Julian Frick

Endocrine profiles after radiotherapy in stage I seminoma: impact of two different radiation treatment modalities

BACKGROUND AND PURPOSE In patients with stage I seminoma treated with elective lymph node irradiation, testicular scatter doses are often thought to be responsible for later disturbances in fertility. We studied the influence of radiation field extensions and testicular doses on hormonal function. MATERIALS AND METHODS FSH (follicle stimulating hormone) and LH (luteinizing hormone) were evaluated before radiotherapy (RT) and by serial analyses after treatment for 4 years. Twenty-three patients were irradiated by hockey stick fields with a mean dose of 31.9 Gy (+/-4.7 SD) and a mean scatter dose of 54 8 cGy (+/-16.6 SD). Twenty-one patients received limited RT to the paraaortic nodes with 28.1 Gy (+/-2.4 SD). The mean testicular dose was only 25 cGy (+/-7.8 SD). All patients had normal pre-treatment hormonal values. RESULTS Six months after the end of RT, mean FSH values were significantly elevated in the hockey stick group (P = 0.032), returning to normal after 3 years. The increase in LH was also significant, but stayed within normal ranges. Limited RT resulted in a minimal, dose-dependent increase of FSH; no changes in LH were noted. CONCLUSIONS In patients with a normal hormonal status after semicastration, FSH is a reliable monitor for transient radiation-induced effects. To avoid treatment-related disturbances in spermatogenesis, scatter doses should be reduced to less than 20 cGy.

Fluorescence-optical measurements of chloride movements in cells using the membrane-permeable dye diH-MEQ.

Fluorescence-optical measurements of the intracellular chloride concentration facilitate identification of chloride movements across the cell membrane of living cells. The two main dyes used for this purpose are 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ) and 6-methoxy-quinolyl acetoethyl ester (MQAE). The use of both substances is impaired by their poor membrane permeability and therefore limited loading of the cells to be studied. Here we report the use of 6-methoxy-N-ethylquinolinium iodide (MEQ), a chloride-sensitive dye for which a membrane-permeable form is easily prepared. This makes the loading procedure as easy as with the acetoxymethyl (AM) forms of other dyes for sensing intracellular ions. In addition, the original method, which described absolute concentration measurements of chloride in the cytosol, was modified in so far as only relative measurements were made. This avoids the known limitations of single wavelength excitation and emission dyes with respect to exact concentration measurements. More-over, to enhance the signal-to-noise ratio the driving force for chloride was considerably increased by changing the original direction of the anion flux in the cells under investigation. We verified the method by using fibroblasts and activating ICln, a putative chloride channel cloned from epithelial cells and of paramount importance in the regulatory volume decrease in these cells. In the presence of SCN− the MEQ quench measured in NIH 3T3 fibroblasts is dramatically enhanced in hypotonically challenged cells compared with cells under isotonic conditions. Antisense oligodeoxynucleotides sensing ICln considerably impeded the swelling-induced chloride current (ICl) in NIH 3T3 fibroblasts. Accordingly, the chloride movement measured by the SCN− quench of the MEQ signal was significantly reduced. Similar results can be obtained in the presence of 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) or 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS), two known blockers of chloride transport in the plasma membrane of a variety of cells. In conclusion, fluroscence-optical measurements using MEQ as the chloride-sensitive dye provide a reliable and easy-to-use method for measuring changes of the chloride flux across the cell membrane of living cells.

Significance of Urinary Neopterin in Patients With Malignant Tumors of the Genitourinary Tract

The urinary neopterin excretion was measured by high‐performance liquid chromatography in 417 healthy subjects and in 76 patients with clinically and pathohistologically verified neoplasias of the urinary tract (bladder tumor, carcinoma of the prostate, and renal cell carcinoma). The patients with early tumor stages both with bladder tumor and carcinoma of the prostate had normal urinary neopterin levels, except one patient with bladder tumor who had a value at the upper confidence limit. Of 40 patients with higher stages of bladder tumor and carcinoma of the prostate, 35 had elevated urinary neopterin levels. Two of 10 patients with bladder tumor in stage T3, 1 of 4 patients with carcinoma of the prostate Stage C, and 2 of 15 patients with prostatic cancer Stage D showed normal neopterin levels. The patients with renal cell carcinoma did not demonstrate any definite correlation between tumor stage and urinary neopterin excretion. The current study suggests that the neopterin assay may supplement laboratory measurements in tumors of the urinary tract, providing helpful information regarding case selection for the most convenient therapeutic management and postoperative follow‐up.

ICln: a chloride channel paramount for cell volume regulation.

Cell volume regulation is a ubiquitous cell regulatory mechanism based on meticulously controlled ion transport mechanisms. Keeping the absolute volume constant seems to be of the highest priority for most cells and is achieved at the expense of altered intracellular ion concentrations. We have been able to demonstrate that ICln, a chloride channel cloned from epithelial cells, is paramount for the ability of swollen cells to regulate their volume back to that under resting conditions. A unique feature of ICln is the distinct sensitivity of these channels for nucleotides and nucleoside analogues added to the extracellular fluid. In addition, cromolyn sodium and nedocromil sodium, drugs used by patients with asthma, are able to impede the function of these channels.

