Andreas P. Berger

Circulating Tumor-Specific DNA: A Marker for Monitoring Efficacy of Adjuvant Therapy in Cancer Patients

Adjuvant systemic therapy (a strategy that targets potential disseminated tumor cells after complete removal of the tumor) has clearly improved survival of patients with cancer. To date, no tool is available to monitor efficacy of these therapies, unless distant metastases arise, a situation that unavoidably leads to death. We analyzed RASSF1A DNA methylation in pretherapeutic sera and serum samples collected 1 year after surgery from 148 patients with breast cancer who were receiving adjuvant tamoxifen; 19.6% and 22.3% of patients with breast cancer showed RASSF1A DNA methylation in their pretherapeutic and 1-year-after serum samples, respectively. RASSF1A methylation 1 year after primary surgery (and during adjuvant tamoxifen therapy) was an independent predictor of poor outcome, with a relative risk (95% confidence interval) for relapse of 5.1 (1.3-19.8) and for death of 6.9 (1.9-25.9). Measurement of serum DNA methylation allows adjuvant systemic treatment to be monitored for efficacy: disappearance of RASSF1A DNA methylation in serum throughout treatment with tamoxifen indicates a response, whereas persistence or new appearance means resistance to adjuvant tamoxifen treatment. It remains to be seen whether modifications made in adjuvant therapeutic strategies based on detection of circulating nucleic acids will improve survival as well as quality of life.

Photodynamic therapy with intravesical instillation of 5-aminolevulinic acid for patients with recurrent superficial bladder cancer: a single-center study

OBJECTIVES Photodynamic therapy (PDT) is an effective treatment option for patients with superficial bladder cancer uncontrolled by transurethral resection and/or intravesical bacille Calmette-Guérin (BCG) immunotherapy alone. We determined the efficacy and side effects of PDT in patients with recurrent superficial bladder cancer. METHODS Between April 1994 and July 2001, PDT was performed in 31 patients (23 men and 8 women). 5-Aminolevulinic acid (50 mL) in a 3% concentration was instilled intravesically. Patients were instructed to hold the solution as long as possible and were irradiated transurethrally with a mean light dose of 3.9 W using laser light emitting a wavelength of 633 nm for a mean time of 1260 seconds. RESULTS The mean patient age at the procedure was 70.2 years. At an average follow-up of 23.7 months (range 1 to 73), 16 patients were free of tumor recurrence; 15 patients had developed tumor recurrence after a mean of 8.3 months. Of 10 patients with prior BCG treatment, 4 were free of tumor recurrence. Treatment was well tolerated, with the only side effect being dysuria due to urinary tract infection in 4 patients and hematuria in 7 patients. No phototoxic skin reactions were observed. CONCLUSIONS PDT represents a safe, effective, and less-invasive treatment for patients with recurrent superficial bladder cancer. Because of the favorable side-effect profile, PDT can also be applied to patients with comorbidity precluding surgical treatment. Furthermore, PDT represents a second-line treatment for patients with tumor recurrence after BCG failure.

Accelerated in Vivo Growth of Prostate Tumors that Up-Regulate Interleukin-6 Is Associated with Reduced Retinoblastoma Protein Expression and Activation of the Mitogen-Activated Protein Kinase Pathway

