M. Craig Hall

Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients

OBJECTIVES To review a large single-center experience of patients treated for upper tract transitional cell carcinoma (TCC) with extended follow-up in order to identify patterns of recurrence, assess patient outcomes, and determine the impact of traditional prognostic factors. METHODS We reviewed 252 patients treated surgically for upper tract TCC with a median follow-up of 64 months. Most patients (77%) underwent nephroureterectomy, whereas 17% were treated with a parenchymal sparing approach. Traditional prognostic factors including age, sex, tumor stage, grade, location, and type of surgical treatment were analyzed with respect to disease recurrence and survival. RESULTS Disease relapse occurred in 67 patients (27%) at a median time of 12.0 months. Recurrences were local in the retroperitoneum (9%), the bladder (51%), remaining upper tract (18%), or distant in the lung, bone, or liver (22%). The 6 patients with local relapse were among the 73 patients with pT3 or pT4 tumors, and all died of TCC at a median time from diagnosis of 37 months. Significant prognostic factors for recurrence by univariate analysis were tumor grade (P = 0.0014) and stage (P = 0.0001). On multivariate analysis, only tumor stage (P = 0.017) and treatment modality (P = 0.020) were predictors of recurrence. Actuarial 5-year disease-specific survival rates by primary tumor stage were 100% for Ta/cis, 91.7% for T1, 72.6% for T2, and 40.5% for T3. Patients with primary Stage T4 tumors had a median survival of 6 months. Although tumor stage and grade correlated with disease-specific survival on univariate analysis, only patient age (P = 0.042) and stage (P = 0.0001) were significant on multivariate analysis with the type of surgical procedure performed approaching significance (P = 0.0504). CONCLUSIONS Primary tumor stage and surgical procedure performed (radical versus parenchymal sparing) are important predictors of disease recurrence. Patient age and tumor stage were the only predictors of disease-specific survival on multivariate analysis with the type of surgical procedure approaching significance. Radical nephroureterectomy achieves excellent local control even in the setting of locally advanced (pT3 or T4) disease. The major clinical feature in this setting is distant failure, and the development of effective systemic therapy is needed to improve the outcome in these patients.

Long-Term Metabolic Effects of Urinary Diversion: A Comparison of Myelomeningocele Patients Managed by Clean Intermittent Catheterization and Urinary Diversion

We previously reported that chronic urinary diversion through intestinal segments may have adverse effects on bone and mineral metabolism. This study examined the long-term health of patients managed by urinary diversion (94% by ileal conduit) for neuropathic bladders secondary to myelomeningocele defects and compared them to a control population of myelomeningocele patients managed by intermittent catheterization. Of the patients 93 were studied by personal interview, chart review, morphometric analysis, serum studies and dual-photon bone density determination. Average followup was 23 +/- 6 years in the urinary diversion group and 17 +/- 5 years in the intermittent catheterization group. Fractures occurred in 40% of the patients in both groups. Patients with a urinary diversion had an increased need for surgery to correct spinal curvature (57% versus 40%) and a significantly increased incidence of complications resulting from orthopedic procedures (17% versus 3%, p less than or equal to 0.05). There was also an adverse effect on renal function. The urinary diversion group had an increased incidence of radiographic renal deterioration (57% versus 8%, p less than 0.001), nephrolithiasis (43% versus 2%, p less than 0.001), pyelonephritis (60% versus 21%, p less than 0.001) and intermittent metabolic acidosis (20% versus 5%, p = 0.05). Surgery was required in 37% for stomal complications and in 17% for ureterointestinal stricture. Linear growth was adversely affected by urinary diversion. Patients with urinary diversion had decreased lengths for all morphometric parameters and a greater percentage of them were at or below the 10th percentile standards. Serum electrolytes, liver function studies, vitamin D3 and parahormone showed no differences in the 2 groups. No patient had a significant metabolic acidosis at the time of study. Bone densities were significantly diminished in both groups and not significantly different. This study strongly suggests that urinary diversion through intestinal segments is associated with adverse effects on bone health.

Prospective determination of the hormonal response after cessation of luteinizing hormone-releasing hormone agonist treatment in patients with prostate cancer

