Re-purposing cryoablation: a combinatorial 'therapy' for the destruction of tissue.

It is now recognized that the tumor microenvironment creates a protective neo-tissue that isolates the tumor from the various defense strategies of the body. Evidence demonstrates that, with successive therapeutic attempts, cancer cells acquire resistance to individual treatment modalities. For example, exposure to cytotoxic drugs results in the survival of approximately 20-30% of the cancer cells as only dividing cells succumb to each toxic exposure. With follow-up treatments, each additional dose results in tumor-associated fibroblasts secreting surface-protective proteins, which enhance cancer cell resistance. Similar outcomes are reported following radiotherapy. These defensive strategies are indicative of evolved capabilities of cancer to assure successful tumor growth through well-established anti-tumor-protective adaptations. As such, successful cancer management requires the activation of multiple cellular 'kill switches' to prevent initiation of diverse protective adaptations. Thermal therapies are unique treatment modalities typically applied as monotherapies (without repetition) thereby denying cancer cells the opportunity to express defensive mutations. Further, the destructive mechanisms of action involved with cryoablation (CA) include both physical and molecular insults resulting in the disruption of multiple defensive strategies that are not cell cycle dependent and adds a damaging structural (physical) element. This review discusses the application and clinical outcomes of CA with an emphasis on the mechanisms of cell death induced by structural, metabolic, vascular and immune processes. The induction of diverse cell death cascades, resulting in the activation of apoptosis and necrosis, allows CA to be characterized as a combinatorial treatment modality. Our understanding of these mechanisms now supports adjunctive therapies that can augment cell death pathways.

Clinical experience with open renal cryoablation.

OBJECTIVES: To evaluate the safety and efficacy of open renal cryoablation of small solid renal masses, since the delivery of freezing temperatures has been shown to effectively ablate solid neoplasms of the liver, uterus, and prostate. METHODS: A total of 29 patients were treated with open renal cryoablation since December 1996 and followed up to evaluate the treatment safety and initial radiographic response. RESULTS: The median preoperative lesion size was 2.2 cm, with 22 solid renal masses and 7 complex renal lesions. Five serious adverse events occurred in 5 patients, with only one event directly related to the procedure. One patient experienced a biopsy-proven local recurrence, and 91.3% of patients (median follow-up 16 months) demonstrated a complete radiographic response with only a residual scar or small, nonenhancing cyst. CONCLUSIONS: Open renal cryoablation appears to be a safe technique for the in situ destruction of solid or complex renal masses. However, inadequate freezing of renal cell carcinoma may result in local disease persistence. The expected slow growth rate of small renal cancers necessitates prolonged radiologic follow-up. Continued clinical research is required before renal cryoablation can be considered an acceptable curative treatment for renal cancer.

Increased cellularity of tumor-encased native vessels in prostate carcinoma is a marker for tumor progression.

Changes in the native vasculature of the prostate gland associated with prostate adenocarcinoma have not been well characterized. Eighty-nine whole mounts of entirely submitted radical prostatectomies were reviewed. Thirty prostates with a minimum of five native arteries surrounded by carcinoma with corresponding control arteries were found and included in this study. The number of nuclei in the media of native arteries was recorded per 0.138 mm2 using a 40x objective. The number of nuclei in vessels embedded in carcinoma (n = 204) was increased when compared with controls (26.37 versus 20.58 mean nuclei per 0.138 mm2; P < .001). Pathologic Stage T3 carcinomas contained vessels that were more cellular than stage T2 (P < .001). Vessels embedded in Gleason Grade 4 showed more cellularity than arteries embedded in Gleason Grade 3 (P < .002). Increased media cellularity of native prostate vessels encased in carcinoma is a histologic feature of higher grade/stage prostate carcinoma and provides positive indicator of advanced prostate cancer.

Transdermal estrogen in the treatment of hot flushes in men with prostate cancer.

