Sub-chronic (13-week) oral toxicity study in rats with recombinant human lactoferrin produced in the milk of transgenic cows.

The oral toxicity of recombinant human lactoferrin (rhLF) produced in the milk of transgenic cows was investigated in Wistar rats by daily administration via oral gavage for 13 consecutive weeks, 7 days per week. The study used four groups of 20 rats/sex/dose. The control group received physiological saline and the three test groups received daily doses of 200, 600 and 2000 mg of rhLF per kg body weight. Clinical observations, growth, food consumption, food conversion efficiency, water consumption, neurobehavioural testing, ophthalmoscopy, haematology, clinical chemistry, renal concentration test, urinalysis, organ weights and gross examination at necropsy and microscopic examination of various organs and tissues were used as criteria for detecting the effects of treatment. Overall, no treatment-related, toxicologically significant changes were observed. The few findings that may be related to the treatment (lower cholesterol in high-dose females, lower urinary pH in high-dose males and females and very slightly higher kidney weight in high-dose females) were considered of no toxicological significance. Based on the absence of treatment-related, toxicologically relevant changes, the no-observed-adverse-effect level (NOAEL) was considered to be at least 2000 mg/kg body weight/day.

Targeted delivery of oligodeoxynucleotides to parenchymal liver cells in vivo.

Anti-sense oligodeoxynucleotides (ODNs) hold great promise for correcting the biosynthesis of clinically relevant proteins. The potential of ODNs for modulating liver-specific genes might be increased by preventing untimely elimination and by improving the local bioavailability of ODNs in the target tissue. In the present study we have assessed whether the local ODN concentration can be enhanced by the targeted delivery of ODNs through conjugation to a ligand for the parenchymal liver cell-specific asialoglycoprotein receptor. A capped ODN (miscellaneous 20-mer sequence) was derivatized with a ligand with high affinity for this receptor, N2-[N2-(N2,N6-bis{N-[p-(beta-d-galactopyranosyloxy) anilino] thiocarbamyl}-L-lysyl)-N6-(N-{p-[beta-D -galactopyranosyloxy] anilino} thiocarbamyl)-L-lysyl]-N6-[N- (p-{beta-D-galactopyranosyloxy}anilino)thiocarbamyl]-L-lysine (L3G4) (Kd 6.5+/-0.2 nM, mean+/-S.D.). Both the uptake studies in vitro and the confocal laser scan microscopy studies demonstrated that L3G4-ODN was far more efficiently bound to and taken up by parenchymal liver cells than underivatized ODN. Studies in vivo in rats showed that hepatic uptake could be greatly enhanced from 19+/-1% to 77+/-6% of the injected dose after glycoconjugation. Importantly, specific ODN accumulation of ODN into parenchymal liver cells was improved almost 60-fold after derivatization with L3G4, and could be attributed to the asialoglycoprotein receptor. In conclusion, the scavenger receptor-mediated elimination pathway for miscellaneous ODN sequences can be circumvented by direct conjugation to a synthetic tag for the asialoglycoprotein receptor. In this manner a crucial requisite is met towards the application of ODNs in vivo to modulate the biosynthesis of parenchymal liver cell-specific genes such as those for apolipoprotein (a), cholesterol ester transfer protein and viral proteins.

Liver uptake of phosphodiester oligodeoxynucleotides is mediated by scavenger receptors.

