Thomas E. Keane

Poor prognosis associated with thrombocytosis in patients with renal cell carcinoma

Objectives To better define the relationship between platelet count and survival using a retrospective analysis in patients with thrombocytosis and metastatic renal cell carcinoma (RCC), some of whom had a shorter life expectancy than those with a normal platelet count.

Relationship of Cytokeratin 20 and CD44 Protein Expression with WHO/ISUP Grade in pTa and pT1 Papillary Urothelial Neoplasia

The aim of this study was to assess the relationship of immunoreactivity of cytokeratin 20 (CK20) and CD44 across the spectrum of urothelial neoplasia using the WHO/ISUP consensus classification. A total of 120 papillary urothelial pTa and pT1 tumors (8 papillomas, 8 neoplasms of low malignant potential, and 42 low-grade and 62 high-grade carcinomas) were immunostained by using CK20 and CD44 antibodies. The relationships of tumor grade, pathologic stage, recurrences, and progression in stage with CK20 and CD44 immunoreactivity were assessed. WHO/ISUP grade correlated with tumor stage (P < 0.005), recurrence (P = 0.02), and progression in stage (P = 0.031). Normal urothelium showed CK20 immunoreactivity restricted to a few umbrella cells. Expression of CD44 in normal urothelium was restricted to the basal cell layer. Loss of CD44 immunoreactivity and increasing CK20 positivity were significantly associated with increasing tumor grade and stage (P < 0.005). An inverse relationship was observed in the staining patterns of CK20 and CD44 within individual cases, as well as in the aggregate data, with 79.2% of tumors with CD44 loss showing CK20 positivity (P < 0.001). In conclusion, CK20 and CD44 immunoreactivity are significantly related to the WHO/ISUP grade and to each other, and our data suggest their potential combined utility in predicting biologic behavior in patients with papillary urothelial pTa and pT1 neoplasms.

Normal range prostate-specific antigen versus age-specific prostate-specific antigen in screening prostate adenocarcinoma

OBJECTIVES Prostate-specific antigen (PSA) has become the most useful serum tumor marker in the diagnosis and screening of prostate adenocarcinoma. The currently cited reference range of normal (0 to 4.0 ng/mL monoclonal) lacks both the sensitivity and specificity to be universally accepted as a screening test, and alternatives to serum PSA have been proposed, such as PSA density, PSA velocity, and age-adjusted PSA. Age-adjusted PSA takes into account the facts that as men grow older the prostate enlarges and that screening should have maximum sensitivity in younger men and maximum specificity in older men. METHODS A population of 4,710 men with no known history of prostate adenocarcinoma underwent 5,629 examinations by transrectal ultrasound of the prostate (TRUS) from 1987 to 1994. This population consists of Mobile Urology Group, Mobile, Alabama, and Emory University, Atlanta, Georgia, patient databases. We have examined our data to determine the sensitivity, specificity, and positive predictive values for normal range PSA (0 to 4 ng/mL) versus age-specific PSA values. RESULTS A total of 2040 patients had an abnormal digital rectal examination (DRE) and 3581 procedures were performed for an elevated PSA and a normal DRE. Biopsies were performed in 2,657 patients with 945 (35.6%) positive for cancer. Criteria for biopsy included elevated PSA (more than 4 mg/mL), PSA density more than 0.15 abnormal DRE, or suspicious TRUS. Patients were grouped according to decade: group 1 (ages 40 to 49 years, n = 183), group 2 (ages 50 to 59 years, n = 1018), group 3 (ages 60 to 69 years, n = 2358), and group 4 (ages 70 to 79 years, n = 1687). CONCLUSIONS Use of the age-specific range for PSA increases the sensitivity in younger men more likely to benefit from treatment, and decreases the biopsy rate in older patients who may not be candidates for aggressive treatment. Age-adjusted PSA is the most valuable for patients over the age of 70 years of whom 22% would be spared TRUS with biopsy.

pT1 urothelial carcinoma of the bladder: criteria for diagnosis, pitfalls, and clinical implications.

Summary: One of the challenging areas in genitourinary pathology is the recognition of early invasion in urothelial neoplasia. Not uncommon, the patterns of invasion into lamina propria are subtle because a desmoplastic response is absent. Tangential sectioning due to inability to orient transurethral resection of bladder tumor specimens, crush and cautery artifacts further compound this problem. This review is presented to familiarize surgical pathologists with the criteria and different patterns of lamina propria invasion by urothelial carcinoma. Problems and pitfalls associated with the recognition of invasion and the clinicopathologic significance of lamina propria invasive urothelial cancer are also discussed.

Evaluation of staging lymphadenectomy in prostate cancer.

