Low-pressure monopolar electroresection of the prostate for glands sized > 70 vs. < 70 cc performed with continuous irrigation and suprapubic suction: perioperative and long-term outcome.

PURPOSE: To evaluate long-term efficacy and safety of low-pressure transurethral resection of the prostate for prostates < 70 cc (group 1) vs. > 70 cc (group 2). PATIENTS AND METHODS: In this study patients operated with monopolar TURP between 2009 and 2012 were evaluated retrospectively. During surgery a specially designed trocar (18 Fr) was placed suprapubically and connected to a suction pump to maintain stable low-pressure conditions. After sample size calculations, long-term follow-up was completed for 70 invited patients in each group up to 9/2015. RESULTS: Follow-up period was 57 vs. 56 months for group 1 and 2, respectively (p = 0.56). At baseline there was no significant difference in age, IPSS, peak flow, and post void residual (PVR). Mean prostate volume was 47 cc (15-65) vs. 100 cc (70-163). Mean operating time was 55.4 vs. 82.6 min (p = 0.00). Blood transfusion was necessary in 0.0 vs. 2.9% (p = 0.16), and 0.0 vs. 1.4% developed TUR syndrome (p = 0.32). At follow-up mean relative improvement in IPSS was 63 vs. 57% (p = 0.29), QoL 64 vs. 64% (p = 0.93), peak flow 139 vs. 130% (p = 0.85), and PVR 58 vs. 63% (p = 0.80). Long-term complications included recurring adenoma in 1.4 vs. 4.3% (p = 0.31), and stricture in 7.2 vs. 5.8% (p = 0.73). 1 patient in each group reported worsening incontinence symptoms. CONCLUSIONS: In terms of safety and efficacy, the aforementioned modality of standardized monopolar TURP using suprapubic suction was non-inferior for prostates > 70 cc compared to the same procedure for prostates < 70 cc. This technique is a potential low-cost alternative for clinics that cannot afford modern laser approaches. STUDY REGISTER NUMBER: DRKS00006527.

Impact of Methadone on Cisplatin Treatment of Bladder Cancer Cells.

BACKGROUND: Cisplatin-based chemotherapy is the treatment of choice for advanced bladder cancer. Since many tumor cells show inherent or acquired cisplatin resistance, research is needed to improve the therapeutic efficacy. Since the analgesic methadone is discussed as being a sensitizer for chemotherapy, we tested its effects on the cisplatin treatment of bladder cancer cells. MATERIALS AND METHODS: T24 and HT-1376 bladder cancer cells were incubated with cisplatin in combination with methadone. Cytotoxicity was examined using the WST-1 viability assay and induction of apoptosis was analyzed via phase-contrast microscopy, flow cytometry, and western blot analysis. RESULTS: Methadone was shown to enhance the cytotoxic effects of cisplatin on T24 cells based on the induction of apoptosis. In contrast, HT-1376 cells were identified as non-responders to methadone. CONCLUSION: Methadone could act as a chemosensitizer in the future treatment of advanced bladder cancer. Further research is needed to identify the underlying molecular mechanisms.

Methadone as a "Tumor Theralgesic" against Cancer.

Methadone has beneficial characteristics as an analgesic against cancer pain, including high bioavailability, multiple receptor affinities, and lack of active metabolites that might induce adverse side effects. However, methadone has an own pharmacological profile that should be considered in the treatment of cancer patients. There is evidence from preclinical studies that methadone could also elicit antitumor activity by downregulating the threshold of apoptosis and to enhance the effects of different chemotherapeutic agents. This confirms the concept of using methadone as a chemosensitizer in the future treatment of cancer. Our article discusses major issues about the role of methadone as a possible "tumor theralgesic," combining tumor therapeutic and analgesic activities.

Androgen deprivation of prostate cancer: Leading to a therapeutic dead end.