The therapeutic activity of antisense oligodeoxynucleotides (ODNs) often is impaired due to premature degradation and poor ability to reach the (intra)cellular target. In this study, we addressed the in vivo fate of ODNs and characterized the major sites responsible for the clearance of intravenously injected phosphodiester ODN. On injection into rats, 32P-ODNs (miscellaneous sequences and GT-containing ODNs with variable G content) are rapidly cleared from the bloodstream (t1/2 = 0.6-0.7 min), with the liver being the main site of elimination. The contribution of the liver to ODN clearance depended on its sequence and varied considerably. Hepatic uptake tended to be lower for G-rich ODNs as a result of increased bone marrow uptake. Within the liver, both Kupffer cells (KC) and endothelial cells (EC) were responsible for 32P-ODN uptake. To elucidate the mechanism of liver uptake, 32P-ODN binding studies using isolated EC and KC were performed. Binding to both cell types seemed to be saturable, of moderate affinity, and mediated by a membrane-bound protein. The inhibition profiles of 32P-ODN binding to EC and KC by various (poly)anions were essentially equal and corresponded closely to those of 125I-acetylated low-density lipoprotein. In summary, the results indicate that scavenger receptors on nonparenchymal liver and bone marrow cells contribute to the elimination of ODNs from the bloodstream. Minor changes in ODN sequence markedly affect receptor recognition, resulting in considerable shifts in the biodistribution of antisense ODNs.

Antagonists of the mannose receptor and the LDL receptor-related protein dramatically delay the clearance of tissue plasminogen activator.

BACKGROUND: Clinical application of tissue plasminogen activator (TPA) as a fibrinolytic agent is complicated by its rapid clearance from the bloodstream, which is caused by TPA liver uptake. The mannose receptor on endothelial liver cells and the LDL receptor-related protein (LRP) on parenchymal liver cells were reported to contribute to liver uptake. METHODS AND RESULTS: In this study, we addressed whether TPA clearance can be delayed by inhibiting receptor-mediated endocytosis of TPA. A series of cluster mannosides was synthesized, and their affinity for the mannose receptor was determined. A cluster mannoside carrying six mannose groups (M6L5) displayed a subnanomolar affinity for the mannose receptor (Ki = 0.41 +/- 0.09 nmol/L). Preinjection of M6L5 (1.2 mg/kg) reduced the clearance of 125I-TPA in rats by 60% because of specific inhibition of the endothelial cell uptake. The low toxicity of M6L5, combined with its accessible synthesis and high specificity for the mannose receptor, makes it a promising agent to improve the pharmacokinetics of TPA. Blockade of LRP by 39-kD receptor-associated protein (GST-RAP) also inhibited TPA clearance by 60%. Finally, combined preinjection of M6L5 and GST-RAP almost completely abolished reduced liver uptake of TPA and delayed its clearance by a factor of 10. CONCLUSIONS: It can be concluded that (1) the mannose receptor and LRP appear to be the sole major receptors responsible for TPA clearance and (2) therapeutic levels of TPA can be maintained for a prolonged time span by coadministration of the aforementioned receptor antagonists.

Induction of hepatic uptake of lipoprotein(a) by cholesterol-derivatized cluster galactosides.

We have previously developed triantennary galactosides [TG(4A)C and TG(20A)C] that lower cholesterol levels by inducing liver uptake of lipoproteins via galactose-recognizing hepatic receptors. In this study, we have investigated whether this strategy could also be applied to reduce elevated serum levels of the atherogenic lipoprotein(a) [Lp(a)]. Both TG(4A)C and TG(20A)C could be incorporated into Lp(a). Incorporation of these glycolipids induced a rapid clearance of Lp(a). Concomitantly, the hepatic uptake of 125I-Lp(a) was enhanced from 4 +/- 1% to 80 +/- 4% of the injected dose for TG(4A)C (P < .0001) and to 17 +/- 4% of the injected dose for TG(20A)C (P < .006). TG(4A)C was apparently more effective in accelerating the serum decay of 125I-Lp(a), which may be caused by the higher hydrophobicity of this glycolipid relative to TG(20A)C. The TG(4A)C- and TG(20A)C-induced stimulation of the serum decay and liver uptake of 125I-Lp(a) could be significantly inhibited (> 85%) by preinjection of N-acetyl-galactosamine (150 mg), indicating that galactose-recognizing receptors are involved in the liver uptake of the glycolipid/Lp(a) complexes. The TG(4A)C-induced liver uptake of 125I-Lp(a) could be ascribed mainly to Kupffer cells (76 +/- 7%), whereas the parenchymal liver cell was the major site for liver uptake of TG(20A)C-laden 125I-Lp(a) (55 +/- 12%). In conclusion, both TG(4A)C and TG(20A)C stimulate the catabolism of 125I-Lp(a) by enhancing hepatic uptake. Because endocytosis of the substrate via galactose-recognizing receptors on Kupffer and parenchymal liver cells is followed by lysosomal degradation, we anticipate that both approaches for Lp(a) targeting may prove valuable as therapeutic modalities for lowering atherogenic levels of Lp(a).

