Andreas Hinkel

Interleukin 2 gene therapy for prostate cancer : Phase I clinical trial and basic biology

Twenty-four patients with locally advanced prostate cancer (CaP) were enrolled in a phase I clinical trial using gene-based immunotherapy. A functional DNA-lipid complex encoding the interleukin 2 (IL-2) gene (Leuvectin; Vical, San Diego, CA) was administered intraprostatically into the hypoecogenic tumor lesion, using transrectal ultrasound guidance. Two groups of patients having locally advanced tumors were enrolled to receive a treatment regimen composed of two serial intraprostatic injections of the IL-2 gene agent administered 1 week apart. The first groups of patients included radical prostatectomy candidates who subsequently underwent surgery after the completion of the treatment regimen. The second group consisted of patients who had failed a prior therapy. Prostate specimens of the treated areas were attained after treatment and compared with the transrectal biopsies performed at baseline to assess for any responses. IL-2 gene therapy was well tolerated, with no grade 3 or 4 toxic reactions occurring. The most commonly reported symptoms were mild hematuria, transient rectal bleeding, and perineal discomfort that are likely attributable to the injection itself. During the entire course of treatment, there were no significant changes in American Urologic Association (AUA) symptom scores, in hematologic disturbances, electrolyte imbalances, or hepatic functions. Evidence of systemic immune activation was observed after IL-2 gene therapy, based on an increase in the intensity of T cell infiltration seen on immunohistochemical analysis of tissue samples from the injected tumor sites, and based on increased proliferation rates of peripheral blood lymphocytes that were cocultured with patient serum collected after treatment. Furthermore, transient decreases in serum prostate-specific antigen (PSA) (responders) were seen in 16 of 24 patients (67%) on day 1. Fourteen of the patients persisted in this decrease to day 8 (58%). In eight patients the PSA level rose (nonresponders). More patients (9 to 10) in the group that failed prior therapy responded to the IL-2 gene injections (chi-square test, p = 0.04), and 6 of the 9 also had lower than baseline PSA levels at week 10 after treatment. To the best of our knowledge, this is the first clinical study of its kind aimed at exploring the role of IL-2-based gene therapy in CaP patients. This phase I trial demonstrated the safety of intraprostatic Leuvectin injection, with transient PSA-based responses seen after therapy.

The Impact of Prostate Biopsy and Periprostatic Nerve Block on Erectile and Voiding Function: A Prospective Study

PURPOSE We evaluated the effect of multiple core prostate biopsy and periprostatic nerve block on voiding and erectile function. MATERIALS AND METHODS A total of 198 patients in whom prostate cancer was suspected were randomly assigned to undergo 10-core prostate biopsy with (71) or without (74) periprostatic nerve block. The 53 men with a history of negative prostate biopsy underwent 20-core saturation prostate biopsy with periprostatic nerve block. The International Prostate Symptom Score and International Index of Erectile Function were completed before, and 1, 4 and 12 weeks after biopsy to measure changes in voiding and erectile function, and quality of life. Upon prostate cancer diagnosis patients were excluded from further analysis. RESULTS The International Prostate Symptom Score was significantly increased in all patients at week 1, which persisted at weeks 4 and 12 after saturation biopsy (p = 0.007 and 0.035, respectively). After 10-core prostate biopsy with periprostatic nerve block patients had a higher International Prostate Symptom Score at weeks 4 and 12 but this was not statistically significant (p >0.05). Quality of life was significantly affected at all times after saturation prostate biopsy (p = 0.001, 0.003 and 0.010, respectively). International Index of Erectile Function scores decreased significantly in all groups at week 1 (p <0.05). The decrease persisted at week 4 in each 10-core prostate biopsy group. CONCLUSIONS Prostate biopsy causes impaired voiding. Saturation prostate biopsy and periprostatic nerve block seem to have a lasting impact on voiding function. Erectile function is transiently affected by prostate biopsy regardless of periprostatic nerve block and the number of cores. Patients who undergo prostate biopsy must be informed about these side effects.

Is there a need for the Fournier's gangrene severity index? Comparison of scoring systems for outcome prediction in patients with Fournier's gangrene

Study Type – Prognosis (prospective cohort)

Open radical retropubic prostatectomy gives favourable surgical and functional outcomes after transurethral resection of the prostate.