OBJECTIVES: To assess the effectiveness and tolerability of transdermal estrogen in men with hot flushes after hormonal therapy for prostate cancer. METHODS: Twelve men with moderate to severe hot flushes were randomized to receive either low-dose (0.05 mg) or high-dose (0.10 mg) estrogen patches applied twice weekly for 4 weeks. After a 4-week washout period in which no treatment was given, each patient received the alternative dose for 4 weeks. Treatment response was assessed by daily logs and questionnaires completed every 4 weeks that included a visual analog assessment. Serum luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol levels were also measured every 4 weeks during the study. RESULTS: There was a significant reduction in the overall severity of the hot flushes seen in patients with both the low and high-dose estrogen patch. A significant reduction in the daily frequency of the hot flushes was seen with the high-dose patch only. Overall, 10 (83%) of 12 men reported either mild, moderate, or major improvement in symptoms with either the low or high-dose patch. Mild, painless breast swelling or nipple tenderness was noted in 2 (17%) and 5 (42%) of 12 men treated with the low and high-dose estrogen patch, respectively. FSH levels decreased significantly with both the low and high-dose patch. Estradiol levels increased from 12.1 to 16.4 pg/mL and 26.9 pg/mL with the low and high-dose patch, respectively. There was no significant change in serum testosterone or luteinizing hormone levels. CONCLUSIONS: Transdermal estrogen appears to be a promising, well-tolerated therapy for men with hot flushes after endocrine treatment for prostate cancer. Further study in larger groups of patients is necessary to assess the relative effectiveness and morbidity of this treatment.

High-frequency electrosurgery using the microcomputer-controlled Erbe ICC 350 unit.

To quantitate electrosurgical and tissue variables during transurethral prostatic resection and electrovaporization, these procedures were performed in five patients using standard endoscopic equipment and the Erbe ICC 350 electrosurgical generator. Current, voltage, power, and resistance were monitored continuously. Energy transfer was quantitated during each electrode pass. Prostatic resection or electrovaporization was successful in each patient. Current, voltage, resistance, and power were similar during resection and electrovaporization, whereas energy transfer was greater during electrovaporization. Generator and tissue characteristics can now be precisely monitored and instantaneously altered during transurethral prostatic electrosurgery to minimize energy transfer to the patient while producing the desired tissue effects.

Evaluation of changes in prostate specific antigen in clinically localized prostate cancer managed without initial therapy.

PURPOSE: We define changes in prostate specific antigen (PSA) measurements with time in 49 men 71.9 +/- 7.0 years old (mean plus or minus standard deviation) with clinically localized prostate cancer who remain untreated. MATERIALS AND METHODS: We retrospectively analyzed PSA changes in prostate cancer patients managed by watchful waiting. In all patients a minimum of 3 PSA levels were measured at intervals of at least 6 months after malignancy was diagnosed. The rate of change in serum PSA level with time (PSA velocity) was determined using an exponential, log linear model. RESULTS: In 49 patients treated conservatively mean initial PSA level plus or minus standard deviation was 12.3 +/- 11.1 ng./ml. and mean PSA followup during which no therapy for prostate cancer was introduced was 32.1 +/- 13.2 months. PSA levels decreased during the observation period in 11 of the 49 patients (22%) and median PSA doubling time in the remaining 38 was 55.7 months (range 15.1 to 994.5). There was no significant correlation between age at diagnosis, Gleason sum, initial PSA level or clinical stage and PSA velocity. The short-term rate of change in PSA during the first 9 months after prostate cancer was diagnosed correlated poorly with overall PSA velocity. The short-term rate of PSA change was greater than the overall rate of change in 14 of 37 patients (38%). CONCLUSIONS: There is significant variability in the rate of change of PSA with time in men with clinically localized prostate cancer who remain untreated. The usefulness of serial PSA measurements in the management of watchful waiting is unclear. Changes in PSA may not be helpful or appropriate in determining the need for therapy after a period of observation.

Doxazosin in men with lower urinary tract symptoms: urodynamic evaluation at 15 months.

