Julio M. Pow-Sang

Phase I trial of a B7-1 (CD80) gene modified autologous tumor cell vaccine in combination with systemic interleukin-2 in patients with metastatic renal cell carcinoma.

PURPOSE A reason that the immune system may fail to reject tumors is that T cells encounter tumor antigen derived peptides on the surface of tumor cells in a tolerizing rather than activating context since tumor cells do not express T cell co-stimulatory molecules such as B7-1 (CD80). In preclinical models over expression of B7-1 on the surface of tumor cells has been shown to activate T cells which kill tumor cells. We conducted a phase I clinical trial testing this approach in patients with metastatic renal cell carcinoma. MATERIALS AND METHODS Resected tumors from 15 patients were disaggregated and adapted to tissue culture, transduced with the B7-1 gene and injected subcutaneously as a vaccine. The dose of the vaccine was escalated in 3 separate cohorts of patients, and systemic interleukin-2 (IL-2) was administered as an adjuvant designed to enhance the proliferation of the vaccine activated T cells. RESULTS Of the 15 patients 9 had measurable disease, 2 had a partial response and 2 had stable disease. Perivascular T cell infiltrates at autologous tumor delayed type hypersensitivity skin test sites developed in 3 of the 4 patients with stable disease or partial response. Although the patients experienced the usual and expected toxicity from the IL-2, there was no significant toxicity observed with the vaccine. CONCLUSIONS The B7-1 gene modified autologous tumor cell vaccine is safe and can be combined with systemic IL-2 with acceptable toxicity. Immunological and clinical responses were observed in some of the patients. A phase II trial is reasonable to determine the efficacy of this approach.

Deletion Polymorphism of UDP-Glucuronosyltransferase 2B17 and Risk of Prostate Cancer in African American and Caucasian Men

Purpose: UDP-glucuronosyltransferases (UGT) are a family of enzymes that glucuronidate many endogenous chemicals, including androgens. This makes them more hydrophilic, alters biological activity, and facilitates their excretion. A deletion polymorphism in the UGT2B17 gene was recently described that was associated with a reduced rate of glucuronidation in vivo. The purpose of this study was to determine if the deletion polymorphism is associated with susceptibility to prostate cancer. Materials and Methods: UGT2B17 expression was determined by reverse transcription-PCR of pathologically normal prostate tissues (n = 5). In a case-control study with 420 patients with incident primary prostate cancer (127 African Americans and 293 Caucasians) and 487 controls (120 African Americans and 367 Caucasians), the frequency of UGT2B17 deletion polymorphism in genomic DNA was compared between cases and controls with PCR analysis. Results: UGT2B17 mRNA was detected only in individuals with at least one UGT2B17 allele. The frequency of the null genotype was present in 0.11 and 0.12 of Caucasian and African American controls, respectively. When all subjects were considered, a significant association was found between the UGT2B17 deletion polymorphism and prostate cancer risk [odds ratio (OR), 1.7; 95% confidence interval (95% CI), 1.2-2.6]. There was an increase in prostate cancer risk among individuals with UGT2B17 deletion polymorphism in Caucasians (OR, 1.9; 95% CI, 1.2-3.0) but not in African Americans (OR, 1.3; 95% CI, 0.6-2.7). Conclusions: These results suggest that the UGT2B17 enzyme may play a role in the metabolism of androgens in prostate tissue and that the UGT2B17 deletion polymorphism is associated with prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1473–8)

Epidemiology and Natural History of Penile Cancer

An extensive literature search was performed using the key words squamous cell carcinoma of the penis, phimosis, circumcision, chronic balanitis, cigarette smoking, genital warts and human papillomavirus (HPV) infection. All selected studies were classified according to the level of evidence (LE). The final grades of recommendation were assigned after discussion by the full panel of the International Consultation on Penile Cancer in November 2008. The factors positively associated with invasive penile cancers include the presence of phimosis (LE 3a), tobacco smoking (LE 3a-4), chewing tobacco (LE 3a), injury to the penis (LE 3a), balanitis (LE 3a), genital warts (LE 3a), and high-risk HPV infection (LE 3a-4).

Treatment Decision-Making Strategies and Influences in Patients with Localized Prostate Carcinoma

Patients diagnosed with localized prostate carcinoma need to interpret complicated medical information to make an informed treatment selection from among treatments that have comparable efficacy but differing side effects. The authors reported initial results for treatment decision‐making strategies among men receiving definitive treatment for localized prostate carcinoma.