To assess the peri‐ and postoperative outcome of patients treated with open radical retropubic prostatectomy (RRP) for prostate cancer and who had previously undergone transurethral resection of the prostate (TURP).

Immunomodulatory Dendritic cells generated from nonfractionated bulk peripheral blood mononuclear cell cultures induce growth of cytotoxic T cells against renal cell carcinoma

Dendritic cells (DCs) loaded with tumor antigens have the potential to become a powerful tool for clinical cancer treatment. Recently, the authors showed that a tumor-specific immune response can be elicited in culture via stimulation with autologous renal tumor lysate (Tuly)-loaded DCs that were generated from cytokine-cultured adherent peripheral blood mononuclear cells (PBMCs). Here, the authors show that immunomodulatory DCs can be generated directly from nonfractionated bulk PBMC cultures. Kinetic studies of DC differentiation and maturation in PBMC cultures were performed by monitoring the acquisition of DC-associated molecules using fluorescence-activated cell sorting analysis to determine the percentage of positive immunostained cells and the mean relative linear fluorescence intensity (MRLFI). Compared with conventional adherent CD14+ cultures, which have mostly natural killer, T, and B cells removed before cytokine culture, bulk PBMC cultures exhibited an early loss of CD14+ cells (day 0 = 78.8%, day 2 = 29.6% versus day 0 = 74%, day 2 = 75%) with an increase in yield of mature DCs (DC19- CD83+) (day 5 = 17%, day 6 = 21%, day 7 = 22% versus day 5 = 11%, day 6 = 15%, day 7 = 23%). Although a comparable percentage of DCs expressing CD86+ (B7-2), CD40+, and HLA-DR+ were detected in both cultures, higher expression levels were detected in DCs derived from bulk culture (CD86 = MRLFI 3665.1 versus 2662.1 on day 6; CD40 = MRLFI 1786 versus 681.2 on day 6; HLA-DR = MRLFI 6018.2 versus 3444.9 on day 2). Cytokines involved in DC maturation were determined by polymerase chain reaction demonstrating interleukin-6 (IL-6), IL-12, interferon-gamma, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-alpha mRNA expression by bulk culture cells during the entire 9-day culture period. This same cytokine mRNA profile was not found in the conventional adherent DC culture. Autologous renal Tuly (30 micrograms protein/10(7) PBMCs) enhanced human leukocyte antigen expression by DCs (class I = 7367.6 versus 4085.4 MRFLI; class II = 8277.2 versus 6175.7 MRFLI) and upregulated cytokine mRNAs levels. Concurrently, CD3+ CD56-, CD3+ CD25+, and CD3+ TCR+ cell populations increased and cytotoxicity against autologous renal cell carcinoma tumor target was induced. Specific cytotoxicity was augmented when cultures were boosted continuously with IL-2 (20 U/mL biological response modifier program) plus Tuly stimulation. These results suggest that nonadherent PBMCs may participate in enhancing DC maturation. Besides the simplicity of this culture technique, bulk DC cultures potentially may be used with the same efficiency as conventional purified DCs. Furthermore, bulk culture-derived DCs may be used directly in vivo as a tumor vaccine, or for further ex vivo expansion of co-cultured cytotoxic T cells to be used for adoptive immunotherapy.

Cyproterone acetate in the treatment of advanced prostatic cancer: retrospective analysis of liver toxicity in the long-term follow-up of 89 patients.

Cyproterone acetate (CPA) was the first steroidal antiandrogen used for the treatment of prostatic cancer. In recent studies CPA has been linked with DNA adduct formation and increased DNA repair synthesis in vitro, suggesting an increased risk for the development of hepatic malignancies. To assess liver-toxic and carcinogenic effects, 89 patients who received CPA 50 mg/day p.o. over 4 (range 2-152 months) years for prostatic cancer treatment were retrospectively evaluated. 22 patients (28.2%) showed elevated liver enzyme concentrations. In none of the 89 patients alpha-fetoprotein serum levels were elevated. In no case hepatocellular carcinoma has been observed, and in no case CPA administration was discontinued due to side effects. Considering the life expectancy of patients with advanced prostatic cancer and the long-term and high-dose exposure to CPA necessary to possibly induce liver tumors, it appears highly unlikely that CPA treatment may account for a substantial number of liver carcinomas in such patients.