Increased selective uptake in vivo and in vitro of oxidized cholesteryl esters from high-density lipoprotein by rat liver parenchymal cells.

Oxidation of low-density lipoprotein (LDL) leads initially to the formation of LDL-associated cholesteryl ester hydroperoxides (CEOOH). LDL-associated CEOOH can be transferred to high-density lipoprotein (HDL), and HDL-associated CEOOH are rapidly reduced to the corresponding hydroxides (CEOH) by an intrinsic peroxidase-like activity. We have now performed in vivo experiments to quantify the clearance rates and to identify the uptake sites of HDL-associated [3H]Ch18:2-OH in rats. Upon injection into rats, HDL-associated [3H]Ch18:2-OH is removed more rapidly from the circulation than HDL-associated [3H]Ch18:2. Two minutes after administration of [3H]Ch18:2-OH-HDL, 19.6 +/- 2.6% (S.E.M.; n = 4) of the label was taken up by the liver as compared with 2.4 +/- 0.25% (S.E.M.; n = 4) for [3H]Ch18:2-HDL. Organ distribution studies indicated that only the liver and adrenals exhibited preferential uptake of [3H]Ch18:2-OH as compared with [3H]Ch18:2, with the liver as the major site of uptake. A cell-separation procedure, employed 10 min after injection of [3H]Ch18:2-OH-HDL or [3H]Ch18:2-HDL, demonstrated that within the liver only parenchymal cells take up HDL-CE by the selective uptake pathway. Selective uptake by parenchymal cells of [3H]Ch18:2-OH was 3-fold higher than that of [3H]Ch18:2, while Kupffer and endothelial cell uptake of the lipid tracers reflected HDL holoparticle uptake (as analysed with iodinated versus cholesteryl ester-labelled HDL). The efficient uptake of [3H]Ch18:2-OH by parenchymal cells was coupled to a 3-fold increase in rate of radioactive bile acid secretion from [3H]Ch18:2-OH-HDL as compared with [3H]Ch18:2-HDL. In vitro studies with freshly isolated parenchymal cells showed that the association of [3H]Ch18:2-OH-HDL at 37 degrees C exceeded [3H]Ch18:2-HDL uptake almost 4-fold. Our results indicate that HDL-associated CEOH are efficiently and selectively removed from the blood circulation by the liver in vivo. The selective liver uptake is specifically exerted by parenchymal cells and coupled to a rapid biliary secretion pathway. The liver uptake and biliary secretion route may allow HDL to function as an efficient protection system against potentially atherogenic CEOOH.

[Testicular epidermoid cyst: orchiectomy or enucleation resection?]. / Testikuläre Epidermiszyste: Orchiektomie oder Enukleationsresektion?

Our experience with 18 patients with simple epidermoid cysts of the testis is reported. In each patient the tumour was enucleated completely and two biopsies of the adjacent parenchyma were obtained for exclusion of associated germ cell cancer, scars or carcinoma in situ. There was no evidence of malignancy in any of the biopsy specimens. Preoperative evaluation included physical examination, testicular sonography, and determination of AFP and hCG serum levels. Although epidermoid cyst can be strongly suspected on sonography the ultrasound appearance is not specific, and inguinal testicular exploration was required in these patients. In 1 patient multiple epidermoid cysts of the right testis were associated with an adult teratoma containing embryonal carcinoma and choriocarcinoma of the left testis; no similar case has been described in the literature. On the basis of our results and experience we consider tumour enucleation and biopsy of the adjacent parenchyma to be adequate treatment for benign epidermoid cyst. The world literature concerning organ-sparing surgery in testicular epidermoid cyst is reviewed.