OBJECTIVES: To assess the results of doxazosin treatment in men with lower urinary tract symptoms (LUTS) treated for 15 months and to correlate symptomatic changes with alterations in urodynamic measures. METHODS: After an initial 3-month treatment period with doxazosin 4 mg/day, 50 men with LUTS were given the choice of continued treatment with this agent or other therapeutic options. All patients were evaluated by International Prostate Symptom Score (IPSS) questionnaires and urodynamic evaluation initially and after 3 months of treatment. Patients were followed for an additional 12 months and those who continued doxazosin treatment underwent repeat urodynamic testing. RESULTS: Among the original 50 patients, 24 men (48%) continued doxazosin treatment for 15 months, 18 men (36%) discontinued therapy, and 8 men (16%) were either dead or lost to follow-up or had been diagnosed and treated for prostate cancer. Comparison of values at 3 and 15 months of follow-up (9.4 versus 13.4, P = 0.03) showed significant worsening of voiding symptoms, as assessed by the IPSS, in the 24 men still receiving doxazosin. This deterioration of subjective results with doxazosin occurred despite continued improvements in peak urinary flow rate (Qmax), detrusor pressure at peak flow (PdetQmax), and objective measures of obstruction (Abrams-Griffiths number) from 3 to 15 months of follow-up. CONCLUSIONS: Relief of voiding symptoms in men with LUTS treated with doxazosin over prolonged intervals of 15 months does not correlate well with changes in urodynamic measures.

Results of radical prostatectomy in men with locally advanced prostate cancer: multi-institutional pooled analysis.

OBJECTIVE: We investigated the disease-specific and metastasis-free survival rates in men with locally advanced (clinical stage T3) prostate cancer who were treated surgically. METHODS: A retrospective, multi-institutional pooled analysis of the results of surgical treatment in 345 men with clinical stage T3 disease was performed. Survival curves were generated using the Kaplan-Meier method. RESULTS: Among 298 evaluable patients, pelvic lymphadenectomy alone was performed in 56 men (19%), while 242 men (81%) underwent node dissection and radical prostatectomy. In total, 122 of 298 patients (41%) had nodal metastases and/or seminal vesicle tumor spread. Pathologically organ-confined disease was noted in 27 men (9%). The actuarial 10-year disease-specific and metastasis-free survival rates for all patients managed surgically were 57 and 32%, respectively. For patients with well, moderately and poorly differentiated tumors, cancer-specific survival rates at 10 years were 73, 67 and 29%, respectively. CONCLUSIONS: A large number of men with clinical stage T3 prostate cancer have advanced disease and are unlikely to achieve improved long-term survival with surgery alone. Although there may be a role for radical prostatectomy in selected patients with low to intermediate grade tumors, such treatment appears unlikely to result in long-term survival in men with high grade disease. A prospective study is necessary to determine the optimal treatment approach in men with locally advanced prostate cancer.

Ambulatory urodynamic evaluation of men with lower urinary tract symptoms treated with doxazosin.

We investigate the results of ambulatory urodynamic evaluation of men with lower urinary tract symptoms (LUTS) believed secondary to benign prostatic hyperplasia (BPH) treated with doxazosin and compare these results to conventional urodynamic study. Ten men with previously untreated LUTS underwent conventional urodynamic evaluation, which was repeated after treatment with doxazosin (4 mg daily) for 3 months. All patients continued on doxazosin and subsequently underwent ambulatory urodynamic evaluation. All men completed an International Prostate Symptom Score (I-PSS) questionnaire with a decrease in score from a mean of 20.4 initially to 8.7 after treatment with doxazosin for 3 months. The mean maximum urinary flow rate increased from 11.9 to 15.3 cc/s and the mean detrusor pressure at peak flow decreased from 99 to 82 cm H2O. The mean duration of ambulatory study was 5 h and 8 minutes (mean 6 voiding cycles). The mean ambulatory voiding pressure in the ten patients treated with doxazosin was 75 cm H2O. Ambulatory urodynamic monitoring is well tolerated by most men with LUTS. Intravesical voiding pressures remain in the obstructed range in most men treated with doxazosin despite marked improvement in urinary symptoms. Ambulatory urodynamic evaluation demonstrates that these elevated detrusor pressures are present during routine daily activities. The long-term effect of increased voiding pressures on urinary tract function is unclear.

Urinary nuclear matrix protein as a marker for transitional cell carcinoma of the urinary tract.

