Stefan Machtens

Positron emission tomography with 11C-acetate and 18F-FDG in prostate cancer patients

Visualisation of primary prostate cancer, its relapse and its metastases is a clinically relevant problem despite the availability of state-of-the-art methods such as CT, MRI, transrectal ultrasound and fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET). The aim of this study was to evaluate the efficacy of carbon-11 acetate and 18F-FDG PET in the detection of prostate cancer and its metastases. Twenty-five patients were investigated during the follow-up of primary prostate cancer, suspected relapse or metastatic disease using 11C-acetate PET; 15 of these patients were additionally investigated using 18F-FDG PET. Fourteen patients were receiving anti-androgen treatment at the time of the investigation. Lesions were detected in 20/24 (83%) patients using 11C-acetate PET and in 10/15 (75%) patients using 18F-FDG PET. Based on the results of both PET scans, one patient was diagnosed with recurrent lung cancer. Median 18F-FDG uptake exceeded that of 11C-acetate in distant metastases (SUV =3.2 vs 2.3). However, in local recurrence and in regional lymph node metastases, 11C-acetate uptake (median SUVs =2.9 and 3.8, respectively) was higher than that of 18F-FDG (median SUVs =1.0 and 1.1, respectively). A positive correlation was observed between serum PSA level and both 11C-acetate uptake and 18F-FDG uptake. 11C-acetate seems more useful than 18F-FDG in the detection of local recurrences and regional lymph node metastases. 18F-FDG, however, appears to be more accurate in visualising distant metastases. There may be a role for combined 11C-acetate/18F-FDG PET in the follow-up of patients with prostate cancer and persisting or increasing PSA.

Possible role of bradykinin and angiotensin II in the regulation of penile erection and detumescence

OBJECTIVES To examine the functional effects of bradykinin (BK) and angiotensin II (AN II) on isolated human cavernous tissue and to detect any changes in the AN II levels in cavernous and peripheral blood samples taken from healthy volunteers at different functional conditions of the penile erectile tissue. Metabolites of the renin-angiotensin system and endothelium-derived vasoactive substances are known to be involved in the regulation of arterial vascular tone. The human corpus cavernosum (HCC), consisting of endothelial and smooth muscle cells, can be regarded as a compartment comparable to the vascular system. METHODS The relaxing and contracting properties of BK and AN II on isolated HCC were investigated using the organ bath technique. Tissue levels of adenosine-3,5-cyclic monophosphate (cAMP) and guanosine-3,5-cyclic monophosphate (cGMP) were determined using specific radioimmunoassays, after exposing isolated HCC strips in a dose-dependent manner to BK, forskolin, and sodium nitroprusside. Blood samples were drawn simultaneously from the corpus cavernosum and cubital vein of 34 healthy volunteers at stages of penile flaccidity, tumescence, rigidity, and detumescence. Penile erection was induced by audiovisual and tactile stimulation. AN II levels were determined using a radioimmunoassay. RESULTS In vitro, BK, forskolin, and sodium nitroprusside elicited dose-dependent relaxation of norepinephrine-induced tension of isolated HCC, and AN II evoked dose-dependent contraction of the HCC strips. The relaxing potency of BK was paralleled by its ability to elevate the intracellular levels of cAMP and cGMP. In vivo, the AN II levels in the cavernous plasma increased from 21.8 +/- 4.6 pg/mL in the flaccidity phase to 27.9 +/- 10 pg/mL in the detumescence phase. In the peripheral plasma, the AN II levels were 17.2 +/- 6.2 to 19.5 +/- 6.5 pg/mL in the respective penile stages. Thus, the mean AN II levels in the cavernous blood were about 30% higher than in the blood samples taken from the cubital vein. In the cavernous blood, the increase in the AN II plasma levels in the detumescence phase (27.9 +/- 10 pg/mL) was statistically significant. CONCLUSIONS Our results suggest that penile cavernous smooth muscle tone is partially balanced by kinin-induced relaxation and AN II-induced contraction. Since the tissue and plasma levels of both peptides are regulated by the activity of the angiotensin-converting enzyme, there might be a rationale for the use of angiotensin-converting enzyme inhibitors in the treatment of erectile dysfunction associated with arterial hypertension.

