John A. Heaney

Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802.

PURPOSE This phase II study was designed to evaluate effectiveness and toxicity of a combined chemoradiotherapy program with selective bladder preservation in the management of patients with invasive bladder cancer. PATIENTS AND METHODS Ninety-one eligible patients with invasive bladder cancer stages T2M0 to T4AM0 suitable for radical cystectomy received two courses of methotrexate, cisplatin, and vinblastine (MCV regimen) followed by radiotherapy with 39.6 Gy and concurrent cisplatin. After complete urologic evaluation, operable patients who achieved complete response were selected for bladder preservation and treated with consolidation cisplatin-radiotherapy. RESULTS Of 91 eligible patients, 85 underwent complete urologic evaluation and 68 (75%; 95% confidence interval [CI], 59% to 84%) had documented complete responses. Fourteen operable patients with residual tumor underwent immediate cystectomy. Of 70 patients treated with consolidation cisplatin-radiotherapy, 36 subsequently developed bladder recurrences, 23 of which were invasive. Patients with invasive recurrence (n = 16), extensive noninvasive recurrence (n = 6), or severe treatment complications (n = 1) underwent salvage cystectomy. Thus, a total of 37 of 91 patients (40%) required cystectomy. The 4-year cumulative risk of invasive local failure (which includes induction failures) was 43% (95% CI, 33% to 53%). The 4-year actuarial risk of distant metastasis was 22% (95% CI, 13% to 31%). The 4-year actuarial survival rate of the entire group was 62% (95% CI, 52% to 72%). The 4-year actuarial rate of survival with bladder intact was 44% (95% CI, 34% to 54%). CONCLUSION Initial results of this combined chemoradiotherapy program show that bladder preservation can be achieved in the majority of patients, and that overall survival is similar to that reported with aggressive surgical approaches. Long-term survival and quality-of-life assessments require longer follow-up study.

THE EFFECT OF HOSPITAL VOLUME ON MORTALITY AND RESOURCE USE AFTER RADICAL PROSTATECTOMY

PURPOSE The value of radical prostatectomy for patients with prostate cancer depends on low morbidity and mortality. We assessed whether patient outcome is associated with how many of these procedures are performed at hospitals yearly. MATERIALS AND METHODS Using the Nationwide Inpatient Sample, which is a stratified probability sample of American hospitals, we identified 66,693 men who underwent radical prostatectomy between 1989 and 1995. Cases were categorized into volume groups according to hospital annual rate of radical prostatectomies performed, including low-fewer than 25, medium-25 to 54 and high-greater than 54. We performed multivariate logistic regression to control for patient characteristics when assessing the associations of hospital volume, in-hospital mortality and resource use. RESULTS Overall adjusted in-hospital mortality after radical prostatectomy was relatively low (0.25%). However, patients at low volume centers were 78% more likely to have in-hospital mortality than those at high volume centers (adjusted odds ratio 1.78, 95% confidence interval 1.7 to 2.6). Overall length of stay decreased at all hospitals between 1989 and 1995. However, average length of stay was longer and total hospital charges were higher at low than at high volume centers (7.3 versus 6.1 days, p<0.0001, and

Incidence of transitional cell carcinoma of the bladder and arsenic exposure in New Hampshire

15,600 versus

Nodal Involvement as A Prognostic Indicator in Patients with Prostatic Carcinoma

13,500, p<0.0001, respectively). CONCLUSIONS Hospital volumes inversely related to in-hospital mortality, length of stay and total hospital charges after radical prostatectomy. Further study is necessary to examine the association of hospital volume with other important outcomes, including incontinence, impotence and long-term patient survival after radical prostatectomy.

