging agents in bladder cancer chemoprevention. Rhodiola rosea, growing in high altitude or cold regions of the world, has been reported to have anti-aging effects in Drosophila. Metformin, a popular anti-diabetics drug, has also shown anti-aging effect in mice. In addition, both agents have been shown to inhibit the mTOR pathway. Therefore, we examined the effect of SHR-5 and Metformin on bladder carcinogenesis in the UPII-mutant Ha-ras transgenic mouse bladder model. This model mimics human papillary transitional cell carcinoma and exhibits enhanced mTOR activity in the bladder tumors. The homozygous mutant Ha-ras transgenic mice were identified through genotyping using Southern blotting analysis. 0.625% SHR-5 or 0.1% Metformin in drinking water was given to the mice starting at 6 weeks of age and ending at 6 months of age. About 42% of homozygous mutant Ha-ras male transgenic mice which drank normal water died of urinary tract obstruction and hydronephrosis within 6 months of age, while more than 93% and 89% of mice which drank SHR-5 or Metformin containing water survived. The mean bladder weights in male mice drinking SHR-5 or Metformin decreased by 69% and 62%, respectively, compared to control group (Bladder weights for mice drinking normal water versus SHR-5 or Metformin are 0.3382± 0.061versus 0.1278± 0.02 or 0.1053±0.015 gram, P=0.0197 or 0.0082). The mean bladder weights in female mice which drank SHR-5 or Metformin containing water also decreased by about 40% or 39.8 %, respectively, compared to those which drank normal water (Bladder weights for normal water versus SHR-5 or Metformin: 0.07149 ±0.0036 versus 0.04301 ±0.0032 or 0.04295±0.0115 gram, P&amp;lt;0.0001 or =0.0007). Chemstrip tests showed that mice which drank SHR-5 or metformin water developed less hematurine than those which drank normal water. Histological analysis of H&amp;E staining bladder sections from SHR-5 and Metformin treated mice demonstrated more differentiated tumors compared to those from the transgenic mice which drank normal water. Immunohistochemistry staining revealed that SHR-5 and Metformin treatments decreased cell proliferation in the urothelium. Taken together, our results suggest a potential new method for bladder cancer prevention by drinking SHR-5 or Metformin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 618. doi:1538-7445.AM2012-618

Restored Renal Transplants From Donors With Distal Ureteral Carcinomas

To the Editor: We performed eight renal transplants between April 5, 1993 and February 21, 2003 from donors with distal papillary and nonpapillary transitional cell carcinomas (TCC) whose pathologic staging ranged from pTa to pT3. Kidney donation was discussed and consented after the patient decided total nephrectomy. The recipients were fully notified of its recurrence risk. This had been reported in 2008 (1). We would like to provide 3-year more updated report to address the issue of risk of donor transmitted malignancies as presented in AJT June 2011 article (2). Of these eight patients, three died—two of causes un-related to the TCC. The third patient had recurrence of TCC in the transplanted kidney 15 months after transplant. Although graft nephrectomy was recommended, the patient adamantly refused to remain off of dialysis. Instead, the cancerous area of the urinary tract was excised and reconstructed with an ileal replacement. He eventually went on to die from presumed primary lung cancer with liver metastasis 3 years after his second operative procedure, although this could not be confirmed as no autopsy was performed. As of July 2011, four patients are alive with functioning grafts. The fifth patient is also alive but returned to dialysis. From this small cohort, we observed a 12.5% recurrence rate. Graft survival rates at 1, 3, 5 and 10 years are 100%, 100%, 50% and 50%, patient survival rate at 1, 3, 5 and 10 years were 100%, 100%, 75% and 60%. Although a 12.5% recurrence rate would place grafts with ureteral TCC in the high-risk category for transmission according to the June 2011 AJT article (2), we would like to point out that the single recurrence noted in this group did occur in a recipient whose donor had pT3 TCC whereas the remainder of the donors had a TCC with a pT2 stage or less. This would suggest that utilizing grafts from donors with T2 or less TCC may be reasonable. In such cases, it may be reasonable to utilize fresh frozen sectioning during the back-table procedure to help determine which grafts have early stage TCC. In conclusion, we offer that utilization of grafts from donors with TCC may be reasonable when there are limited resources, the recipient has undergone a thorough and fully informed consent, and efforts have been made to determine those grafts with early stage TCC. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Skeletal Muscle Metastases from Urothelial Cell Carcinoma

Hematogenous metastasis to skeletal muscle from urothelial carcinoma is extremely rare and metastatic disease to skeletal muscle tends to be found in people with advanced-stage neoplasm. We report in this paper a case of left sartorius muscle metastasis from urothelial cell carcinoma. A left nephroureterectomy with bladder cuff excision was performed and revealed a high-grade papillary transitional cell carcinoma (TCC) of the pelvis. And 6 month later, recurrent bladder cancer was found regular cystoscopy and then treated with transurethral resection of the bladder. After 6 times resection of bladder, an invasion into the bladder muscle layer was found. We recommended additional radical cystectomy to prevent the disease from advancing. However, the patient refused additional surgery. 6 month later, the patient complained of left thigh pain, so ultrasonography-guided biopsy of the nodular mass lesion in the left sartorius muscle was performed. The pathological analysis of the biopsy specimen revealed poorly differentiated metastatic urothelial carcinoma.

Polypoid Cystitis in an Adult Without History of Catheterization

Polypoid cystitis is a benign exophytic mucosal lesion of the bladder. Differentiating it from papillary transitional cell carcinoma is difficult due to their similar characteristics. Although indwelling catheter is the main well-known cause of polypoid cystitis, some case reports unrelated to catheterization have been described. However, the radiological findings of polypoid cystitis have rarely been reported. We hereby describe polypoid cystitis in a 20-year-old man without a history of catheterization along with the computed tomographic findings.