Initial clinical experience with the selective phosphodiesterase-I isoenzyme inhibitor vinpocetine in the treatment of urge incontinence and low compliance bladder.

Abstract Current pharmacological treatment modalities for urge incontinence and low compliance bladder are limited by a low clinical efficacy and the significant side effects of the standard drugs available. Previous in vitro studies indicated a possible functional relevance of the intracellular phosphodiesterase (PDE)-1 isoenzyme in the regulation of human detrusor smooth muscle contractility. We therefore investigated the effect of the PDE-1 inhibitor vinpocetine in nonresponders to standard pharmacological therapy. In 11/19 patients (57.9%) clinical symptoms and/or urodynamic parameters were improved. Although these initial data are preliminary, they represent the first evidence that isoenzyme-selective PDE inhibition may be a novel approach to the treatment of lower urinary tract disorders.

Long-term results of interstitial brachytherapy (LDR-Brachytherapy) in the treatment of patients with prostate cancer.

Permanent interstitial brachytherapy represents the most conformal form of radiation therapy of the prostate and the number of patients with prostate cancers treated with permanent radioactive implants is increasing world wide. In the meanwhile long-term data on tumor control and treatment morbidity become available. Biochemical and clinical tumor control appears to be as effective as after radical prostatectomy or external beam radiation therapy in early prostate cancer. The risk of postreatment urinary incontinence and bowel dysfunction is low and erectile function can be preserved in the majority of patients. However, prostate brachytherapy requires a careful selection of patients as pretreatment factors predict for long-term outcome. The need for combined modality approaches in intermediate and high-risk patients remains controversely discussed. The continous refinement of intraoperative planning techniques and the elucidation of the etiology of urinary, sexual, and bowel dysfunction should result in further improvements in biochemical outcomes and decreased morbidity. Improved and standardized postimplantation evaluation will make outcome data more reliable and comparable.

The need for routine adrenalectomy during surgical treatment for renal cell cancer: the Hannover experience.

Objectives To further clarify the need for routine adrenalectomy during the surgical treatment of renal cell cancer, as in the absence of clinically overt metastatic disease, tumorous lesions within the adrenal gland are found in only 2–10% of patients, with most being over‐treated by adrenalectomy.

Effects of various nitric oxide-donating drugs on adrenergic tension of human seminal vesicles in vitro

OBJECTIVES To evaluate the effects of the nitric oxide (NO)-donating compounds sodium nitroprusside (SNP), S-nitroso-glutathione (GSNO), S-nitroso-N-acetylcysteine (SNAC), S-nitroso-N-acetylcysteine-ethylester (SNACET), and linsidomine (SIN-1) on the adrenergic tension of isolated human seminal vesicle strip preparations. The significance of the NO-cyclic guanosine monophosphate (cGMP) pathway in the regulation of smooth muscle tone in the human genitourinary tract has been well established. However, information on the significance of NO-mediated signal transduction in the functional control of the mammalian seminal vesicles is still sparse. METHODS Seminal vesicle strip preparations were applied to an organ bath system under standard conditions. Tension was induced by the addition of 10 microM norepinephrine. After stable tension plateaus had been reached, the drugs were added in a cumulative manner (0.01 to 100 microM) and the isometric responses of the tissue registered. The effects of the compounds on the phasic contractility of the tissue preparations were also evaluated. The adenylyl cyclase-stimulating agent forskolin was used as a reference compound known to interfere with the cyclic adenosine monophosphate pathway. RESULTS Adrenergic tension was dose dependently attenuated by the drugs. The rank order of potency, from greater to lesser, was GSNO, SNAC, SNP, SIN-1, forskolin, and SNACET. The rank order (from greater to lesser) with regard to the inhibitory effects of the compounds on the frequency of phasic contractions of the tissue induced by the addition of norepinephrine was GSNO, SNAC, SNP, and SIN-1; the effects of SIN-1, forskolin, and SNACET on the frequency of contractions were nearly equipotent. CONCLUSIONS Our results strongly support the hypothesis that the contractility of the human seminal vesicle is under the control of the NO-cGMP pathway. This finding may give a rationale for the use of S-nitrosothiols, such as GSNO and SNAC, in the pharmacotherapy of hyperexcitatory disturbances of ejaculation (premature ejaculation).