PURPOSE: The purpose of this trial was to evaluate an immunoassay for urinary nuclear matrix protein, NMP22, as an indicator for transitional cell carcinoma of the urinary tract. MATERIALS AND METHODS: Three groups of subjects participated in this trial of NMP22: 1-175 with transitional cell carcinoma, 2-117 with benign urinary tract conditions and 3-375 healthy volunteers. Each subject provided a single (3 voids) urine sample for analysis at the time of study entry. Each sample was assayed for the level of NMP22. RESULTS: In normal healthy volunteers and in subjects with benign conditions median NMP22 levels were 2.9 and 3.3 units per ml., respectively. Median urinary NMP22 levels in patients with transitional cell carcinoma were significantly greater than in comparison subjects. Patients with active transitional cell carcinoma had significantly greater median urinary NMP22 levels than those with no evidence of disease (6.04 versus 4.11 units per ml., p = 0.027, 1-tailed Mann-Whitney U test). We noted no effect of tumor grade, extent of disease or exposure to intravesical therapy on urinary NMP22 levels. CONCLUSIONS: NMP22 is a promising urinary tumor marker for monitoring transitional cell carcinoma. Nuclear matrix proteins are a new class of tumor markers that represent the basis for the development of assays with increased efficacy for the detection and treatment of cancer.

Use of a new tumor marker, urinary NMP22, in the detection of occult or rapidly recurring transitional cell carcinoma of the urinary tract following surgical treatment.

PURPOSE: We evaluated the ability of an immunoassay for nuclear matrix protein 22 (NMP22 test kit) to predict the subsequent disease status of patients with transitional cell carcinoma of the urinary tract at approximately 10 days after transurethral resection of bladder tumor. MATERIALS AND METHODS: A total of 90 patients with transitional cell carcinoma provided voided urine samples at least 5 days postoperatively. NMP22 was determined using a commercial test kit. At initial cystoscopic examination 3 to 6 months later the disease status was recorded, and the NMP22 values before and after transurethral resection of bladder tumor were compared. RESULTS: Of 125 followup cystoscopic examinations (60 patients had 1, 26 had 2, 3 had 3 and 1 had 4 recurrences) transitional cell carcinoma was pathologically confirmed in 33. No malignancy was present at 79 examinations (if tumor was seen endoscopically, pathological evaluation indicated atypia, dysplasia or no abnormality). NMP22 values in these 2 populations were significantly different (malignancy median 20.81 units per ml. and no malignancy median 5.72 units per ml., Mann-Whitney U test for differences between 2 medians p = 0.00005). Of the 33 recurrences 23 (70%) had NMP22 values greater than the reference range (10 units per ml.). Additionally, NMP22 identified all 6 subjects (100%) who had invasive disease 3 to 6 months later. Of 72 patients with NMP22 less than 10 units per ml. 62 (86%) had no malignancy at subsequent cystoscopy. CONCLUSIONS: NMP22 was highly predictive of tumor status at followup cystoscopy. This quantitative, noninvasive assay, with high negative predictive value (86%) and sensitivity to detect malignancy (100% for invasive disease and 70% overall), may be a helpful adjunct to cytology and endoscopy for monitoring disease status after endoscopic tumor resection.

Results of radical prostatectomy in men with clinically localized prostate cancer.

OBJECTIVE: To assess the results of radical prostatectomy in men with early prostate cancer. DESIGN: Retrospective, nonrandomized, multi-institutional pooled analysis. SETTING: Eight university medical centers in the United States and Europe. PATIENTS: A total of 2758 men with stage Tl and T2 prostatic cancer. MAIN OUTCOME MEASURES: Disease-specific and metastasis-free survival rates. RESULTS: Tumor grade was the most important preoperative factor in determining outcome. Disease-specific survival 10 years following surgery and associated 95% confidence intervals were 94% (range, 87%-98%), 80% (range, 74%-85%), and 77% (range, 65%-86%) for those men with grade 1, 2, and 3 tumors, respectively. Metastasis-free survival at 10 years was 87% (range, 78%-92%), 68% (range, 62%-73%), and 52% (range, 38%-64%) for patients with grade 1, 2, and 3 cancers, respectively. CONCLUSIONS: Radical prostatectomy leads to high 10-year disease-specific survival rates in men with all tumor grades. However, caution is needed in comparing these results with similar studies of alternative treatment strategies, such as watchful waiting, due to the inherent potential biases in uncontrolled trials. Nevertheless, these results offer the best currently available estimates of 10-year outcome of radical prostatectomy in men with clinically localized prostate cancer and may be useful in counseling patients with early malignancy.