Effective long-term androgen suppression in men with prostate cancer using a hydrogel implant with the GnRH agonist histrelin ☆

OBJECTIVES To evaluate the effectiveness of a hydrogel implant containing the gonadotropin-releasing hormone (GnRH) agonist histrelin in suppressing testosterone production in men with prostate cancer and to determine the effective dose (one, two, or four implants). METHODS Forty-two men with prostate cancer and indications for androgen ablation were treated with one, two, or four implants. In two of the clinics, comprising 27 subjects, the treatment period was 12 months, with replacement with the same number of implants at 12-month intervals. In a third clinic, which treated 15 subjects, the implants were left in place for up to 30 months. The total experience was 605 treatment months. RESULTS The histrelin levels were detected in serum proportional to the number of implants placed. The response, however, was similar among all three dose levels, with testosterone and luteinizing hormone essentially completely suppressed. Serum testosterone levels decreased from 21.9 +/- 17.6 nmol/L to 0.93 +/- 1.57 nmol/L within 1 month and were maintained at 0.55 +/- 0.24 nmol/L at 6 months and 0.60 +/- 0.28 nmol/L after 12 months of treatment. Of the 38 assessable patients, 35 (92%) had castrate levels of testosterone within 4 weeks of the initial implant placement. All patients followed for up for 12 months after placement of the initial set of implants maintained suppression of testosterone production while the implant was in place. CONCLUSIONS The histrelin hydrogel implant provided adequate and reliable delivery of the potent GnRH agonist histrelin during at least 1 year using a single implant in men with prostate cancer. No apparent advantages were found in using more than one implant, and the question of the possible effectiveness of even lower doses remains open. This treatment modality appears to be both safe and effective.

Effect of active immunization against luteinizing hormone-releasing hormone on the androgen-sensitive Dunning R3327-PAP and androgen-independent Dunning R3327-AT2.1 prostate cancer sublines.

The objective of this study was to determine the effect of active immunization against LHRH on the growth characteristics and histology of subcutaneously implanted tumors of the androgen‐sensitive Dunning R3327‐PAP and androgen‐independent R3327‐AT2.1 rat prostate adenocarcinoma sublines.

Blockade of swelling-induced chloride channels by phenol derivatives

1 . In NIH3T3 fibroblasts, the chloride channel involved in regulatory volume decrease (RVD) was identified as ICln, a protein isolated from a cDNA library derived from Madin Darby canine kidney (MDCK) cells. ICln expressed in Xenopus laevis oocytes gives rise to an outwardly rectifying chloride current, sensitive to the extracellular addition of nucleotides and the known chloride channel blockers, DIDS (4,4′‐diisothiocyanatostilbene‐2,2′‐disulphonic acid) and NPPB (5‐nitro‐2‐(3‐phenylpropylamino)‐benzoic acid). We set out to study whether substances structurally similar to NPPB are able to interfere with RVD. 2 . RVD in NIH3T3 fibroblasts and MDCK cells is temperature‐dependent. 3 . RVD, the swelling‐dependent chloride current and the depolarization seen after reducing extracellular osmolarity can be blocked by gossypol and NDGA (nordihydroguaiaretic acid), both structurally related to NPPB. 4 . The cyclic AMP‐dependent chloride current elicited in CaCo cells is less sensitive to the two substances tested while the calcium‐activated chloride current in fibroblasts is insensitive. 5 . The binding site for the two phenol derivatives onto ICln seems to be distinct but closely related to the nucleotide binding site identified as G × G × G, a glycine repeat located at the predicted outer mouth of the Icln channel protein.

Pulsatile luteinizing hormone-releasing hormone treatment of male hypogonadotropic hypogonadism

Luteinizing hormone-releasing hormone (LH-RH) secretion from the hypothalamus follows a rhythmic pattern, inducing pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion from the pituitary gland. Consideration of this physiologic principle led to the introduction of pulsatile LH-RH therapy via infusion pump for the treatment of different forms of hypogonadotropic hypogonadism. We report on 10 male patients, 16 to 28 years of age, suffering from idiopathic hypogonadotropic hypogonadism (IHH) including Kallmans syndrome (n = 2) and delayed puberty (n = 2). All presented with complete eunuchoidism and had undergone no treatment for their conditions during the previous 2 years. LH-RH was administered in subcutaneous pulses of 4 to 16 micrograms, with a portable infusion pump (ZYKLOMAT, Ferring Corp., Kiel, FRG); treatment periods ranged from 6 to 24 months. With therapy, the subjects improved secretion of LH, FSH and testosterone. Testicular volumes and penis size increased; all patients developed normal secondary sexual characteristics. Spermatogenesis was induced in all patients. The time to onset of spermatogenesis ranged from 3 to 15 months. No major side effects were observed, and no patient dropped out of the study. The results indicate that pulsatile LH-RH therapy is an highly effective treatment for IHH and delayed puberty.

Androgens and the prostate

The prostate is androgen-dependent, requiring testosterone for its growth, development, differentiation and function. The involution of the prostate gland is initiated by testosterone depriviation (orchidectomy, medical castration). Subsequent administration of exogenous androgen and/or cessation of medical androgen blockade, however, results in re-growth of the prostate gland. However, it only attains its original size, and the response to androgen does not cause prostatic overgrowth.

Traumatic Rupture of Corpus cavernosum

Fracture of the corpus cavernosum occurs when one or both corpora are ruptured usually during sexual intercourse and less often owing to blunt trauma. The injury may be associated with an urethral lesion and is easy to recognize; the treatment, however, remains controversial. 7/8 patients had primary or secondary surgical therapy, 1/8 was treated by conservative measures. The results after surgery were very satisfactory, with no immediate perioperative or postoperative complications. The success rate of the surgical management corresponds to a high degree with reports from the literature (complication rate is less than 10%). Based on literature review, conservative treatment is associated with a 25-30% complication rate. Early surgical repair might be the treatment of choice for rupture of the corpus cavernosum with and/or without concomitant lesion of the urethra.