OBJECTIVES To determine the hormonal (luteinizing hormone [LH] and testosterone) and biochemical (serum prostate-specific antigen [PSA]) response to withdrawal of luteinizing hormone-releasing hormone (LHRH) agonists in patients who received more than 2 years of LHRH therapy for advanced prostate cancer. METHODS Fourteen patients with clinical Stage T3 or higher prostate cancer and no evidence of clinical or biochemical progression, who had received 2 years or more of LHRH therapy, were enrolled at the time of their scheduled 3-month depot injection. Patients underwent history, physical examination, and measurement of serum PSA, LH, and testosterone at baseline, monthly for 3 months, and then every 3 months for 1 year following LHRH withdrawal. RESULTS The mean age of patients was 70.3 years (range 56 to 84). Patients previously received LHRH agonist for a mean of 38.6 months (range 25 to 82). All patients had castrate levels of testosterone (median 10.0 ng/dL) and suppressed LH levels (median 0.1 mIU/mL) at baseline. Median baseline PSA was 0.15 ng/mL. On multiple groupwise comparison, there was no significant change (compared with baseline) in LH or testosterone until 6 months after withdrawal and no change in PSA throughout the duration of the study (median PSA at 1 2 months 0.30 ng/mL). Despite significant increases in LH and testosterone when compared with baseline beginning at 6 months, both LH and testosterone remained markedly suppressed, with median testosterone remaining in the castrate range at both 6 and 9 months and significantly below the lower limit of normal at 12 months (median 111.0 ng/dL). Despite no statistically significant change for the entire cohort in serum PSA, a rising PSA was noted in 4 patients between 3 and 9 months, and LHRH therapy was reinitiated. The remaining patients continued to have suppressed LH and testosterone, with 4 patients remaining in the castrate range at 12 months. CONCLUSIONS The recovery of function of the hypothalamic-pituitary-testicular axis after prolonged LHRH administration is variable. Castrate levels of testosterone and suppressed LH may persist even up to 1 year after discontinuing LHRH. These results have significant implications regarding the interpretation of clinical trials incorporating neoadjuvant and adjuvant hormonal therapy. Further studies are needed to expand on these preliminary observations and should also address the feasibility of incorporating LHRH withdrawal into clinical practice.

Phase I/II Study of 19-nor-1α-25-Dihydroxyvitamin D2 (Paricalcitol) in Advanced, Androgen-Insensitive Prostate Cancer

Purpose: We assessed the safety and efficacy of the vitamin D analogue, 19-nor-1α-25-dihydroxyvitamin D2 (paricalcitol), in patients with androgen-independent prostate cancer. Experimental Design: Patients received paricalcitol i.v. three times per week on an escalating dose of 5 to 25 μg (3-15 μg/m2). The primary end point was prostate-specific antigen (PSA) response. Secondary end points were characterization of toxicity in this population, changes in serum parathyroid hormone (PTH), and survival. Results: A total of 18 patients were enrolled. No patient showed a sustained 50% drop in serum PSA, despite several large declines in PSA (e.g., 1,300 ng/mL). Paricalcitol was well tolerated. One instance of significant hypercalcemia, a serum calcium of 14.3 mg/dL, was observed at the highest dose (25 μg). At entry into the study, seven (41%) of the patients had elevated serum levels of PTH, which were significantly reduced by paricalcitol. Higher levels of serum PTH at study entry were significantly and negatively associated with survival (P < 0.01). Conclusion: No objective responses were seen in the primary end point. However, elevated serum levels of PTH, a common feature of advanced prostate cancer, were reduced by paricalcitol. Because elevated PTH is associated with increased cardiovascular and skeletal morbidity, including an increased risk for pathologic fracture, further evaluation of paricalcitol in the reduction of skeletal morbidity in advanced prostate cancer is warranted.

Advanced transitional cell carcinoma of the upper urinary tract : Patterns of failure, survival and impact of postoperative adjuvant radiotherapy

PURPOSE We review the outcome of patients with advanced stage III or IV transitional cell carcinoma of the upper urinary tract and the impact of postoperative radiotherapy. MATERIALS AND METHODS We identified 74 patients who were treated surgically with curative intent for stage III (49) or IV (25) transitional cell carcinoma of the upper urinary tract. Median followup was 21 months (range 1 to 236) for all patients and 60 months (range 29 to 172) for those alive at last contact. A median dose of 40 Gy. adjuvant radiotherapy was delivered to the tumor bed and regional nodes of 15 patients (30%) with stage III and 13 (52%) with stage IV disease. RESULTS The actuarial 5-year overall and disease specific survival for patients with stage III disease was 28 and 40%, respectively. Median disease specific survival was 37 months. Median overall and disease specific survival for patients with stage IV disease was 7 months. Isolated local recurrence was identified in 5 of 49 patients with stage III and only 1 of 25 with stage IV disease. The 5-year actuarial disease specific survival rate in patients with stage III disease whether or not they were treated with postoperative radiotherapy was 45 versus 40%, respectively. For patients with stage IV disease median survival was 7 and 9 months for those who were and those who were not treated with postoperative radiotherapy, respectively. CONCLUSIONS Patients with stages III and IV transitional cell carcinoma of the upper urinary tract have a high risk of disease relapse and cancer mortality. The major clinical feature is distant failure with isolated local relapse uncommon following initial aggressive surgical therapy. There is no survival benefit with postoperative adjuvant radiotherapy. More effective systemic adjuvant therapy is necessary to improve the outcome of these patients.