Bullous pemphigoid is a rare paraneoplastic syndrome in patients with renal cell carcinoma

Renal cell carcinoma is associated with paraneoplastic syndromes in up to 40% of cases. Dermatological manifestations are rare. A case of a bullous pemphigoid as a paraneoplastic symptom was diagnosed in a 52-year-old patient with a partially sarcomatoid papillary renal cell carcinoma.

Identification of Bladder Cancer Patients at Risk for Recurrence or Progression: An Immunohistochemical Study Based on the Expression of Metallothionein

Despite similarities in tumor stage and grade the individual outcome of bladder cancer patients is not predictable. The ideal tool for treatment stratification has not yet been found. Metallothionein (MT) overexpression is correlated with poor tumor differentiation, resistance to chemotherapy, and impaired survival in different malignancies. The clinical relevance of MT expression for defining patients at high risk for recurrence or progression was assessed. MT was detected immunohistochemically and evaluated semiquantitively in tumor specimens of 103 male and 19 female patients (transsurethral resection: n = 94, cystectomy: n = 28). Mean age of the patients was 68 (38–87) yr. According to histopathological features, three groups were distinguished for further analysis (pTa-1G1–2, pTis/pT1G3, and muscle invasive tumors). A cutoff value of 50% immunoreactive cells was used for further analysis. The 5-yr tumor specific survival rate was significantly lower in patients with high MT expression (32 vs. 72%). Accordingly, impaired 5-yr recurrence (90 vs. 58%), and progression rates (78 vs. 54%) were associated with high MT expression. All patients suffering from pTis and pT1G3 tumors with MT expression above the cutoff value showed recurrence within less than 40 mo, whereas 26% of those patients with MT expression below the cutoff value remained long-term recurrence free. Long term progression free survival was detected in 75% of pT1G3 patients with MT expression below the cutoff value. In contrast, 68% of pT1G3 tumor patients with MT expression above the cutoff value progressed, all within the first 12 mo after initial tumor resection. A correlation between high MT expression and prognosis was demonstrated especially in pT1G3 and pTis tumors, where >50% MT expression was linked to shorter tumor-specific survival and increased recurrence/progression rates. Thus, MT expression seems to be a promising marker for further risk stratification in the clinical treatment of bladder cancer patients.

The First Description of an Extramedullary Plasmacytoma of the Ureter

Causes for acquired unilateral obstruction of the ureter are numerous: calculi, infections, blood clots and tumors are the most common underlying pathologies. Hematologic tumors with initial clinical manifestation in the lower urinary tract are rare. Primary localization of plasmocytoma has been described in kidney, bladder and urethra. Herein, we describe the first manifestation of a primary solitary extramedullary plasmacytoma of the ureter. The tumor was discovered upon diagnostic workup of gross hematuria and asymptomatic hydronephrosis. Thus far, after radical surgery the patient remains free of disease.

Observation of de novo bladder dysfunction under treatment with Her2-neu antibodies.

Purpose: We diagnosed de novo bladder dysfunction in several breast cancer patients under cancer-specific therapy with trastuzumab. The goal of this retrospective analysis was to investigate whether bladder dysfunction is common in a larger population of breast cancer patients receiving trastuzumab therapy. Patients and Methods: We identified 93 patients who received at least two doses of trastuzumab at our institution in the years 2003–2006. 57 of those patients were still alive at the time of this analysis. We mailed a validated global questionnaire for the assessment of incontinence (King’s Health Questionnaire, KHQ) to them, additionally asking for bladder dysfunction observed under trastuzumab therapy. Results: 43 (75%) of the patients returned the questionnaire, 11 (25%) of them reporting severe de novo bladder dysfunction under therapy. Significant differences between symptomatic and asymptomatic patients were detected in all KHQ subscales. Previous conditions and surgeries as well as medications, especially hormonal therapy, were excluded as underlying causes. However, there were more patients under taxane-based chemotherapy in the symptomatic group. Conclusions: The epidermal growth factor receptor is involved in the cellular response to mechanical stretch in the urinary bladder. Based on our findings, we hypothesize that interfering with this pathway may well be the cause of symptomatic bladder dysfunction in patients under trastuzumab medication. A prospective study is required to further elucidate this hypothesis.