Organ preserving surgery in testicular epidermoid cysts.

Our experience with 18 patients with simple epidermoid cysts of the testis (monodermal teratoma) is reported. In all patients the tumor was enucleated completely and 2 biopsies of the adjacent parenchyma were obtained for exclusion of associated germ cell cancer, scar or carcinoma in situ. There was no evidence of malignancy in any biopsy specimen. Preoperative evaluation included physical examination, testicular sonography, and determination of alpha-fetoprotein and beta-human chorionic gonadotropin levels. Although epidermoid cyst was strongly suggested by sonography, the ultrasonic appearance was not specific and inguinal testicular exploration was required. In 1 patient multiple epidermoid cysts of the right testis were associated with an adult teratoma containing embryonal carcinoma and choriocarcinoma of the left testicle. To our knowledge no similar case has been described in the literature. Based on our results and our experience, we consider tumor enucleation and biopsy of the adjacent parenchyma as adequate treatment for the benign epidermoid cyst. The literature concerning organ sparing surgery in testicular epidermoid cysts is reviewed.

Cholesterol derivative of a new triantennary cluster galactoside lowers serum cholesterol levels and enhances secretion of bile acids in the rat.

BACKGROUND: Previous studies have demonstrated that cholesterol-derivatized galactosides exert a hypocholesterolemic effect by inducing hepatic uptake of atherogenic lipoproteins by means of galactose-recognizing receptors in the liver. However, a prolonged infusion of high concentrations of these compounds was required for this effect, possibly because of low affinity for the galactose-recognizing asialoglycoprotein receptor on the parenchymal liver cell. METHODS AND RESULTS: We have designed a new series of triantennary galactosides to optimize the affinity and specificity for this receptor. The affinity of a triantennary galactoside for the asialoglycoprotein receptor appeared to be dramatically enhanced by proper spacing of the three terminal galactose groups. In rats, a single injection of N-[tris-O-(3,6,9-trioxaundecanyl-beta-D-galacto- pyranosyl)methoxymethyl]methyl-N alpha-[1-(6-(5-cholesten-3 beta- yloxy)glycyl)adipyl]glycinamide [TG(20A)C], the cholesterol derivative of the most selective galactoside, causes a dose-dependent decrease of < or = 45% in the serum cholesterol concentration (P < .001). This decrease is mainly attributed to a decrease in the level of serum HDL (P = .0066) and, to a lesser extent, serum LDL (P = .036). In addition, TG(20A)C strongly enhances the bile-acid secretion in rats during the first 2 hours after administration, which indicates that TG(20A)C-induced clearance of cholesterol from the bloodstream is efficiently coupled to hepatic bile-acid secretion. CONCLUSIONS: We conclude that TG(20A)C efficiently directs lipoproteins that contain cholesterol to the liver at a 30-fold-lower concentration than previously developed cholesterol-derived cluster galactosides. This newly developed approach to lower cholesterol levels may prove valuable for familial hypercholesterolemic patients or those with familial defective apolipoprotein B-100 who do not respond or who respond insufficiently, respectively, to conventional therapies.

A conservative approach to bilateral testicular germ cell tumors.

We report on 6 patients with bilateral testicular germ cell tumors treated by organ sparing surgery. Tumors 6 to 30 mm. in diameter were enucleated, and biopsies of the tumor bed and peripheral parenchyma were taken. Histological examination revealed seminoma in 4 cases, embryonal carcinoma in 1 and a Leydig cell tumor in 1. All patients underwent testicular radiation therapy with 20 Gy. for carcinoma in situ. A testicular biopsy was performed 6 months postoperatively to evaluate therapeutic success. Median followup was 43 months, all patients were free of disease and there was no local recurrence. Luteinizing hormone and testosterone were within the normal range and no androgen substitution was necessary. Our study suggests that organ sparing surgery for bilateral testicular germ cell tumors represents a new therapeutic approach with endocrinological and psychological advantages. In our experience conservative surgery is possible under certain prerequisites, including organ confined tumor without infiltration of the rete testis, obtaining multiple biopsies of the tumor bed and peripheral parenchyma, associated carcinoma in situ treated by radiation therapy and close followup of patients.