THE GROWTH INHIBITORY EFFECT OF p21 ADENOVIRUS ON HUMAN BLADDER CANCER CELLS

PURPOSE To evaluate whether p21 (WAF-1/CIP1) should be considered a potential candidate for human bladder cancer gene therapy, we determined: (1) the basal level of p21 expression in bladder cancer cell lines, (2) the response of bladder cancer cells to increased p21 expression following p21 adenovirus infection, and (3) the mechanism of growth inhibition produced by p21 overexpression. MATERIALS AND METHODS Five established human bladder cancer cell lines and one primary culture derived from an invasive transitional cell carcinoma were used in this study. To examine the effect of p21 protein on the growth of human bladder cancer cells, a recombinant adenovirus vector system containing p21 cDNA, under the control of cytomegalovirus promoter, was constructed. A control virus containing p21 in an antisense orientation was used to eliminate potential artifacts caused by viral toxicity. RESULTS Human bladder cancer cell lines exhibit variable endogenous p21 levels which correlate with the in vitro growth status. Significant, but highly variable increases in the steady-state level of p21 were detected in p21 adenovirus infected cells. Human bladder cancer cell lines responded heterogeneously to p21 adenovirus infection. Growth of the WH cell line was substantially inhibited in a dose and time-course dependent fashion. The mechanism of p21 growth inhibition was found to be due to G0/G1 arrest and not the induction of apoptosis. In contrast, p21 adenovirus failed to inhibit the growth of T24 bladder cancer cells because T24 cells were resistant to viral infection. The 253J bladder cancer cells exhibited marked sensitivity to adenovirus; substantial growth inhibition was seen with both sense and antisense p21 very early in the time course of infection. CONCLUSIONS We found significant variation in the basal level of p21 protein expression in several human bladder cancer cell lines. Increased p21 expression as a result of adenoviral infection may be a potent growth suppressor in some human bladder cancer because it elicits cell cycle arrest in G0/G1 stage, but not the induction of apoptosis. Bladder cancer cells exhibit a wide spectrum of sensitivity to adenoviral infection that may be caused by the presence of viral receptor heterogeneity. This wide spectrum of sensitivity has significant basic scientific and clinical implications and warrants further study.

Deoxyribonucleic acid flow cytometry and traditional pathologic variables in invasive penile carcinoma : Assessment of prognostic significance

OBJECTIVES The identification of reliable prognostic factors to guide the selection of patients at high risk of harboring subclinical metastases in penile cancer is important. We evaluated traditional pathologic variables and deoxyribonucleic acid (DNA) flow cytometry to determine the prognostic significance of these variables for the subsequent development of lymph node metastases. METHODS Clinical data and pathologic specimens were retrospectively reviewed from patients treated surgically at university-affiliated hospitals from 1958 to 1987. Pathologic analysis (grade, depth of invasion, and pathologic stage) and DNA flow cytometry were performed on specimens from 46 patients with invasive penile carcinoma and complete medical records. Pathologic variables were compared with DNA flow cytometry results in patients who never developed lymph node metastasis (32 patients, median follow-up 121 months) and in those who presented with or developed proved lymph node metastases (14 patients, median follow-up 18 months). RESULTS The distributions of diploid and nondiploid tumors were similar in patients with or without lymph node metastasis. In addition, there was no significant difference in the grade distributions of tumors with respect to lymph node status. Patients with positive nodes more commonly had tumors that invaded greater than 0.5 cm or that exhibited pathologic Stage T2 or greater (deep invasion). All 14 patients who presented with or subsequently developed metastasis had deep primary tumors. Thirteen of 36 patients with clinically negative nodes had superficially invasive tumors (pathologic Stage T1 and depth of invasion 0.5 cm or less), and none developed metastasis (median follow-up 124 months [range 58 to 240]). Tumor grade was significantly related to the likelihood of deep invasion but was not an independent prognostic factor for metastasis. CONCLUSIONS DNA flow cytometry does not add prognostic information to that obtained by pathologic assessment in patients with invasive penile carcinoma. The presence of pathologic Stage T2 or greater or depth of invasion greater than 0.5 cm defines a group of patients at high risk of inguinal node metastasis. A novel finding was that patients with minimally invasive lesions (0.5 cm or less) and no evidence of corporal invasion (pathologic Stage T1) have little risk of inguinal node metastasis. Close observation of reliable patients meeting these criteria may be a safe alternative to prophylactic lymphadenectomy.