Devastating complications after brachytherapy in the treatment of prostate adenocarcinoma

Once again, there have been a significant number of papers on prostate cancer submitted and accepted, and this is reflected in that six of the nine papers published in this section this month relate to this disease. Many aspects of the condition are discussed. Readers may be interested learn of the severe complications associated with brachytherapy which the authors from Miami have described, and how they dealt with them. This type of therapy will continue to be reported in this journal, with several comments appearing in subsequent editions.

Continent colonic urinary reservoir (Florida pouch): Long-term surgical complications (greater than 11 years)

PURPOSE We analyzed the long-term results (greater than 10 years) of a continent cutaneous colonic urinary reservoir (Florida pouch), focusing primarily on the incidence of significant complications. MATERIALS AND METHODS Between January 1986 and October 1991, 179 patients underwent continent cutaneous colonic urinary reservoir construction. Of these patients 105 died of primary disease or were lost to followup, leaving 38 males and 36 females with a mean followup of 133 months with adequate data for analysis who are the subject of this report. The surgical technique has been previously reported. Briefly, a detubularized right colonic segment forms the reservoir, a tapered external limb reinforced at the ileocecal valve level allows continent catheterization and the ureters are directly anastomosed to the pouch. The diseases that prompted urinary diversion included bladder cancer in 28 cases, conversion from another diversion in 12, neurogenic bladder in 11, interstitial cystitis in 10, crippling incontinence in 4, radiation cystitis in 6, hemorrhagic cystitis in 1, exstrophy in 1 and colon cancer in 1. A total of 146 direct ureterocolonic reimplantations were performed. RESULTS Complications were grouped by etiology and the number of patients, including abdominal wall (peristomal hernia in 3 patients or 4%), external limb (incontinence in 5 or 6.7%, stomal stenosis in 3 or 4% and difficult catheterization in 1 or 1.4%), reservoir stones (4 or 5.4%), ureteral obstruction (primary reimplantation in 7 of 108 or 6.3%, repeat reimplantation in 4 of 24 or 16.4% and radiated ureters in 4 of 14 or 28.4%) and metabolic (persistent diarrhea in 2 or 2.7%, renal failure in 2 or 2.7% and low vitamin B12 in 3 or 4%). Severe acidosis developed in 4 individuals (5.5%). Of the 12 patients who underwent conversion from another type of diversion 7 (58%) experienced metabolic alterations. CONCLUSIONS In the long term continent colonic reservoirs have an acceptable complication rate. The most common problem is ureteral obstruction, especially in patients who have previously undergone irradiation (28.4% versus 6.3%, Fishers test p = 0.02). Patients in whom longer bowel segments were resected, such as those with conversion from another type of diversions, experienced a greater number of complications, especially ureteral obstruction associated with repeat reimplantation (16.4% versus 6.3%, Fishers test p = 0.23) and metabolic derangements (58% versus 6.4%, Fishers test p = 0.0001).

Association between polymorphisms in the DNA repair genes XRCC1 and APE1, and the risk of prostate cancer in white and black Americans.

PURPOSE XRCC1 and APE1 are enzymes involved in the repair of DNA strand breaks and base damage that arise from various endogenous and exogenous oxidants. We determined whether polymorphisms in XRCC1 and APE1 increase the risk of prostate cancer. MATERIALS AND METHODS We performed a case-control study in 228 white American men, 124 black American men, and 335 age, sex and race matched controls. Polymorphisms at codon 399 in XRCC1, and at codons 51 and 148 in APE1 were determined using an restriction fragment length polymorphism method. Frequencies were compared between cases and controls. RESULTS A significantly increased risk of prostate cancer was observed in white men with the XRCC1(399Gln) allele (OR 1.6, 95% CI 1.1 to 2.4). When APE1 and XRCC1 polymorphisms were evaluated together, we found an increased risk of the XRCC1(399Arg/Gln+Gln/Gln)/APE1(51Gln/Gln) (OR 4.0, 95% CI 1.3 to 12.5) and XRCC1(399Arg/Gln+Gln/Gln)/APE1(148Asp/Asp) (OR 2.9, 95% CI 1.4 to 6.1) genotypes in white men. Significant associations were found between combined genotypes and prostate cancer risk with a dose-effect relationship in white men (trend test p = 0.035 and 0.039, respectively). No significant associations were observed between polymorphisms in these genes and prostate cancer risk in black men. CONCLUSIONS Our results suggest that inherited variability in DNA repair capacity, as reflected by polymorphisms in XRCC1 and APE1, is a risk factor for prostate cancer.

