Joan Sweet

The Uncertainty Of Radio Frequency Treatment Of Renal Cell Carcinoma: Findings At Immediate And Delayed Nephrectomy

PURPOSE Radio frequency thermal therapy for the ablation of renal cell carcinoma has been reported. Outcomes are usually measured by imaging alone. We have performed ex vivo and in vivo experiments using radio frequency in porcine models in our laboratory. We now report our early experience in the treatment of renal cell carcinoma in patients who underwent post-radio frequency radical or partial nephrectomy. MATERIALS AND METHODS We treated 10 patients diagnosed with small renal masses with radio frequency. All masses were biopsied before treatment. In 4 patients 5 renal cell carcinomas were treated with radio frequency after surgical exposure of the tumor followed immediately by partial or radical nephrectomy (acute group). Six other patients were treated percutaneously with ultrasound or computerized tomography guided radio frequency under local anesthesia and intravenous sedation 7 days before partial or radical nephrectomy (delayed group). A median of 2 radio frequency cycles was applied. Mean total heating time was 17 minutes 15 seconds. Specimens were analyzed grossly and histologically. Triphasic contrast-enhanced computerized tomography and/or magnetic resonance imaging was performed before and 7 days after radio frequency treatment in the delayed group. RESULTS Mean radiological largest diameter of all 11 masses was 2.4 cm. and mean gross diameter was 2.2 cm. Pathological examination demonstrated residual viable tumor in approximately 5% of the volume in 4 of the 5 tumors in the acute group and in 3 of the 6 masses of the delayed group. In 1 delayed case the viable tumor appeared to be in contact with the renal vein. No significant complications were observed in 9 of the 10 patients. In 1 delayed case, a subcapsular hepatic hematoma, biliary fistula and pneumonia developed and resolved. CONCLUSIONS Based on our experience, we continue to consider percutaneous radio frequency for the treatment of small renal cell carcinomas as a potentially curative therapy. However, complete tumor cell death appears to be difficult to achieve with our current treatment protocol. More phase II testing is indicated to ensure that this technique is an effective and reproducible treatment alternative.

POLAROGRAPHIC ELECTRODE STUDY OF TUMOR OXYGENATION IN CLINICALLY LOCALIZED PROSTATE CANCER

PURPOSE To describe the oxygenation of clinically localized prostate cancer. METHODS AND MATERIALS Intraprostatic oxygen tension was measured using the Eppendorf electrode in 55 unanesthetized men with localized prostate cancer before radiotherapy. Measurements were made along two tracks through regions of suspected tumor in the prostate, and core needle biopsies were then obtained from the same regions. RESULTS The median pO(2) ranged from 0.2 to 57.3 mm Hg, and the grand median pO(2) was 4.5 mm Hg. The percentage of oxygen readings <5 mm Hg (HP(5)) ranged from 0% to 100% (median 60%). The track 1 oxygen readings were greater than those from track 2. Statistically significant heterogeneity was found in the individual oxygen readings: the between- and within-tumor components accounted for 32% and 68% of the total variability, respectively. However, the between-tumor variability in HP(5) significantly exceeded the within-tumor variability (61% vs. 39%). No association was found between oxygen values and clinical factors, including age, T stage, Gleason score, prostate-specific antigen level, hemoglobin concentration, or prior hormonal treatment. No difference was noted in the oxygenation between regions of tumor and normal prostate tissue, as determined from the core biopsies. CONCLUSION Localized prostate cancer is characterized by marked hypoxia and significant heterogeneity in oxygenation, similar to other human tumors. The normal prostate may contain regions of low oxygen concentration. HP(5), as determined in this study, should adequately discriminate among patients with prostate cancer and allow the independent prognostic significance of oxygenation to be evaluated once the study matures.