Tissue-shrinkage correction factor in the calculation of prostate cancer volume

AbstractObjective: Arsenic is a known bladder carcinogen and populations exposed to high arsenic levels in their water supply have reported elevated bladder cancer mortality and incidence rates. To examine the effects of lower levels of arsenic exposure on bladder cancer incidence, we conducted a case–control study in New Hampshire, USA where levels above 10 μ/l are commonly found in private wells. Methods: We studied 383 cases of transitional cell carcinoma of the bladder cancer, newly diagnosed between July 1, 1994 and June 30, 1998 and 641 general population controls. Individual exposure to arsenic was determined in toenail clippings using instrumental neutron activation analysis. Results: Among smokers, an elevated odds ratio (OR) for bladder cancer was observed for the uppermost category of arsenic (OR: 2.17, 95% CI: 0.92–5.11 for greater than 0.330 mcg/g compared to less than 0.06 μ/g). Among never smokers, there was no association between arsenic and bladder cancer risk. Conclusions: These, and other data, suggest that ingestion of low to moderate arsenic levels may affect bladder cancer incidence, and that cigarette smoking may act as a co-carcinogen.

Clinical and immunologic effects of intranodal autologous tumor lysate-dendritic cell vaccine with aldesleukin (interleukin 2) and IFN-α2a therapy in metastatic renal cell carcinoma patients

Between 1969 and 1976, 92 patients with proved prostatic carcinoma in stages T0 and T4 underwent pelvic lymphadenectomy. Median followup has been 43 months. All patients had normal serum acid phosphatase levels and no clinical evidence of metastases as determined by physical examination, bone scans and metastatic bone surveys. Pelvic lymph node metastases were noted in 32 cases. Radical prostatectomy was done in 34 cases and 45 patients received radiotherapy, 11 of whom had 125iodine seeds implanted. Progression of the neoplastic process, almost exclusively in the form of bony metastases, occurred in 18 of the 32 patients who had positive pelvic nodes and in 6 of the 60 patients with negative nodes (p less than 0.001). Patients with poorly differentiated carcinoma were more likely to have progression of the disease than those with moderately differentiated carcinoma (p less than 0.01) and no patient with a well differentiated carcinoma had disease progression.

Prognosis of clinically undiagnosed prostatic carcinoma and the influence of endocrine therapy.

Many studies that have calculated prostate cancer volumes from microscopic slides have used correction factors, ranging from 1.22 to 1.5, to compensate for tissue shrinkage during tissue processing. We undertook a study to measure tissue shrinkage directly because our experience suggested less shrinkage than that reported by others. Ten prostatectomy specimens were processed in a uniform manner. Multiple identical linear measurements were taken at four stages of processing: in the fresh state, following fixation, following processing, and from the microscopic slide. Linear shrinkage following fixation was minimal (4.1%) but increased to 14.5% following tissue processing. With rehydration and expansion on the flotation bath, tissues swelled so that net linear tissue shrinkage was 4.3%, and net volumetric tissue shrinkage was 12.4%, which translates into a correction factor for tissue shrinkage of 1.14. The following variables had no statistically significant effect on shrinkage: concentration of formalin, whole-mount versus quadrant sections, thickness of tissue slices, length of time in the alcohol dehydration steps, and temperature of the flotation bath over a range of 35 to 45 degrees C. This study suggests that (a) tissue-shrinkage correction factors that have been used in some previous studies may not be applicable for all laboratories because of interlaboratory variations in tissue-processing procedures or differences in measuring shrinkage; and (b) some calculated tumor volumes that have been used for prognostic thresholds may be high because of inflated tissue-shrinkage correction factors.