OBJECTIVES To prospectively evaluate a clinical algorithm that predicts nodal status in patients with prostate cancer and to assess the impact on the outcome. METHODS Between September 1988 and December 1994, 192 patients with organ-confined prostate cancer and considered surgical candidates for radical perineal prostatectomy (RPP) were stratified using the algorithm: prostate-specific antigen (PSA) 20 ng/mL or less, Gleason score 7 or lower, and clinical Stage T2a or lower. Patients failing any of these criteria were placed in the high-risk group and underwent a pelvic lymphadenectomy. Patients who satisfied all the criteria were placed in the low-risk group and underwent RPP without evaluation of the pelvic lymph nodes. Another contemporaneous cohort of patients (n = 65) underwent pelvic lymphadenectomy and radical retropubic prostatectomy (RRP) without use of the algorithm and were used as a control group. Patients were monitored for at least 24 months. RESULTS In the RPP group, 177 patients were considered low risk according to the algorithm and were not offered staging lymphadenectomy before surgery, whereas 15 patients were categorized as high risk for metastasis and underwent staging lymphadenectomy. In the RRP and lymphadenectomy group, 41 patients were considered at low risk and 24 at high risk of disease spread according to the algorithm. In the RPP group, low-risk patients (no lymphadenectomy) had a PSA recurrence rate (27%) similar to that of low-risk patients in the RRP group with negative lymph nodes (29%), P = 0.8. Similarly, high-risk patients with negative lymph nodes in both groups had a similar recurrence rate (53% for RPP and 50% for RRP). Univariate logistic regression analysis showed that PSA was the most significant predictor for disease recurrence (P = 0.0004) followed by preoperative Gleason scores (P = 0.02) and clinical stages (P = 0.03). Multivariate stepwise analysis demonstrated that Gleason score and clinical stage did not add to the prediction of recurrence over PSA alone. CONCLUSIONS Staging lymphadenectomy can be omitted in low-risk patients without deleterious effects on the outcome as measured by PSA recurrence.

Concomitant intraoperative renal artery embolization and resection of complex renal carcinoma

BACKGROUND Renal cell carcinoma, which has the propensity for rapid enlargement and local invasion, may present a surgical challenge, in part because of extensive vascularity. Conventional treatment typically involves staged preoperative renal artery embolization followed by nephrectomy after 1 or 2 days. We evaluated the clinical outcome of concomitant intraoperative embolization and nephrectomy. METHODS Over 7 years, eight patients with renal cell carcinoma underwent combined intraoperative renal artery coil embolization and nephrectomy. A cohort of 14 patients who underwent staged renal embolization and nephrectomy during the same period served as the control group. Renal tumor embolization was achieved via percutaneous femoral artery approach, followed by coil placement in the distal portion of the main renal artery. Complete renal artery embolization was confirmed with intraoperative angiography. Nephrectomy was performed either concomitantly or after renal artery embolization, dependent on treatment group. Intraoperative data, clinical outcome, and hospital cost were compared between the two groups. RESULTS Renal artery embolization and nephrectomy were successfully performed in all patients. There was no perioperative mortality. Mean hospital length of stay in the combined and staged treatment groups was 5.6 +/- 1.3 days and 10.2 +/- 3.2 days, respectively. Post-infarction syndrome developed in four patients (36%) in the staged group, compared with no patients in the combined treatment group. Decreased room cost and radiology cost was noted in the combined treatment group compared with the staged group. Mean total hospital cost was significantly less in patients who underwent the combined treatment compared with the staged treatment approach (mean difference, US dollars 9214; P =.02) During mean follow-up of 36 months, six patients (27%) died of unrelated causes. There was no evidence of tumor recurrence in surviving patients. DISCUSSION In patients with renal cell carcinoma, combined renal embolization and nephrectomy minimizes patient discomfort and post-infarction syndrome associated with traditional staged treatment. Moreover, it is associated with reduced hospital costs, due in part to decreased hospital length of stay. Vascular surgeons with endovascular skills are well suited to perform intraoperative renal artery embolization. Use of adjunctive endovascular techniques to facilitate large open procedures is a growing role for the endovascular-competent vascular surgeon.

CAMPTOTHECIN ANALOGUES/CISPLASTIN: AN EFFECTIVE TREATMENT OF ADVANCED BLADDER CANCER IN A PRECLINICAL IN VIVO MODEL SYSTEM

OBJECTIVE To evaluate the impact of the camptothecin analogs on human TCC xenograft, both as monotherapy and in combination with cisplatin (CDDP). MATERIALS AND METHODS Human transitional cell carcinoma (TCC) xenograft tumor line (DU4184) tested by subrenal capsule assay in 112 nude mice(NM-SRCA). CDDP and the camptothecin analogs irinotecan (CPT-11) and 9-aminocamptothecin(9-AC) were evaluated. RESULTS Both of the camptothecin analogs showed significant short term tumor inhibition which translated into enhanced survival. Maximal tumor inhibition (>95%) was achieved when either of the camptothecin analogs was combined with CDDP with minimal host toxicity. This translated into 400% increase in median survival. While all controls were dead 39 days following tumor implantation, none of the combination treated animals had died. CONCLUSION The combination of CDDP with these camptothecin analogs is an effective therapy against this model of advanced TCC. These observations suggest potential clinical value.