Diagnosis of penile hemangioma by use of biopty gun for corpus cavernosum biopsy.

Penile hemangiomas are very uncommon mesenchymal tumors with less than 20 cases described in the literature. We report on a case of sclerosing hemangioma of the corpus cavernosum diagnosed by MRI and needle biopsy. MRI could delineate the exact anatomical relationship of the hemangioma, corpus cavernosum, tunica albuginea and Buck's fascia. However, the tumor revealed an unspecific inhomogeneous high and low signal intensity shown to be typical for carcinoma, inflammation, fibrosis or plaques. MRI cannot distinguish between benign and malignant penile tumors. A needle biopsy was performed with the Biopty gun and a good tissue sample was obtained for pathological analysis. Our case report demonstrates that this technique is rapid, safe, painless and effective in obtaining adequate tissue samples for microscopic studies. Since sclerosing hemangioma is a benign tumor and the patient was asymptomatic, no further treatment had to be performed.

Specific targeting of the antiviral drug 5-iodo 2'-deoxyuridine to the parenchymal liver cell using lactosylated poly-L-lysine.

In this study, we describe the development and characterization of lactosylated poly-L-lysine as a potential carrier for targeting anti-viral drugs to the parenchymal liver cell. Poly-L-lysine (M(r) 38,000) was modified with 2 to 130 lactose residues per molecule poly-L-lysine. In vitro competition studies for the asialoglycoprotein receptor on parenchymal liver cells using 125I-asialoorosomucoid as radioligand revealed that mild modification of poly-L-lysine with only five lactose residues was sufficient for high affinity competition. In vivo studies showed that, after injection of poly-L-lysine modified with at least five lactose residues, about 70-80% of the injected dose was taken up by the liver. Preinjection of N-acetyl galactosamine almost completely blocked the hepatic uptake of lactosylated poly-L-lysine, indicating that galactose-recognizing receptors are involved. At 10 min following injection, the contribution of the various liver cell types to the hepatic uptake of lactosylated poly-L-lysine was determined; the parenchymal cell appeared to be responsible for more than 98% of the total liver uptake. To assess the applicability of lactosylated poly-L-lysine as an anti-viral drug carrier, it was derivatized with 4 to 15 residues of the antiviral drug 5-iodo 2'-deoxyuridine, 5'-monophosphate per molecule poly-L-lysine (4-16% by weight) via an acid-labile phosphamide bond. Maximally 0.7% of the conjugated 5-iodo 2'-deoxyuridine 5'-monophosphate was released after 1 h incubation of the drug/carrier conjugate with serum at 37 degrees C, thus establishing the stability of the conjugate in serum. The drug-carrier conjugate was rapidly cleared from the bloodstream within 1 min. Approximately 90% of the injected dose could be recovered in the liver. The parenchymal liver cell was responsible for 97% of the hepatic uptake. In vitro studies on the kinetics of endocytosis of lactosylated poly-L-lysine, derivatized with 5-iodo 2'-deoxyuridine 5'-monophosphate, by parenchymal liver cells revealed that the ligand was immediately internalized and, after a 10-min lag phase, deacetylated. Internalization and degradation did not occur in the presence of 100 mM N-acetyl galactosamine. In conclusion, the bioavailability of 5-iodo 2'-deoxyuridine 5'-monophosphate to the parenchymal liver cell is dramatically enhanced as a result of the conjugation of the anti-viral drugs to lactosylated poly-L-lysine. Accordingly, lactosylated poly-L-lysine constitutes a suitable carrier for targeting anti-viral drugs to the parenchymal liver cell.(ABSTRACT TRUNCATED AT 400 WORDS)

Cholesterol derivative of a new triantennary cluster galactoside directs low- and high-density lipoproteins to the parenchymal liver cell.