V89L polymorphism of type-2, 5-alpha reductase enzyme gene predicts prostate cancer presence and progression

OBJECTIVES The valine (V) to leucine (L) polymorphism of the SRD5A2 gene is associated with 5-alpha reductase-2 activity; patients with the V allele have high activity and patients with the L allele have low activity. We examined whether this polymorphism predicts the presence of prostate cancer in 320 men without cancer who underwent biopsy and cancer progression in 318 men who underwent radical prostatectomy. METHODS The effect of the SRD5A2 gene in predicting the presence of prostate cancer was examined using logistic regression analysis, controlling for established risk factors. The effect of the SRD5A2 gene in predicting prostate cancer progression was examined using a nested, matched, case-control design. Most of the participants were white. RESULTS Of the 320 men, 158 (49.4%) were found on biopsy to have prostate cancer. The overall distribution of the V/V, V/L, and L/L genotypes was 47.5%, 42.5%, and 10.0%, respectively. The adjusted odds ratio for having prostate cancer for patients with at least one V allele was 2.53 compared with patients with the L/L genotype (P = 0.03). Of the 318 patients with cancer, 80 had biochemically detected recurrence and 238 had no evidence of recurrence. The odds ratio for progression for patients with at least one V allele was 3.32 (95% confidence interval 1.67 to 6.62, P = 0.0006) compared with patients with the L/L genotype. CONCLUSIONS Men who have the V allele of the SRD5A2 gene have a twofold increase in the risk of prostate cancer development and an additional twofold increase in the risk of progression compared with men with the L/L genotype.

Interobserver Variability Between Expert Urologic Pathologists for Extraprostatic Extension and Surgical Margin Status in Radical Prostatectomy Specimens

Accurate Gleason score, pathologic stage, and surgical margin (SM) information is critical for the planning of post-radical prostatectomy management in patients with prostate cancer. Although interobserver variability for Gleason score among urologic pathologists has been well documented, such data for pathologic stage and SM assessment are limited. We report the first study to address interobserver variability in a group of expert pathologists concerning extraprostatic soft tissue (EPE) and SM interpretation for radical prostatectomy specimens. A panel of 3 urologic pathologists selected 6 groups of 10 slides designated as being positive, negative, or equivocal for either EPE or SM based on unanimous agreement. Twelve expert urologic pathologists, who were blinded to the panel diagnoses, reviewed 40× whole-slide scans and provided diagnoses for EPE and SM on each slide. On the basis of panel diagnoses, as the gold standard, specificity, sensitivity, and accuracy values were high for both EPE (87.5%, 95.0%, and 91.2%) and SM (97.5%, 83.3%, and 90.4%). Overall κ values for all 60 slides were 0.74 for SM and 0.63 for EPE. The κ values were higher for slides with definitive gold standard EPE (κ=0.81) and SM (κ=0.73) diagnoses when compared with the EPE (κ=0.29) and SM (κ=0.62) equivocal slides. This difference was markedly pronounced for EPE. Urologic pathologists show good to excellent agreement when evaluating EPE and SM. Interobserver variability for EPE and SM interpretation was principally related to the lack of a clearly definable prostatic capsule and crush/thermal artifact along the edge of the gland, respectively.

SIGNIFICANCE OF THE CAG REPEAT POLYMORPHISM OF THE ANDROGEN RECEPTOR GENE IN PROSTATE CANCER PROGRESSION

PURPOSE The CAG repeat polymorphism of the androgen receptor gene has been associated with an increased prostate cancer risk, and the repeat length correlated with cancer stage and grade at presentation. Men with an allele length of </= 18 CAG repeats have a 2-fold increase in risk for high-stage or high-grade prostate cancer, compared with patients with a longer CAG repeat. We examined the significance of the CAG repeat polymorphism of the androgen receptor gene for predicting prostate cancer progression among 318 patients treated by radical prostatectomy for clinically localized prostate cancer between 1987 and 1994. MATERIALS AND METHODS Leukocyte DNA was collected and genotyping of the CAG repeat polymorphism was performed using a PCR-based direct sequencing method. Risk ratios were calculated for developing biochemical recurrence for patients associated with an allele length of </= 18 CAG repeats, compared with patients with an allele length of >18 CAG repeats, controlling for grade, stage and serum PSA level at diagnosis using Cox proportional hazard modeling. RESULTS Overall, the CAG repeat allele was not predictive of recurrence; tumor grade, stage and PSA level at diagnosis were the only predictors of recurrence in a multivariate analysis. However, for patients at low risk for recurrence (Gleason score 2 to 6, stage pT2, and PSA </= 10 ng./ml.), the relative risk of recurrence associated with an allele of </= 18 CAG repeats was 8.07 (95% C.I., 2.02 to 32.2, p = 0.004), compared with patients with an allele length of >18 CAG repeats. In contrast, for patients at high risk of recurrence (Gleason score >/= 7, stage pT3/4, or PSA >10 ng./ml.), the relative risk associated with the </= 18 CAG repeat allele was 0.72 (95% C.I., 0.33 to 1.57, p = 0.41), compared with patients with the >18 CAG repeat allele. CONCLUSIONS The length of the CAG repeat polymorphism of the androgen receptor gene may be important for prostate cancer recurrence among patients who are otherwise at low risk for recurrence after radical prostatectomy. These findings have potential implications for patient selection for adjuvant treatment, and for the development of novel treatments.