Electrical Impedance Spectroscopy of the Human Prostate

Purpose: To evaluate the clinical and immunologic outcomes of DC (dendritic cell) vaccine with interleukin (IL)-2 and IFN-α 2a in metastatic renal cell carcinoma patients. Experimental Design: Eighteen consented and eligible patients were treated. Peripheral blood monocytes were cultured ex vivo into mature DCs and loaded with autologous tumor lysate. Treatment consisted of five cycles of intranodal vaccination of DCs (1 × 107 cells/1 mL Lactated Ringers solution), 5-day continuous i.v. infusion of IL-2 (18MiU/m2), and three s.c. injections of IFN-α 2a (6MiU) every other day. Response Evaluation Criteria in Solid Tumors criteria were used for disease assessment. Correlative immunologic end points included peripheral blood lymphocyte cell phenotype and function as well as peripheral blood anti–renal cell carcinoma antibody and cytokine levels. Results: All patients received between two and five treatment cycles. Toxicities consisted of known and expected cytokine side effects. Overall objective clinical response rate was 50% with three complete responses. Median time to progression for all patients was 8 months, and median survival has not been reached (median follow up of 37+ months). Treatment-related changes in correlative immunologic end points were noted and the level of circulating CD4+ T regulatory cells had a strong association with outcome. Pre–IP-10 serum levels approached significance for predicting outcome. Conclusions: The clinical and immunologic responses observed in this trial suggest an interaction between DC vaccination and cytokine therapy. Our data support the hypothesis that modulation of inflammatory, regulatory, and angiogenic pathways are necessary to optimize therapeutic benefit in renal cell carcinoma patients. Further exploration of this approach is warranted.

IN VIVO DESCRIPTION OF DENDRITIC CELLS IN HUMAN RENAL CELL CARCINOMA

A 10-year series of 100 patients with clinically undiagnosed prostatic adenocarcinoma is presented. In 50 per cent of these patients the tumor was well differentiated and the survival was normal, while the remainder of the patients had moderately to poorly differentiated tumors and survival rates significantly less than normal. Of 8 deaths caused by cancer 7 were associated with less-than-well differentiated tumor. Patients who received endocrine therapy and died of causes other than cancer had a significantly shorter interval to death and a higher incidence of cardiovascular deaths than those who were untreated. While the majority of patients with incidental, clinically undiagnosed prostatic carcinoma is not at risk from the disease a minority exists who may benefit from radical therapy.

A RANDOMIZED PHASE II TRIAL COMPARING TWO DIFFERENT SEQUENCE COMBINATIONS OF AUTOLOGOUS VACCINE AND HUMAN RECOMBINANT INTERFERON γ AND HUMAN RECOMBINANT INTERFERON α2B THERAPY IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA: CLINICAL OUTCOME AND ANALYSIS OF IMMUNOLOGICAL PARAMETERS

Tissue electrical impedance is a function of its architecture and has been used to differentiate normal and cancer tissues in a variety of organs including breast, cervix, skin, and bladder. This paper investigates the possibility of differentiating normal and malignant prostate tissue using bioimpedance spectra. A probe was designed to measure impedance spectra over the range of 10 kHz to 1 MHz. The probe was fully characterized using discrete loads and saline solutions of different concentrations. Impedance spectra of five ex vivo prostates were measured in the operating room immediately following radical prostatectomy. Wilcoxon signed-rank tests were used to compare the normal and malignant findings. The impedance probe had a signal-to-noise ratio (SNR) > 84 dB across the entire spectrum and measured a tissue volume of approximately 46 mm3. At 10 kHz, prostate conductivity (sigma) ranged from 0.232 S/m to 0.310 S/m for tumor and from 0.238 S/m to 0.901 S/m for normal tissue. At 1 MHz the ranges were 0.301 S/m to 0.488 S/m for tumor and 0.337 S/m to 1.149 S/m for normal. Prostate permittivity (epsivr) ranged from 6.64 times104 to 1.25 times105 for tumor and from 9.08 times104 to 4.49 times105 for normal tissues at 10 kHz. And, at 1 MHz the er ranges were 9.23 times102 to 1.88 times103 for tumor and 1.16 times103 to 2.18 times103 for normal tissue. Both sigma and epsivr of tumor tissue were found to be significantly lower than that of normal tissue (P < 0.0001). Conductivity and permittivity are both higher in normal prostate tissues than they are in malignant tissue making them suitable parameters for tissue differentiation. This is in agreement with trends observed in other tissues reported in much of the literature. Expanded studies are needed to further validate this finding and to explore the biological mechanism responsible for generating the results.