Tissue disposition of 5-o-carboranyluracil--a novel agent for the boron neutron capture therapy of prostate cancer.

The carboranyl nucleotides β‐d‐5‐o‐carboranyl‐2′‐deoxyuridine (d‐CDU), 1‐(β‐l‐arabinosyl)‐5‐o‐carboranyluracil (d‐ribo‐CU) and the nucleotide base 5‐o‐carboranyluracil (CU), were developed as sensitizers for boron neutron capture therapy (BNCT). A structure activity study was initiated to determine the agent most suitable for targeting prostate tumors. Cellular accumulation studies were performed using LNCaP human prostate tumor cells, and the respective tumor disposition profiles were investigated in male nude mice bearing LNCaP and 9479 human prostate tumor xenografts in their flanks. d‐CDU achieved high cellular concentrations in LNCaP cells and up to 2.5% of the total cellular compound was recovered in the 5′‐monophosphorylated form. In vivo concentrations of d‐CDU were similar in LNCaP and 9479 tumor xenografts. Studies in 9479 xenografted bearing mice indicated that increasing the number of hydroxyl groups in the sugar moeity of the carboranyl nucleosides corresponded with an increased rate and extent of renal elimination, shorter serum half‐lives and an increased tissue specificity. Tumor/normal prostate ratios were greatest with the nucleoside base CU. These studies indicate that similar nucleoside analogues and bases may have different tissue affinities and retention properties, which should be considered when selecting agents for sensitizing specific tumors for eventual BNCT treatment. CU was found to be the most suitable compound for further development to treat prostate cancer. †In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.

Methoxypsoralen phototherapy oftransitional cell carcinoma

Abstract Objectives. The goal of this research was to assess whether methoxypsoralencompounds in combination with ultraviolet light were effective in preventing cellular proliferation in an in vitro model of human transitional cell carcinoma. Methods. Three methoxypsoralen compounds, 5-methoxypsoralen (5-MOP), 8-methoxypsoralen (8-MOP), and 4′-aminomethyl 4,5′-8′-trimethylpsoralen (AMT), were added in vitro to T-24 transitional cell carcinoma cells. Psoralens directly bind to DNA, cross-linking the strands when exposed to ultraviolet light and thereby prevent cellular division. Results. In vitro activity was demonstrated utilizing AMT and ultraviolet radiation at 320 to 340 nm, preventing cellular proliferation in T-24 transitional cell carcinoma. Conclusions. Methoxypsoralen compounds in combination with ultraviolet light are effective in preventing proliferation of bladder carcinoma cells in vitro. This therapy may prove to be effective in clinical early stage transitional cell carcinoma and warrants further assessment.

Camptothecin analogues and vinblastine in the treatment of renal cell carcinoma: an in vivo study using a human orthotopic renal cancer xenograft ☆

To perform a series of in vivo cytotoxicity studies using a variety of doses of the comptothecin analogues 9-Aminocamptothecin (9-AC) and Irinotecan (CPT-11) with a human RCC xenograft tumor line (DU11983m). Using the subrenal capsule assay (80 nude mice) (NM-SRCA), 9-AC was evaluated at both low and high dosage levels (0.75 mg/kg and 1.25 mg/kg oral x10 doses over 12 days). Following an initial assessment of acute tumor inhibition, the study was extended to a survival assay with some cohorts receiving retreatment boluses on a once or twice weekly basis. CPT-11 was assessed at a dose of 100 mg/kg x3 over 9 days with weekly retreatment and two cohorts received 9-AC combined with Vinblastine (2.7 mg/kg) and Vinblastine alone, respectively. Tumor inhibition: tumor growth inhibition was significant (over 80%) with all cohorts receiving any camptothecin analogue and was virtually complete (>99% tumor inhibition) at the high dose 9-AC (1.25 mg/kg). Vinblastine alone achieved only moderate cytotoxic effect (46%) and induced the largest recorded cohort weight loss (toxicity). Survival analysis: the low and high dose 9-AC single agent cohorts were not significantly different; however, the CPT-11 cohort experienced maximal survival benefit. (P = 0.003) and the addition of Vinblastine did not enhance this survival advantage among the 9-AC cohorts. Control and single agent Vinblastine cohorts had the poorest survival with the treated group still surviving longer (P = 0.02). At 35 days after final assessment of acute tumor inhibition, all animals in both the control and Vinblastine alone cohorts were dead. None of the animals in any of the other cohorts (all of which had experienced a greater than 80% tumor inhibition) had died. No deaths occurred due to surgery or treatment toxicity and all deaths were deemed tumor related. CPT-11 and 9-AC produced a marked survival advantage in an orthotopic model of human advanced renal carcinoma and are identified as agents for further clinical assessment.