Evidence of multifocality of telomere erosion in high-grade prostatic intraepithelial neoplasia (HPIN) and concurrent carcinoma.

Mechanisms underlying prostate cancer (CaP) initiation and progression are poorly understood. A chromosomal instability mechanism leading to the generation of numerical and structural chromosomal changes has been implicated in the preneoplastic and neoplastic stages of CaP. Telomere dysfunction is one potential mechanism associated with the onset of such instability. To determine whether there was alteration in telomere length and chromosome number, 15 paraffin-embedded prostatectomy specimens were investigated using quantitative peptide nucleic acid (PNA) FISH analysis of representative foci of carcinoma, putative precancerous lesions (high-grade prostatic intraepithelial neoplasia, HPIN) and nondysplastic prostate epithelium. A significant decrease in telomere length was shown in both HPIN and CaP in comparison with normal epithelium. In addition, elevated rates of aneusomy suggested that increased levels of chromosomal aberrations were associated with decreased telomere length. Moreover, multiple foci of HPIN were shown to have a heterogeneous overall reduction of telomere length. This reduction was more evident in the histologic regions of the prostate containing CaP. Such observations lend support to the hypothesis that telomere erosion may be a consistent feature of CaP oncogenesis and may also be associated with the generation of chromosomal instability that characterizes this malignancy.

PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade.

Prostatic adenocarcinoma is an epithelial malignancy characterized by marked histological heterogeneity. It most often has a multifocal distribution within the gland, and different Gleason grades may be present within different foci. Data from our group and others have shown that the genomic deletion of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene and the disruption of the ETS gene family have a central role in prostate cancer and are likely to be associated with Gleason grade. In this study, prostate cancer samples were systematically analyzed to determine whether there was concordance between PTEN losses and TMPRSS2–ERG fusion rearrangements, within or between foci in multifocal disease, using well-annotated tissue microarrays (TMAs) consisting of 724 cores derived from 142 radical prostatectomy specimens. Three-color fluorescence in situ hybridization analysis of both the PTEN deletion and the TMPRSS2–ERG fusion was used to precisely map genetic heterogeneity, both within and between tumor foci represented on the TMA. PTEN deletion was observed in 56 of 134 (42%) patients (hemizygous=42 and homozygous=14). TMPRSS2–ERG fusion was observed in 63 of 139 (45%) patients. When analyzed by Gleason pattern for a given TMA core, PTEN deletions were significantly associated with Gleason grades 4 or 5 over grade 3 (P<0.001). Although TMPRSS2–ERG fusions showed a strong relationship with PTEN deletions (P=0.007), TMPRSS2–ERG fusions did not show correlation with Gleason grade. The pattern of genetic heterogeneity of PTEN deletion was more diverse than that observed for TMPRSS2–ERG fusions in multifocal disease. However, the marked interfocal discordance for both TMPRSS2–ERG fusions and PTEN deletions was consistent with the concept that multiple foci of prostate cancer arise independently within the same prostate, and that individual tumor foci can have distinct patterns of genetic rearrangements.