Androgen deprivation therapy (ADT) is considered as the standard therapy for men with de novo or recurrent metastatic prostate cancer. ADT commonly leads to initial biochemical and clinical responses. However, several months after the beginning of treatment, tumors become castration-resistant and virtually all patients show disease progression. At this stage, tumors are no longer curable and cancer treatment options are only palliative. In this review, we describe molecular alterations in tumor cells during ADT, which lead to deregulation of different signaling pathways and castration-resistance, and how they might interfere with the clinical outcome of different second-line therapeutics. A recent breakthrough finding that early chemotherapy is associated with a significant survival benefit in metastatic hormone-sensitive disease highlights the fact that there is time for a fundamental paradigm shift in the treatment of advanced prostate cancer. Therapeutic intervention seems to be indicated before a castration-resistant stage is reached to improve therapeutic outcome and to reduce undesirable side effects.

Different basal expression of type T1 and T2 cytokines in peripheral lymphocytes of patients with adenocarcinomas and benign hyperplasia of the prostate.

BACKGROUND: It has been proposed that a reduced immunological competence and a dysregulation in the T1/T2 balance may be implicated in the development of cancer. In order to study the immunological situation in vivo, we compared the mRNA expression of the T1 cytokine IFN-gamma and the T2 cytokine IL-10 in freshly isolated, not in vitro stimulated, peripheral blood lymphocytes from patients with localized prostate carcinomas (PCa) and benign prostate hyperplasia (BPH). MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMC) were isolated by gradient centrifugation. CD4(+)- and CD8(+)-lymphocytes were selected with magnetic beads against these determinants. In these lymphocyte preparations, mRNA expression of IL-10 and IFN-gamma was determined by using a semiquantitative RT-PCR, standardized to the beta-actin expression. RESULTS: In the PBMC from 35 patients with localized PCa a significantly lower expression of IFN-gamma and IL-10 was found, compared to 28 patients with BPH. Cytokine expression also was lower in the isolated CD4(+)- and CD8(+)-lymphocytes of the carcinoma patients. However, the difference was statistically significant only for IL-10. CONCLUSION: Our data reflect a reduced basal cytokine expression in peripheral lymphocytes of patients with localized PCa compared to BPH. Since the T2 response was more strongly reduced than T1, there seems to be a decreased immune activation, but a relative T1 dominant cytokine pattern in the cancer patients.

Retrograde intrarenal surgery in treatment of nephrolithiasis: is a 100% stone-free rate achievable?

PURPOSE: To achieve an almost 100% stone-free rate by means of further developing and standardizing the procedure. PATIENTS AND METHODS: 100 consecutive patients with single or multiple renal calculi were prospectively enrolled in the study. Flexible ureterorenoscopy was performed as a completely standardized operation by the same two experienced surgeons. Primary outcome was an "endoscopic" (immediate) stone-free status as determined by endoscopic inspection at the end of surgery. In cases of residual fragments, a reevaluation by CT was performed after 3 months. RESULTS: The endoscopic stone-free rate was 97%. In three patients with a cumulative stone size >20 mm, a completely stone-free status could not be achieved in the primary procedure. In these patients, a CT scan after 3 months showed complete clearance from all residual fragments in two; this translates into a primary (after one procedure) stone-free rate after 3 months of 99%. Medium cumulative stone size was 9.8 mm (4-40 mm); in 44 patients, multiple calculi were extracted. Forty-nine patients received a ureteral stent at the end of the operation; two patients had to have stent placement for new onset hydronephrosis and/or colicky pain or fever. Overall complication rate was 7%. Results are limited, because no routine CT scan was used to evaluate stone clearance. CONCLUSION: By means of a standardized surgical approach and use of technical equipment of the newest generation, it is possible to achieve very high stone-free rates without compromising safety. This approach, however, necessitates use of considerable resources, both technical/surgical and financial.

Preclinical evaluation of a recombinant anti-prostate specific membrane antigen single-chain immunotoxin against prostate cancer.

The prostate-specific membrane antigen (PSMA) is abundantly expressed on prostate cancer epithelial cells and its expression correlates with tumor progression. Therefore, a specific immunotherapy against this antigen may be a novel therapeutic option for the management of prostate cancer. We generated an anti-PSMA single-chain antibody fragment (scFv), called D7, by phage display from the monoclonal antibody 3/F11. By C-terminal ligation of the toxic domain of Pseudomonas Exotoxin A (PE40) to the genes of D7, the immunotoxin D7-PE40 was generated. D7 and D7-PE40 specifically bound to PSMA transfectants and to the PSMA expressing prostate cancer cell line C4-2. In addition, D7-PE40 showed a high serum stability and induced a 50% reduction of viability (IC50) in C4-2 cells at a concentration of 140 pM. In vivo, D7-PE40 was well tolerated in SCID mice up to a single dose of 20 microg, whereas higher doses induced severe hepatotoxicity with deaths of the animals. Immunotoxin treatment of mice bearing C4-2 tumor xenografts caused a significant inhibition of tumor growth, whereas mice with PSMA-negative DU 145 tumors remained unaffected. Owing to its high and specific cytotoxicity and its capability to inhibit prostate tumor growth in vivo the immunotoxin D7-PE40 represents a promising candidate for the immunotherapy of prostate cancer.