Interleukin-6 (IL-6) is a multifunctional cytokine that activates the signaling pathways of Janus kinases-signal transducers and activators of transcription (STAT) and/or mitogen-activated protein kinases (MAPK) in various tumors. Thus, it modulates cell growth and apoptosis. IL-6 levels are elevated in tissues and sera from prostate cancer patients and IL-6 receptor expression has been detected in prostate cancer cell lines and clinical specimens. Continuous exposure of prostate cancer cells to IL-6 might alter their responsiveness to this cytokine. To gain more insight into the function of IL-6 in prostate carcinoma, we have inoculated LNCaP-IL-6+ cells, generated after prolonged treatment with IL-6, into nude mice (total n = 16, two independent experiments). Controls included animals bearing LNCaP-IL-6- cells, passaged at the same time as LNCaP-IL-6+ cells without supplementation of IL-6. LNCaP-IL-6+ tumor volumes were larger than those of their counterparts at all time points. There were no signs of cachexia in any of the experimental animals and all mice were free of metastases. To better understand the mechanisms responsible for accelerated growth of LNCaP-IL-6+ tumors, we have investigated the expression of cell-cycle regulatory molecules by Western blot analysis. The levels of cyclin-dependent kinase 2 were elevated in LNCaP-IL-6+ cells. There was a strong down-regulation of cyclins D1 and E in the LNCaP-IL-6+ subline. The cell-cycle inhibitor p27 was expressed at a low level in LNCaP-IL-6+ cells and could not be up-regulated by addition of IL-6. Most notably, LNCaP-IL-6+ cells exhibited a reduced expression of the hypophosphorylated form of the retinoblastoma protein (pRb). Accelerated tumor growth in our model system was also associated with alterations in IL-6-signaling pathways. The ability of IL-6 to induce tyrosine phosphorylation of STAT3 was abolished in the LNCaP-IL-6+ subline. In contrast, the levels of the MAPK extracellular signal-regulated kinases 1/2 increased in cells generated after long-term IL-6 treatment. The inhibitor of MAPK kinase PD 98059 retarded the proliferation of LNCaP-IL-6+ but not that of control cells. In summary, we show in the present study that chronic exposure of prostate cancer cells to IL-6 facilitates tumor growth in vivo by abolishment of the growth control by pRb and activation of the MAPK signaling pathway. These findings could be relevant to understand the role of IL-6 in prostate cancer progression.

Frozen section analysis-guided organ-sparing approach in testicular tumors: Technique, feasibility, and long-term results

OBJECTIVES To evaluate retrospectively the indications, surgical technique, feasibility, and follow-up data of our frozen section analysis-guided organ-sparing approach to small testicular tumors. Removal of a solitary testis or bilateral orchiectomy for testicular neoplasm results in androgen deprivation and infertility. Moreover, removal of a testis for benign lesions is to be avoided. Organ-sparing surgery aims at preserving enough testicular parenchyma to maintain physiologic endocrine function and, if possible, fertility. METHODS Tumors of 25 mm or less in diameter were managed by an organ-sparing approach. Normal preoperative plasma levels of luteinizing hormone and testosterone were a prerequisite. After localization of the tumor by ultrasonography and accurate staging, organ-sparing surgery was performed under cold ischemia. Frozen section analyses of the tumor and tumor bed biopsies were obtained. In the case of malignant germ cell tumor with a normal contralateral testis, ablation of the tumor-bearing testis was performed. RESULTS A total of 32 organ-preserving procedures were performed in 30 patients without any complications. Local recurrence was observed in 1 patient who refused to undergo local radiotherapy for concomitant testicular intraepithelial neoplasia; repeat organ-sparing surgery was performed in this patient. After organ-sparing surgery, ablation of the remaining testis was performed in 1 patient because of positive margins on final histologic analysis and in another patient because of endocrine insufficiency. In all other patients, the serum testosterone levels remained within normal limits. No retroperitoneal, pulmonary, or other recurrences were encountered; all patients were free of disease at a mean follow-up of 46.3 months. CONCLUSIONS The organ-sparing frozen section analysis-guided approach to testicular masses represents a promising treatment alternative to orchiectomy in selected patients with bilateral malignant testicular tumors, tumors in a solitary testis, or unilateral or bilateral benign tumors. The technique is oncologically efficient, lifelong hormonal substitution can be prevented, and, in some patients, even fertility may be preserved, provided certain criteria concerning patient selection and surgical technique are observed.

Atherosclerosis as a risk factor for benign prostatic hyperplasia

To evaluate the relationship between clinical benign prostatic hyperplasia (BPH) and atherosclerosis, using colour Doppler ultrasonography (CDUS) and symptom scores.

Long-term experience with carboplatin monotherapy for clinical stage I seminoma: a retrospective single-center study