Mechanism of ammonium transport by intestinal segments following urinary diversion : evidence for ionized NH4- transport via K+-pathways

Using a previously reported in vivo intestinal perfusion model in the rat, we have shown that net total ammonium absorption accounts for the majority of the acid load resulting from urinary intestinal diversion. In the present study, by varying perfusate pH and therefore NH3 concentrations, we demonstrated that the net flux of total ammonium did not correlate with non-ionized NH3 concentrations (r = .039). This indicates that the basic mechanism of total ammonium flux is via ionized NH4+ movement. To more precisely define the transport processes involved, we manipulated this system with the following chemical and pharmacologic probes of electrolyte transport: amiloride (0.5 mM/l.), furosemide (1 mM/l.), 2,4,6-triaminopyrimidine (TAP) (15 mM/l.), methylprednisolone (3 mg./100 gm./B.W.) S.Q. x 3 days followed by perfusion, and barium (Ba2+) (15 mM/l.). Net solute flux was not significantly altered by the mucosal addition of amiloride or TAP. Methylprednisolone treated rats exhibited significantly diminished Na+ secretion (p less than .01) and increased Cl- absorption (p less than .05) without affecting net total ammonium flux providing evidence for the inducibility of Na+ conductance channels and against significant NH4+ movement via this pathway. The mucosal addition of furosemide resulted in significantly decreased net absorption of both total ammonium (p less than .001) and K+ (p less than .05). The addition of Ba2+ resulted in a three-fold reduction of ammonium absorption (p less than .001) and a greater than ten-fold reduction in K+ absorption (p less than .001). The observation of significant inhibition of ammonium absorption by furosemide and barium suggests that K+ transport pathways play a significant role in the intestinal transport of NH4+.

LOSS OF ADENOVIRAL RECEPTOR EXPRESSION IN HUMAN BLADDER CANCER CELLS- A POTENTIAL IMPACT ON THE EFFICACY OF GENE THERAPY

There is great interest in the development of gene therapeutic strategies for the treatment of benign and malignant diseases. Recombinant adenovirus has a wide spectrum of tissue specificity and is an efficient vector delivery system. Successful gene delivery, however, requires viral entry into the target cells via specific receptor-mediated uptake. Recently, a cDNA clone (the coxsackie and adenovirus receptor [CAR]) encoding a 46-kDa protein was identified as the receptor for group C adenovirus (e.g., adenovirus type 2 and 5). Currently, little is known regarding the expression of adenoviral receptor in normal tissue and cancer. In this paper, we have documented a significant difference in viral receptor levels that may be due to transcriptional regulation of the CAR gene in several human bladder cancer cell lines. The differences in viral receptor levels in these cells correlated with their sensitivity to viral infection. Transfection of receptor-negative cell line with CAR cDNA led to increased virus binding and increased susceptibility to adenovirus-mediated gene delivery. Our results demonstrate that the expression of adenoviral receptor is variable among human bladder cancer cells. This variability may have a significant impact on the outcome of adenovirus-based gene therapy.

Abstract 2771: Genetic variation in interleukin, TLR, TNF and TRAF genes of NF-κB activation pathway and risk of prostate cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL It has been suggested that NF-κB triggers both the onset and resolution of inflammation by governing the expression of genes essential in activating malignancy-promoting signaling pathways. Members of the NF-κB activation pathway include tumor necrosis factor (TNF), several interleukins (IL), TNF receptor associated factors (TRAFs), and toll-like receptors (TLR). These molecules are involved in cell proliferation, differentiation, apoptosis and response to proinflammatory cytokines and mediating the production of cytokines necessary for the development of effective immunity. Common single nucleotide polymorphisms (SNP) in TNF, IL, TRAF, TLR and the main units of NF-κB genes were assessed for the association with prostate cancer (PrCA) risk in a clinic-based study of Caucasian and African-American cases and controls. A total of 709 tagSNPs (with minor allele frequency > = 5% and r2>=0.8) in 54 genes were genotyped in 903 Caucasians (552 cases and 351 controls) and 174 African-Americans (74 cases and 100 controls) using a custom Illumina Infinium II ® assay. Logistic regression models were used to examine each tagSNP with PrCA (adjusting for age and family history of prostate cancer and using an additive model for the SNP). Empirical p-values were generated by permutation (using 10,000 replicates) to correct for multiple comparisons. Statistically significant associations were observed in Caucasians at the NFkBIL1 and IL1R1 genes. The strongest evidence for association came at a polymorphism in the promoter region of the NFkBIL1 gene (rs3219184) (OR = 0.51 [95% CI 0.35-0.74], p = 0.0005), and a polymorphism in the 3’ flanking region of the IL1R1 gene (rs3917332) (OR = 1.60 [95% CI 1.23-2.09], p = 0.0005). We conclude that common variations in NFkBIL1 and IL1R1 might play important roles in PrCA susceptibility. 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 2771. doi:10.1158/1538-7445.AM2011-2771