Management of the post-chemotherapy residual mass in patients with advanced stage non-seminomatous germ cell tumors (nsgct)

Since it is difficult to predict the probability of persistent teratoma or of a viable tumor in patients with normalized tumor markers and a normal CT scan following chemotherapy for advanced stage testis cancer, recommendations regarding adjunctive surgery have ranged from observation to surgical exploration for all patients. Suggested variables for patients in whom surgery can be omitted safely, include normal post‐chemotherapy CT scans, residual abdominal masses of less than 1.5 cm, a 90% or greater decrease in the volume of the retroperitoneal mass with chemotherapy and no teratomatous elements in the orchiectomy specimen. In contrast, during several investigations, the application of the above mentioned criteria resulted in a false‐negative prediction of approximately 20%. However, recognizing the morbidity of the operative procedure itself in addition to the fact that only 2–4% of patients will develop recurrent tumor confined to the retroperitoneal space that can then be managed surgically or by administration of further chemotherapy, secondary surgery should be avoided if a sufficient follow‐up after chemotherapy is guaranteed. The extent of adjunctive surgery in patients revealing a residual tumor mass after first‐line chemotherapy remains a subject of ongoing discussions. It has been indicated that extensive retroperitoneal surgery after chemotherapy is associated with significant clinical morbidity. A limitation of post‐chemotherapy surgery to a resection of the residual mass with or without an additional modified template dissection appears to result in an acceptable frequency of retroperitoneal recurrences and a decreased complication rate. Int. J. Cancer 83:852–855, 1999.

A possible role for nitric oxide in the regulation of human ureteral smooth muscle tone in vitro

There is ample evidence that nitric oxide (NO) is an important neurotransmitter in many tissues of the urogenital tract. The aim of the present study was to examine the possible role of NO in ureteral relaxation. Human ureteral rings were mounted in organ bath chambers and precontracted with KCl. Increasing doses of the NO donor linsidomine (SIN-1) were added with and without prior blockade of the NO/cGMP pathway by methylene blue and protein kinase (PK) inhibitors Rp-8-pCPT-cGMPS and Rp-8-CPT-cAMPS. Electrical field stimulation (EFS) was done before and after incubation with L-NOARD (NG-nitro-L-arginine) and TTX (tetratodoxin). For detection of neuronal NO synthase (NOS), ureters were stained immunohistochemically. Ureteral strips were dose dependently relaxed by SIN-1; preincubation with methylene blue and protein kinase G inhibitor significantly reduced the SIN-1-induced relaxations. No effects of L-NOARG and TTX on EFS-induced tone alterations were found. NOS-positive neuronal axons and nerve-ending-like structures were found in the muscular layers. Our in vitro findings suggest that ureteral relaxation may involve the NO pathway.

Possible role of bioactive peptides in the regulation of human detrusor smooth muscle - functional effects in vitro and immunohistochemical presence.