An observational urodynamic evaluation of men with lower urinary tract symptoms treated with doxazosin.

OBJECTIVES: To assess the urodynamic changes in men with lower urinary tract symptoms (LUTS) suggestive of bladder outlet obstruction treated with doxazosin and to correlate these changes with voiding symptoms. METHODS: Fifty patients with LUTS were treated with doxazosin at a dose of 4 mg/day for 3 months. All men were initially evaluated by International Prostate Symptom Score (I-PSS) questionnaires, measurements of urinary flow rate, and complex urodynamic study. Those patients completing the 3-month study underwent repeat testing. RESULTS: Forty-four (88%) men underwent initial and follow-up urodynamic evaluation. The mean I-PSS improved from 20.6 to 10.5 (P < 0.001), mean peak urinary flow rate increased for 11.7 to 13.2 cc/s (P = 0.20), mean detrusor pressure at peak flow decreased from 9 3.6 to 83.0 cm H20 (P = 0.15), and mean cystometric bladder capacity increased from 266 to 304 cc (P = 0.07). Using the Abrams-Griffiths nomogram and number, more than 58% of patients remained obstructed after treatment with doxazosin for 3 months. Men with and without objective evidence of bladder outlet obstruction at the outset of the study had similar improvement in voiding symptoms. Most patients elected to continue treatment with doxazosin at the completion of the study (41/44, 93%). CONCLUSIONS: The majority of patients had objective evidence of persistent bladder outlet obstruction after treatment with doxazosin for 3 months despite significant benefit. The results of complex urodynamic evaluation did not predict treatment response in men with LUTS suggestive of bladder outlet obstruction. Urodynamic study does not appear to be helpful in the evaluation of patients with uncomplicated LUTS prior to treatment with doxazosin.

Treatment of prostate cancer using external beam radiotherapy after laparoscopic pelvic lymph node dissection.

OBJECTIVES: To evaluate the results of prostatic irradiation in men with clinically localized prostate cancer and no laparoscopic evidence of nodal metastases compared with a cohort of patients who received radiation therapy with no prior surgical staging. PATIENTS AND METHODS: Thirty-one men with clinically localized prostate cancer and no evidence of pelvic nodal metastases after laparoscopic pelvic lymph node dissection received external beam radiation therapy to the prostate (65-70 Gy). The mean and median prostate specific antigen (PSA) levels in these men before treatment were 41.6 ng/mL and 28.0 ng/mL, respectively, and the mean Gleason sum was 6.1 (range 3-7). During the same interval, a group of 42 consecutive men with clinically localized prostate cancer were treated by external beam radiation therapy with no laparoscopic staging of the pelvic nodes. Treatment failure was defined by the development of bone metastases or a rising PSA level at least 6 months after the completion of radiotherapy. RESULTS: Radiation therapy was generally well tolerated after laparoscopy and no patient required hospitalization or surgery for side-effects related to the treatment. The median duration of follow-up in the 31 men who underwent laparoscopy was 21.5 months. The probability of treatment failure in this group was 41.8% and 56.3% with 24 and 30 months follow-up, respectively. When controlling for pre-treatment PSA level, grade and stage, there was no significant difference in the treatment failure rate between the groups treated with and without laparoscopic staging. CONCLUSIONS: These results suggest that there is no difference in treatment outcome with laparoscopic pelvic lymphadenectomy before external beam radiation therapy in high-risk patients who have significant pre-treatment elevations of PSA level.

Treatment of subclinical intraurethral human papilloma virus infection with interferon alfa-2b.