Primary prostate cancer cultures are models for androgen-independent transit amplifying cells.

Numerous efforts exist for developing primary prostate cancer cultures for studying the biology of this tumor entity and for evaluation of the effectiveness of novel therapies. However, there is doubt if cultures that represent the fully differentiated phenotype can be established. The aim of the present study was to characterize primary outgrowing prostate epithelial cells due to their basal or luminal characteristics and their potential for serving as androgen-responsible model. From fresh prostate cancer radical prostatectomy specimens, pieces of approximately 2-4 mm diameter were placed on top of transwell culture chambers, which were coated with matrigel and cultured in prostate epithelial selection medium with 10% fetal calf serum. The monolayer of outgrowing cells was incubated with a physiological concentration of 1 nM dihydrotestosterone (DHT). One group was additionally cultivated without DHT and another group was treated with the 5-alpha-reductase-inbitors MK-368 and MK-905. From the monolayer of the outgrowing cells, RNA was isolated and the expression of androgen receptor (AR), prostate-specific antigen (PSA), Kallikrein 2 (KlK2), prostate-specific membrane antigen (PSMA), and prostate stem cell antigen (PSCA), cytokeratin (CK)5, and CK18 was determined by realtime quantitative PCR. The outgrowing cells from the prostate cancer tissue pieces could be characterized as epithelial cells with basal and transit amplifying characteristics as shown by co-expression of CK5 and CK18. In all cultures, a very low expression of the luminal cell marker genes AR, PSA and KLK2 was measured. The levels of PSCA were clearly higher with a broad variation. Upon cultivation without DHT or treatment with alpha-reductase inhibitors no regulation of AR, PSA and KlK2 was found. Due to the co-expression of basal and luminal marker genes, primary prostate cancer cultures can be charaterized as models of transit amplifying cells of the prostatic epithelium. They do not represent the differentiated secretory androgen-responsive cell phenotype.

Anti-PSMA immunotoxin as novel treatment for prostate cancer? High and specific antitumor activity on human prostate xenograft tumors in SCID mice.

BACKGROUND: Expression of the prostate specific membrane antigen (PSMA) is highly restricted to prostate epithelial cells. Therefore, toxin-based immunotherapy against this antigen may represent an alternative therapeutic option for prostate cancer. For these purposes, the effects of the recombinant anti-PSMA immunotoxin A5-PE40 on prostate tumor growth were investigated in vitro and in vivo. METHODS: The in vitro binding and cytotoxicity of A5-PE40 were tested on the PSMA-expressing prostate cancer cell line C4-2 and on the PSMA-negative cell line DU145 by flow cytometry and WST assays. The binding of the immunotoxin to SCID mouse xenografts and to various mouse organs was examined by Western blot analysis. In vivo, the antitumor activity of the immunotoxin was tested by injecting A5-PE40 in mice bearing C4-2 or DU145 xenografts. RESULTS: In vitro, a specific binding of A5-PE40 to C4-2 cells could be shown with a concentration-dependent cytotoxicity (IC(50) value=220 pM). In the next step, a specific binding of the immunotoxin to C4-2 xenografts could be demonstrated. In contrast, no binding on mouse organs expressing high homologous mouse PSMA was found. The treatment of mice with C4-2 tumors caused a significant inhibition of tumor growth in vivo, whereas DU145 xenografts remained totally unaffected. CONCLUSIONS: A5-PE40 represents a recombinant anti-PSMA immunotoxin with potent antitumor activity in mice bearing human prostate cancer xenograft tumors. Therefore, A5-PE40 could be a promising candidate for therapeutic applications in patients with prostate cancer.