We have developed a new triantennary galactoside, in which the terminal galactose moieties are connected to the branching point of the cluster galactoside via a 20 A (2 nm) spacer [TG(20A)]. In vitro binding studies have demonstrated that introduction of a 20 A spacer resulted in avid and specific binding of the triantennary galactoside to the asialoglycoprotein receptor on the parenchymal liver cell. Derivatization of this galactoside with a cholesterol moiety afforded a compound [TG(20A)C] that lowered the serum cholesterol concentration when injected into rats. In the present study we have evaluated the direct effect of TG(20A)C on the in vivo fate of high-density lipoprotein (HDL) and low-density lipoprotein (LDL). A direct association of TG(20A)C with HDL and LDL was observed on mixing these components. Incorporation of TG(20A)C into 125I-HDL and 125I-LDL significantly accelerated the serum decay and concomitantly stimulated the hepatic uptake of these lipoproteins in rats. The liver uptake of TG(20A)C-loaded 125I-HDL or 125I-LDL could be inhibited by 81% and 82% respectively by preinjection of 150 mg of N-acetylgalactosamine, indicating that the enhanced liver uptake proceeded via galactose-specific receptors. More than 96% of the hepatic uptake of TG(20A)C-loaded 125I-HDL could be attributed to the parenchymal cell. Surprisingly, the parenchymal cell also accounted for 93% of the liver association of TG(20A)C-loaded 125I-LDL, suggesting that TG(20A)C stimulates the uptake and processing of both lipoproteins by the asialoglycoprotein receptor on the parenchymal liver cell. This contrasts with earlier data indicating that a triantennary cluster galactoside provided with a 4 A spacer between the terminal galactose moieties and the branching point of the dendrite stimulated hepatic uptake of LDL via the Kupffer cells. The parenchymal cell is the only liver cell type that is capable of irreversibly removing cholesterol from the body in the form of bile acids. The above results imply that administration of TG(20A)C not only facilitates the hepatic uptake of lipoprotein-derived cholesterol (esters) but also their elimination from the body. In addition, it might be possible to utilize TG(20A)C as a targeting device to selectively deliver large drug carriers and possibly genes to the parenchymal liver cell.

[Organ saving therapy of bilateral testicular tumor]. / Die organerhaltende Therapie des bilateralen Hodentumors.

Of 368 patients with unilateral testicular cancer, 12 (3.3%) suffered from a second malignant germ cell tumor; five tumors occurred synchronously, seven were treated by bilateral orchiectomy, five were treated by unilateral organ sparing surgery with enucleation of the germ cell tumor in a pilot study. Enucleation was performed for four seminomas and one embryonal carcinoma; an associated carcinoma was found in situ in three cases. The average follow-up time for patients treated conservatively is 22 months; no local recurrence has been detected. Testosterone synthesis is sufficient to obtain normal serum androgen levels. Organ sparing surgery for testicular cancer is possible if the following prerequisites are met: pT 1-tumor, no infiltration of the rete testis, biopsies of the tumor bed are negative, biopsies from peripheral parenchyma are taken and any associated carcinoma in situ is irradiated with 20 Gy.

[Hemangioma of the glans penis. Its therapy by neodymium:YAG laser]. / Hämangiom der Glans penis. Therapie mittels Neodym:YAG-Laser.

We report the case of a young male patient with a massive cavernous hemangioma of the glans penis that had developed since childhood. The patient complained of pain when standing for long periods and during erections; furthermore its appearance disturbed him for cosmetic reasons. After associated hemangiomas of the genitourinary tract had been excluded by ultrasonography, intravenous pyelogram and cystoscopy, laser coagulation of the hemangioma was performed with a neodymium:YAG laser with the patient under local anaesthesia. The results of this conservative form of therapy show that it represents an alternative to surgical procedures; we recommend laser coagulation as the treatment of choice in patients with penile hemangiomas. The pertinent literature is reviewed.