OBJECTIVES To evaluate the long-term oncologic efficacy and morbidity of carboplatin monotherapy, which was introduced at our department 11 years ago for the treatment of Stage I seminoma. Radiotherapy is the standard treatment of patients with clinical Stage I seminoma. Carboplatin has been advocated as a treatment alternative to avoid the late side effects of radiotherapy and the high recurrence rate of surveillance strategies. METHODS From February 1990 until August 2001, 108 patients received two adjuvant cycles of single-agent carboplatin (400 mg/m2 body surface on days 1 and 22) 2 weeks after high inguinal orchiectomy. To assess for myelosuppression, complete blood counts were performed at least once a week until the nadir occurred after the second treatment cycle. RESULTS During a mean follow-up period of 59.8 months (range 6 to 134), 2 patients (1.85%) developed a recurrence (retroperitoneal tumor) within the first year. Both patients received cisplatin-based salvage chemotherapy. At last follow-up, all patients were alive without any evidence of disease. Carboplatin treatment was well tolerated by all patients and was associated with only mild gastrointestinal side effects. Leukopenia was noted in 32 patients (29.6%); 21 (19.4%) of these patients had World Health Organization (WHO) grade 1, 8 (7.4%) had grade 2, 3 (2.8%) had grade 3, and none had grade 4. No patient developed neutropenic fever. Thrombocytopenia was observed in 48 patients (44.4%); of these patients, 38 (35.2%) had WHO grade 1, 5 (4.6%) had grade 2, 2 (1.9%) had grade 3, and 3 (2.8%) had grade 4. CONCLUSIONS From an oncologic standpoint, two cycles of carboplatin monotherapy was highly effective and very well tolerated by all patients.

Vascular damage as a risk factor for benign prostatic hyperplasia and erectile dysfunction.

Associate Editor

Periprostatic administration of local anesthesia during transrectal ultrasound-guided biopsy of the prostate: a randomized, double-blind, placebo-controlled study

OBJECTIVES To evaluate the effect of periprostatic infiltration with local anesthesia on the level of discomfort associated with transrectal ultrasound-guided needle biopsy of the prostate. Transrectal ultrasound-guided needle biopsy of the prostate is the standard procedure to diagnose prostate cancer. METHODS A prospective, randomized, double-blind study was performed on 100 men referred for biopsy of the prostate. Fifty subjects were randomized to periprostatic injection of 10 mL of 2% lidocaine solution without epinephrine, and 50 were randomized to injection of placebo (10 mL of 0.9% NaCl). Each subject completed three 10-point visual analog scales for pain after a series of 15 needle biopsies. Pain was rated during the biopsy, diagnostic investigation, and injection of lidocaine. RESULTS Patients who received local anesthesia had significantly lower visual analog scale scores compared with the group without lidocaine during the biopsy (mean score 0.76 versus 3.62, P <0.001) and diagnostic examination (mean score 1.08 versus 1.86, P = 0.025). Lidocaine injection caused no adverse effects. CONCLUSIONS Periprostatic injection of lidocaine represents a simple and safe procedure that significantly reduces discomfort during probe manipulation and biopsy. We recommend this procedure in men undergoing transrectal ultrasound-guided prostate biopsy.

Vascular resistance in the prostate evaluated by colour Doppler ultrasonography: is benign prostatic hyperplasia a vascular disease?

There is a wide variety of topics in this section of the Journal this month. The papers come from Austria, Israel, Scotland, Denmark, England and Australia. I am, as ever, pleased that the Journal continues to receive papers from so many countries, and that the high standard of these papers help us to maintain a quality product of great general interest to the reader.

The Expression of Transcription Factor Activating Transcription Factor 3 in the Human Prostate and its Regulation by Androgen in Prostate Cancer

PURPOSE ATF3 is a member of the basic leucine zipper/cyclic adenosine monophosphate responsive element binding protein family of transcription factors. There is overwhelming evidence that it is a stress inducible factor acting in a signal-type and cell-type dependent manner, and it is involved in cell proliferation and survival. We found that ATF3 was differently expressed in an in vitro prostate cancer tumor progression model and we investigated the possible role of ATF3 in prostate cancer. MATERIALS AND METHODS ATF3 up-regulation in vivo/in vitro and androgen regulation were assessed by immunohistochemistry and immunoblot analysis. Results after forced ATF3 transfection were evaluated by proliferation assay and cell cycle analysis. RESULTS Immunohistochemistry and immunoblot analysis revealed ATF3 up-regulation in prostate cancer in vitro and in vivo, and stimulation of expression by androgens. Antiandrogen treatment decreased ATF3 expression in androgen sensitive cells but acted as a stimulator in long-term androgen ablated cells representing a model for therapy refractory disease. Expression in tumors increased with higher Gleason scores and highest expression was observed in samples of therapy refractory tumor tissue. Forced ATF3 over expression in a prostate cancer cell line induced cell proliferation and accelerated cell cycle progression from G1 to S-phase. CONCLUSIONS These data provide new insight into the role of ATF3 in prostate cancer development and/or progression. They indicate that ATF3 is an androgen regulated gene that is highly expressed in prostate tumors and stimulating cell proliferation. It represents a possible target for prostate cancer therapy.