Primary large cell neuroendocrine carcinoma of the urinary bladder

Reports of primary large cell neuroendocrine carcinomas of the urinary bladder are few; we identified only 2 cases in the literature. Both of these cases involved male patients with rapid progression of disease culminating in death with widespread metastases. We report a case of primary large cell neuroendocrine carcinoma of the bladder, with an admixed minor element of adenocarcinoma, in an 82-year-old man. This solitary lesion arose in a bladder diverticulum lateral to the left ureteric orifice. Two attempts at transurethral resection were unsuccessful at achieving local control. The patient underwent a partial cystectomy with left-sided pelvic lymphadenectomy following preoperative staging investigations that found no metastatic disease. Pathologically, the tumor invaded into the deep aspect of the muscularis propria, without extension into perivesical fat. The lateral resection margin was microscopically positive for tumor, but no malignancy was found in the pelvic lymph nodes. The adenocarcinoma comprised less than 5% of total tumor volume, and areas of transition between the neuroendocrine and adenocarcinoma components were apparent. The patient developed a local recurrence 8 months postoperatively, which was managed by a combination of transurethral resection and radiation therapy. Currently, the patient has no evidence of local or metastatic disease 2 years after initial diagnosis.

A phase I trial of adenovector-mediated delivery of interleukin-2 (AdIL-2) in high-risk localized prostate cancer

Preclinical studies demonstrate that intratumoral delivery of adenovirus expressing IL-2 eradicates pre-established tumors in mice and confers immune protection from rechallenge. To explore the activity of AdCAIL-2 in prostate cancer, a Phase I clinical trial was conducted in patients with localized disease and Gleason score >7 or prostate-specific antigen (PSA) >10 plus Gleason score 7. A total of 12 patients were injected 4 weeks prior to prostatectomy in a dose-escalation study at doses of 109, 5 × 109 and 1010 PFU of virus. No dose-limiting toxicity was observed. Side effects included perineal discomfort, hematuria, flu-like symptoms in two patients and urinary hesitancy in one patient. Pathology demonstrated an inflammatory response consisting predominantly of CD3+CD8+ T lymphocytes with areas of tumor necrosis. Intracellular cytokine staining of tumor-infiltrating lymphocytes demonstrated increases in both γ-interferon and IL-4 secreting T cells after vaccination. PSA levels fell in five of five evaluable patients treated at the lowest dose (mean decline of 33.3%, range 17–69%). At higher doses, PSA values initially increased after injection, then fell to baseline prior to surgery. This trial demonstrates the feasibility and safety of intraprostatic adenovector-mediated IL-2 gene delivery.

The Use of Genetic Markers to Determine Risk for Prostate Cancer at Prostate Biopsy

Purpose: We examined a panel of 13 polymorphisms in 13 different genes to determine whether specific genotypes can help predict prostate cancer at the time of biopsy among men prescreened with prostate-specific antigen and digital rectal exam. Experimental Design: We examined 2,088 consecutive men who were referred for prostate biopsy from 1997 to 2003. Thirteen genes were examined, including TNF308, GSTT1, KLK2, endostatin, MCRA, MCRV, tyrosinase, MSR1, CHK2, RNasel, HOGG1-326, HOGG1-11657, and HRAS1. Odds ratio for detection of prostate cancer were adjusted for age, race, prostate-specific antigen, digital rectal exam, family history of prostate cancer, and urinary symptoms. Results: Of the 2,088 men, 996 (47.7%) had cancer detected. Four genes (TNF308, GSTT1, KLK2, and HOGG1-326) were significantly associated with prostate cancer. The adjusted odds ratios (OR) for prostate cancer for patients with the AA genotype of the TNF308 gene was 1.92 [95% confidence interval (95% CI), 1.0-1.5, P = 0.05], compared with those with the GG genotype, and for patients with the TT genotype of the KLK2 gene, the OR was 1.5 (95% confidence interval, 1.0-2.2, P = 0.04), compared with the CC genotype. The OR for patients with a homozygous deletion of the GSTT1 gene was 0.81 (95% CI, 0.6-1.0, P = 0.06) compared with those with the deletion, and the OR for patients with the GG genotype of the HOGG1-326 gene was 0.68 (95% CI, 0.5-1.0, P = 0.05) compared with the CC genotype. Patients who had all four alleles that were positively associated with prostate cancer had an OR of 9.33 (95% CI, 2.4-35.8, P = 0.0005) for prostate cancer compared with patients with alleles that were negatively associated with prostate cancer. Conclusions: Of the 13 polymorphisms, two were found to be positively associated with prostate cancer (TNF308 and KLK2) and two were negatively associated with prostate cancer (GSTT1 and HOGG1-326). Future studies are required to confirm these results.