[The synchronous appearance of multiple testicular epidermoid cysts and of a malignant mixed germinal tumor in the contralateral testis]. / Synchrones Auftreten multipler testikulärer Epidermoidzysten und eines malignen germinalen Mischtumors im kontralateralen Hoden.

We describe the simultaneous appearance of multiple epidermoid cysts in the right and an adult teratoma containing embryonal carcinoma and choriocarcinoma in the left testis. No similar case has previously been described. Epidermoid cysts of the testis are rare, accounting for about 1% of all testicular tumors. Epidermoid cysts are now regarded as monoepidermally developed teratomas of germ cell origin. Testicular teratomas in adults, however, are always malignant. Because epidermoid cysts are rare tumors, primary therapy often consists in ablation of the testis. In the case described, excision of the epidermoid cyst protected the patient from complete castration. This case demonstrates the simultaneous appearance of a malignant and a benign testicular germ cell tumor.

[Results of close testicular tumor after-care]. / Ergebnisse einer engmaschigen Hodentumornachsorge.

Close monitoring schedules for patients with malignant germ cell tumors improved cure rates, since early detection and treatment of tumor recurrences was possible. In a retrospective analysis we evaluated 210 of 274 patients with malignant germ cell tumor, 189 (90%) of whom achieved complete remission after primary therapy. There were 15 patients (7.9%) who experienced tumor relapse, 14 patients attaining complete remission after a second treatment. Out of these, 4 patients experienced a second relapse after 5 months. In 2 patients only, a third complete remission was obtained. A total of 3 patients died to their disease. The 19 recurrences were detected by clinical symptoms in 4 cases, by chest X-ray in 10, and by elevation tumor markers in 5. In 6 patients a second malignant germ cell tumor was discovered during follow up by palpation of the testis (n = 4) or marker elevation (n = 2). A second complete remission was achieved in 5 of these patients, while 1 died of chemotherapy-induced sepsis. Of the 19 tumor recurrences, 17 were detected within the first 2 years. The patients with a second malignant germ cell tumor perceived their disease within the first 5 years in 83% of cases. These results support the necessity on close monitoring for a minimum of 5 years after the initial treatment. After 5 years yearly examination is recommended for early detection of any late recurrences and second malignant germ cell tumors.

[Adjuvant systemic interferon alpha-2B treatment in treatment refractory anogenital Condylomata acuminata]. / Adjuvant-systemische Interferon-alpha 2B-Behandlung bei therapieresistenten anogenitalen Condylomata acuminata.

Despite different treatment modalities, resistance to treatment is observed in 4-15% of patients with anogenital condylomata acuminata. A total of 16 patients with resistant condylomata acuminata or extended infection affecting an area of more than 6 cm2 were treated with a prospectively defined therapy entailing laser treatment and adjuvant systemic interferon-alpha 2B (3 x 1 MU/day for 7 days). Of the 16 patients, 13 (81%) were in complete remission after an 8-month period of follow up. The typical side-effects of interferon were attenuated in 80% of cases by simultaneous paracetamol (3 x 500 mg/day). The combination of laser treatment and adjuvant systemic interferon-alpha 2B seems to be highly effective in the treatment of resistant or extended condylomata acuminata. At present, these results are being tested for significance in a prospectively randomized study.

[Penis plication-plasty--an alternative to the treatment of penile deviation]. / Die Penisraffplastik--eine Alternative zur Behandlung der Penisdeviation.

Congenital and acquired penile curvature are observed increasingly often. A new surgical technique (plicating procedure) was applied in 27 patients with penile deviation. All patients retained potency, and 96% were completely satisfied with the functional result of surgical correction. No severe complications were observed. Nesbit's technique of excising ellipses from the tunica albuginea to correct penile deviation should be discontinued as it involves greater surgical trauma. Since the functional and cosmetic results are equally good with the plicating procedure, we believe this is the operation of choice for the correction of penile curvature.