Abstract. Results from basic research implicate a role for bioactive peptides in controlling the mammalian lower urinary tract. Although various peptides are assumed to be involved in the potentiaton or inhibition of cholinergic or purinergic activity in the urinary bladder, there is still much controversy regarding the mode of action and functional significance of such peptides in detrusor smooth muscle. Thus, we evaluated the functional effects of atrial natriuretic peptide (ANP), calcitonin gene related peptide (CGRP), endothelin 1 (ET-1), substance P (SP) and vasoactive intestinal polypeptide (VIP) on isolated strip preparations of human detrusor smooth muscle and determined the presence of those peptides in the human detrusor by means of immunohistochemistry. The effects of peptides on isometric tension of isolated detrusor strip preparations and on tissue levels of cyclic nucleotides cAMP and cGMP were compared to those of adenylyl cyclase activator forskolin (F), nitric oxide donor Na+-nitroprusside (SNP) and non-specific phosphodiesterase (PDE) inhibitor papaverine (P). The effects of the compounds on isometric tension of isolated human detrusor smooth muscle were examined using the organ bath technique. To determine time- and dose-dependent effects on cyclic nucleotide levels, bladder strips were exposed to increasing doses of F, SNP, P, ANP, CGRP and VIP, then rapidly frozen in liquid nitrogen and homogenised in the frozen state. cAMP and cGMP were extracted and assayed using specific radioimmunoassays. The presence of peptides was investigated by light microscopy using the Avidin-Biotin-Complex (ABC) method. F, P and VIP most effectively reversed the carbachol-induced tension of isolated human detrusor strips. Relaxing effects of ANP, CGRP and SNP were negligible. In contrast, ET-1 and SP elicited dose-dependent contractions of the tissue. The relaxing effects of F, P and VIP were accompanied by an increase in cAMP and cGMP levels, respectively. Light microscopy revealed positive immunostaining for CGRP, ET 1, VIP and SP in sections of the detrusor muscle coat. Our results suggest a possible importance of ET 1, SP and VIP in regulating detrusor smooth muscle contraction and relaxation. Even if a peptide is not synthesised, stored or released in a smooth muscle tissue and is, therefore, unable to reach its target cells under physiologic conditions, a functional effect on the tissue might be mediated by peptide-binding to specific cell surface receptors.

Effects of various nitric oxide donating agents on the contractility and cyclic nucleotide turnover of human seminal vesicles in vitro

OBJECTIVES To evaluate the effects of the nitric oxide (NO)-donating drugs sodium nitroprusside, S-nitroso-glutathione (GSNO), S-nitroso-N-acetylcysteineetylester (SNACET), and linsidomine (SIN-1), as well as the adenylyl cyclase-stimulating agent forskolin, on electrically induced contractions and on tissue levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) of isolated human seminal vesicle strip preparations. The significance of the L-arginine-NO-cGMP pathway in the regulation of smooth muscle tone in the human genitourinary tract has been well established; however, information on the relevance of NO-mediated signal transduction in the functional control of mammalian seminal vesicles is still sparse. METHODS Seminal vesicle strip preparations were applied to an organ bath system under standard conditions. Phasic contractions were induced by electrical field stimulation (frequency 80 Hz, amplitude 10 V, single pulse 1 ms, total pulse duration 1 second, pause 90 seconds). After stable contraction amplitudes had been reached, the drugs were added in a cumulative manner (0.001 to 10 microM), and the isometric responses were registered. After drug exposure, freezing, tissue homogenization, and extraction of cyclic nucleotides, cAMP and cGMP were measured by means of enzyme-linked immunosorbent assays. RESULTS Electrical field stimulation-induced amplitudes were attenuated by the drugs in a dose-dependent manner. The rank order of potency was GSNO > sodium nitroprusside > forskolin > SNACET > or = SIN-1. The relaxing effect of GSNO was antagonized in the presence of 10 microM of guanylyl cyclase inhibitor methylene blue. The inhibitory effects of GSNO, sodium nitroprusside, and forskolin on the contractile activity were paralleled by an increase in tissue cGMP (2 to 100-fold) and cAMP (7 to 9-fold). CONCLUSIONS Our results strongly support the hypothesis that the contractility of human seminal vesicles is in part regulated by the NO-cGMP-cascade. This may give a rationale for the use of S-nitrosothiols, such as GSNO, in the pharmacotherapy of hyperexcitatory disturbances of ejaculation.