A continent colonic urinary reservoir : the Florida pouch

A total of 92 patients underwent continent urinary diversion with an extended, detubularized right colonic segment as the urinary reservoir and the distal ileum as a continent catheterizable efferent system. In this series 65 patients were followed for 6 to 46 months (average 17 months). Our reservoir allows the accommodation of a large volume of urine; urodynamic studies in 28 patients demonstrated a maximum reservoir capacity varying between 550 and 1,200 cc (average 747 cc). Maximal reservoir pressures ranged from 10 to 58 cm. water (average 35 cm. water). Of the 127 ureterocolonic reimplantations 4 ureters were initially reimplanted with a modified Le Duc procedure, 26 ureters were managed subsequently with the Goodwin transcolonic approach and 91 reimplantations were done with a direct (nontunneled) mucosa-to-mucosa anastomosis. The overall success rates with each of the 3 techniques (absence of reflux and obstruction) were 75, 88.6 and 90.1%, respectively. Six megaureters underwent imbrication and direct reimplantation, and 3 of these (50%) became obstructed. Two converted ileal conduits were opened at the antimesenteric edge and were patched to the reservoir while the ureteroileal anastomosis was left undisturbed. One patient (1.5%) died of pulmonary embolism. Medical and surgical complications occurred only in the group who underwent simultaneous cystectomy and the over-all rate of complication was comparable to previous series with ileal conduits. The double row plication of the distal ileum and ileocecal valve allows for easy catheterization every 4 to 6 hours and 63 patients (97%) remain continent between catheterization. Four patients (6%) required reoperation for correction of incontinence or other complications. Our satisfactory experience with these patients makes this technique an excellent approach to achieving continent urinary diversion.

Phase II trial of B7-1 (CD-86) transduced, cultured autologous tumor cell vaccine plus subcutaneous interleukin-2 for treatment of stage IV renal cell carcinoma.

We report a single center phase II trial of sequential vaccination followed with vaccine plus interleukin-2 (IL-2). Vaccination consisted of autologous cells cultured from primary tumor or resected metastasis, transduced to express B7.1 surface molecule and then irradiated. The vaccine would hypothetically costimulate tumor-reactive T cells before IL-2 exposure. Treatment plan was 3 subcutaneous vaccine injections at 4-week intervals and subcutaneous IL-2 treatment for 6 weeks starting at week 7. Sixty-six patients enrolled, of whom 39 received at least 1 vaccine; most observed toxicity was attributable to IL-2 not vaccine; best responses were 3% pathologic complete response, 5% partial response, 64% stable disease, and 28% disease progression. Median survival was 21.8 months (95% confidence interval 17.8 to 29.6). Significant postvaccination increases in IFN-γ responses to autologous tumor were observed in 2/26 cases. Eighty-one percent of posttreatment subdermal delayed-type hypersensitivity tests (using nontransduced, irradiated autologous tumor cells) had biopsies demonstrating injection site lymphocytic infiltration. Post hoc comparison of the median survival of subjects whose biopsies had lymphocytic infiltration appears longer than in the 19% noninfiltrated (28.4 vs. 17.8 mo, P=0.045, two-sided log-rank test). The single arm design precludes conclusive comparison of objective response rates (not different here) or median survival (longer here) versus those of historical series using similar IL-2 schedules alone. Better outcomes could be logically associated to vaccine response (detectable lymphocytic infiltrates) or to random events that a single arm study design cannot address. This vaccine approach may merit further clinical development.

Direct (Nontunneled) Ureterocolonic Reimplantation in Association with Continent Reservoirs

A total of 190 patients underwent continent urinary diversion using the Florida pouch. Direct mucosa-to-mucosa ureterocolonic reimplantation was used in 165 patients (326 ureters). Of the first 30 ureters in patients who underwent antireflux tunneled reimplantation obstruction occurred in 4 (13.3%). Obstruction developed directly in 16 of the ureters reimplanted (4.9%), and 3 of the 6 plicated and reimplanted megaureters (50%). Among the obstructed units 3 (13%) were treated unexpectedly by autonephrectomy, while the other 20 units (87%) were treated with percutaneous balloon dilation and internal stenting for 6 to 8 weeks. In the latter group 12 units (60%) recovered function, 3 (15%) had pyelonephritis requiring nephrectomy and 5 (25%) stabilized following a new reimplantation. Reflux was demonstrated in 23 units (7%). All units with reflux are being followed conservatively and renal deterioration has not been demonstrated. The incidence of ureteral obstruction with direct reimplantation is lower compared to a tunneled technique. This reimplantation procedure is technically simpler than others and is safe in adults when performed in association with a large volume, continent colonic reservoir.