OBJECTIVES: Anogenital human papilloma virus (HPV) infection represents a growing concern among physicians in the United States. An intraurethral reservoir of the virus has been suggested as a possible source for reinfection between sexual partners, and may contribute to the increase in the number of affected individuals. Treatment reports of intraurethral HPV infection with adequate follow-up have been lacking. Our goals in this study were to identify the patients with cytologic evidence of HPV intraurethral infection, and to attempt treatment with intraurethral instillations of interferon alfa-2b. METHODS: Eighty-nine men with anogenital lesions or known exposure to HPV underwent cytologic examination using a urethral swab after all visible disease was adequately treated. Sixteen patients with positive cytology results were treated with weekly instillations of 25 million U of interferon alfa-2b solution for 6 weeks. Urethral cytology was monitored at 2 and 6 weeks post-treatment, as well as every 3 months thereafter up to a year. Those who had a recurrence during the study were retreated with a 6-week course using 50 million U per instillation. Patients were monitored for possible side effects. RESULTS: Seventeen (19%) of 89 patients who entered the study had urethral cytology positive for HPV infection with no evidence of visible disease. Seven (41%) of these 17 patients did not show external (meatal or skin) manifestations of the disease. Fourteen of 16 (88%) men who underwent the therapy were followed for an average of 11.8 months. Nine of those 14 (64%) remained disease free throughout the follow-up. Of the 5 who had a recurrence, 3 were successfully retreated, with a mean of 7.2 months of disease-free follow-up after the second course. No adverse effects of the treatment were noted by blood testing, semen analysis, and patient report. CONCLUSIONS: The urethra is a significant HPV reservoir and should be investigated in patients exposed to the virus. Interferon is a potentially safe and effective treatment option for intraurethral HPV.

Laparoscopic approach to retroperitoneal lymph node dissection.

Laparoscopic retroperitoneal lymph node dissection is a new surgical procedure used to enhance staging in men with clinical stage I nonseminomatous germ cell tumors of the testis. The procedure has been performed in a limited number of patients at several centers with extensive laparoscopic experience. Laparoscopic retroperitoneal lymphadenectomy is a technically demanding procedure which can be successfully completed in the majority of patients. However, the risk of complications is greater than in patients who undergo standard open retroperitoneal lymph node dissection. The primary advantage of a laparoscopic approach is shortened hospitalization and rapid return to normal activity. The role of laparoscopy in the management of patients with testis malignancy has not been defined. The use of this staging procedure may help minimize the need for surveillance studies following surgery and may be best utilized in men with a lower likelihood of nodal metastases. Ultimately, prospective study in large groups of patients will be necessary to determine the role of laparoscopic retroperitoneal lymph node dissection in patients with testis cancer.

Molecular mechanisms of testicular carcinogenesis.

Molecular investigations into the neoplastic transformation of a normal spermatogenic precursor cell into a germ-cell malignancy have implicated a wide array of DNA and RNA alterations. Previous epidemiologic and familial patterns of cancer presentation had suggested that testicular cancer developed from one or more genetic alterations. In particular, mutations in cellular oncogenes such as c-kit and tumor-suppressor genes such as the retinoblastoma gene product have been identified as putative etiologic agents in the development and progression of testicular germ-cell tumors. Additionally, alterations in the transcription of RNA that are regulated through a process of genomic imprinting have been identified in human testis cancers. This report provides a framework for integrating this growing literature on the molecular biology of testicular germ-cell tumors into a potential etiologic hypothesis.

Androgen up-regulates epidermal growth factor receptor expression and binding affinity in PC3 cell lines expressing the human androgen receptor.

Androgens are required for the optimal growth and development of both the normal prostate and steroid-sensitive prostate cancer. PC3 prostate cancer cell lines stably expressing the human androgen receptor (AR) and possessing an androgen-sensitive phenotype (PC3-hAR) were used to examine the role of the epidermal growth factor receptor (EGFR) in androgen-stimulated prostate cancer cell growth. Epidermal growth factor (EGF) and dihydrotestosterone (DHT) independently induced the growth of PC3-hAR cells. Moreover, EGF and DHT in combination exerted a synergistic effect on PC3-hAR cell growth. DHT-exposed PC3-hAR cells expressed a greater than 2-fold increase in EGFR mRNA and 50% more EGFR protein than controls. Time course radioligand-binding assays confirmed these findings by showing an elevation in EGF binding in the DHT-exposed PC3-hAR cells. In addition, radioligand competition-binding studies revealed a 2-fold increase in EGFR-EGF binding affinity in the PC3-hAR cells after DHT treatment. However, no enhancement of transforming growth factor alpha or EGF expression was detected because DHT did not affect the levels of these cytokines in the PC3-hAR cell lysate or conditioned media. Our observations suggest that DHT increases both EGFR number and receptor-ligand affinity in androgen-sensitive prostate cancer cells and that these effects correlate with increased EGF binding and an enhanced mitogenic response to EGF.