A Case of Six Different Primary Malignancies in One Patient

Purpose: Individuals with a primary neoplasm can often develop a secondary malignancy, either at the same time or even many years later. Autopsy series have estimated the incidence of a second primary cancer ranges from 3-7%. Furthermore, current research shows that only 2-12% of synchronous tumors go on to develop a third or fourth neoplasia. We present a rare case of an elderly male with known history of testicular cancer, colon cancer, transitional cell carcinoma of the kidney, now diagnosed with small cell neuroendocrine carcinoma of the stomach, adenocarcinoma of the common bile duct and invasive adenocarcinoma of the rectum, all within twenty five years. A 74 year old male was referred for complaints of epigastric pain, decreased appetite, weight loss, and jaundice. After review of the patient's past medical history it was discovered that twenty five years ago he was diagnosed with testicular cancer and underwent a left sided orchiectomy. Ten years later he had a hemicolectomy for a primary colonic neoplasm. Nine years after that he was found to have papillary transitional cell carcinoma of the kidney resulting in a right sided nephrectomy. His family history was significant for a sister who died of ovarian cancer at the age of sixty eight. On exam, he was noted to be jaundiced with scleral icterus. His laboratory studies were suggestive of obstructive jaundice; An ERCP revealed ulcerated necrotic lesions in the gastric cardia and a dilated CBD; an ampullary biopsy was also performed. The biopsy of the gastric cardia revealed small cell neuroendocrine carcinoma while the pathology from the ampulla and CBD brushings was consistent with adenocarcinoma. A PET scan resulted in the discovery of a rectal lesion which was biopsied and revealed invasive adenocarcinoma arising in a tubulovillous adenoma. Extensive genetic testing revealed no recognized mutations. The patient opted for palliative care and expired 6 months later. New data continue to indicate an increased incidence of primary as well as “extraprimary” cancers in the population. The term Multiple Primary Malignant Neoplasms (MPMN) has been used to describe the occurrence of numerous distinct primary cancers in one individual. Various theories have been proposed to describe this phenomenon, including environmental factors, genetic predispositions and individual molecular variations such as microsatellite instabilities. It has also been suggested that patients with colorectal cancer as well as neuroendocrine tumors-as seen in our patient-are more likely to develop additional primary malignancies. Further investigation is warranted to elucidate potential underlying genetic predispositions to these rare but important syndromes.

Changing patterns of bladder cancer in the USA: evidence of heterogeneous disease

To test the hypothesis that bladder cancer is a heterogeneous disease. We examined the temporal trends of bladder cancer by histological subtype and by disease stage and grade using the National Cancer Institute's Surveillance, Epidemiology, and End Results data collected in 1973-2007. The age-adjusted incidence rates of bladder cancer showed a slight decrease from 1973 to 2007 (annual percentage change [APC] = -0.4, P < 0.05). Although the age-adjusted incidence rates of non-papillary transitional cell carcinoma decreased by about 53% from 7.9 per 100,000 in 1973 to 3.7 per 100,000 in 2007 (APC = -2.2, P < 0.05), the age-adjusted incidence rates of papillary transitional cell carcinoma increased by about 56% from 6.8 per 100,000 in 1973 to 10.6 per 100,000 in 2007 (APC = 0.5, P < 0.05). Among other rare histological subtypes, except for small cell carcinoma which showed a slightly rising trend, squamous cell carcinoma, adenocarcinoma and others all presented a decreasing trend. Similar patterns were found for different stages (localized, regional and distant), but a dramatic increasing trend of grade IV was found between 1998 and 2007 when a corresponding decreasing trend was shown for grades I, II and III. The results support the hypothesis that bladder cancer is a heterogeneous disease and taking disease heterogeneity into consideration in future epidemiological studies is essential.

Abstract 855: Flavokawain A inhibits urinary bladder cancer in UPII-mutant Ha-ras transgenic mouse bladder cancer model

Abstract Flavokawain A is the predominant chalcone identified from kava extract. We have recently shown that flavokawain A exhibited strong growth inhibitory effects on human bladder cancer cells both in vitro in cell cultures and in vivo in a xenograft mouse model. To examine whether flavokawain A affects specific-stages or course of bladder cancer development, the UPII-mutant Ha-ras transgenic mouse bladder model that mimics human papillary transitional cell carcinoma was used. The homozygous mutant Ha-ras transgenic mice were identified through genotyping using Southern blotting analysis and fed orally with 1g flavokawain A/kg food or 6 g flavokawain A /kg food for 3 or 6 months starting at 6 weeks of age. After treatments, organs are collected and weighted. H&amp;E staining and immunohistochemstry were used to evaluate bladder cancer pathology and expression of biomarkers. All control food- fed male mice died of ureter obstruction and nephrohydrosis within 6 months of treatment, while more than 50% of mice fed with 6g flavokawain A /kg food for 6 months survived beyond the 6 months of treatment. The mean bladder weight in 6g flavokawain /kg food fed male mice also decreased by 66% compared to control treated mice for 3 months. Mouse pathology analysis showed that control mice exhibited poorly differentiated transitional cell carcinoma, while that flavokawain A treated mice presented well differentiated tumors. Compared to the dose of 6g/kg, a 1g/kg dose of flavokawain A is less effective in inhibition of bladder cancer development in this transgenic model. In addition, immunohistochemistry staining of Skp2 revealed that Skp2 oncoprotein expression in urothelium was also significantly decreased in flavorkawain A treatment group compared to control group. Taken together, our results suggest the potential usefulness of flavokawain A in treatment of superficial urinary bladder cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 855. doi:10.1158/1538-7445.AM2011-855