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Biomedical subjects

G Bartsch

Publications and source records attributed to G Bartsch.

At least 235 records · Page 13Linked to original sources
PubMed1994

Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor.

Aberrant activation of the androgen receptor (AR) may be one of the mechanisms which contribute to progression of prostatic carcinoma to an androgen-independent stage. We investigated effects of growth factors on stimulation of the AR-mediated gene transcription in human prostatic tumor cell lines. DU-145 cells, which do not contain endogenous AR, were cotransfected with an androgen-inducible chloramphenicol acetyltransferase (CAT) reporter gene and an AR expression vector. The reporter gene (CAT) was driven either by artificial promoters consisting of one or two androgen-responsive elements in front of a TATA box or by the promoter of the prostate-specific antigen (PSA) gene, a naturally occurring androgen-inducible promoter. Insulin-like growth factor-I (IGF-I), at a concentration of 50 ng/ml, stimulated AR-mediated reporter gene transcription to the same extent as the synthetic androgen methyltrienolone. This growth factor was effective irrespective of the nature of the androgen-inducible promoter. Keratinocyte growth factor (KGF) and epidermal growth factor (EGF), at concentrations of 50 ng/ml, activated CAT reporter gene transcription only in experiments in which the artificial promoter with two androgen-responsive elements was used. Insulin-like growth factor-II and basic fibroblast growth factor displayed no effect on AR-mediated gene transcription. None of the growth factors stimulated reporter gene activity in control experiments when added to cells cotransfected with the CAT gene and an empty expression vector. AR activation by IGF-I, KGF, and EGF was completely inhibited by the pure AR antagonist casodex, showing that these effects are AR mediated. Activation of endogenous AR by growth factors was studied in the LNCaP cell line by determination of PSA secretion. IGF-I, at a concentration of 50 ng/ml, increased the PSA level in the supernatant of this cell line 5-fold. Again, the IGF-I effect on PSA secretion was blocked by casodex. Our results provide evidence that IGF-I, KGF, and EGF directly activate the AR in the absence of androgens, which means that the androgen-signaling chain may be activated by growth factors in an androgen-depleted environment. These findings may have implications for endocrine therapy for metastatic prostatic carcinoma.

Androgen Antagonists↗
PubMed1994

Androgen receptor alterations in prostatic carcinoma.

Intracellular action of androgens is mediated by the androgen receptor (AR), which is a key element of the androgen signal transduction cascade and a target of endocrine therapy for prostatic carcinoma. Therefore, the qualitative and quantitative alterations of AR expression in prostatic carcinomas and their possible implications for tumor progression and treatment are of great interest. Findings in prostatic tumor cell lines of rat and human origin suggest a reduction of AR protein expression accompanied by an increase in tumor malignancy. However, immunohistochemical studies and binding assays demonstrated presence of ARs in all histological types of prostatic tumors, in therapy-responsive as well as in therapy-unresponsive ones. AR content of prostatic tumor specimens did not correlate with outcome of endocrine therapy of advanced prostatic carcinoma in these studies. Solely the degree of heterogeneity of AR expression may be useful as an indicator of responsiveness to therapy. AR mutations have been detected in the LNCaP cell line and in three primary prostatic tumor specimens. Three of them are point mutations in the hormone-binding domain of the AR, the fourth mutation is a CAG-microsatellite depression in the N-terminus. Evidence coming from studies on AR in prostatic cancer highlights the possibility that AR structural alterations may have significance in tumor progression.

Animals↗
PubMed1994

Androgen signal transduction and prostatic carcinoma.

In the prostate, androgen action affects the growth of the gland, its morphology, and regulation of protein expression. Endocrine therapy of non-organ-confined tumors is based on the androgen dependence of the vast majority of prostatic carcinomas. Although initial response rates are high, this therapy is only temporarily effective. Critical molecular changes ultimately resulting in androgen independence of tumor cells are unknown at this time. The androgen signal-transduction cascade and its central element, the androgen receptor (AR), are possible targets for such changes. Immunohistological analysis using anti-AR antibodies has revealed the presence of AR in a vast majority of therapy-responsive as well as therapy-unresponsive prostatic carcinomas, indicating that loss of AR expression is not the reason for androgen independence. On the other hand, molecular-biology studies have revealed qualitative and quantitative impairment of AR expression in prostatic tumor cell lines that represent very late stages of prostatic carcinoma development. Mutant ARs were detected in the prostatic tumor cell line LNCaP and in two specimens from primary prostatic tumors. The LNCaP mutant AR as well as mutant AR715met, one of the mutant receptors detected in tumor tissue, show a gain of function as compared with the wild-type receptor. In addition to androgens, the natural activators of the AR, the LNCaP receptor is activated also by progestagenic and estrogenic steroids and by the nonsteroidal antiandrogen flutamide. AR715met is activated by adrenal androgens and progesterone in addition to androgens.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgens↗
PubMed1994

Laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous testicular tumor.

OBJECTIVES: An appropriate laparoscopic technique for diagnostic retroperitoneal lymph node dissection in clinical Stage I testicular tumors is presented and its efficiency and morbidity are evaluated. METHODS: A two-step procedure has been developed. In the first step, a ventral approach is used. The colon is dissected free, then the spermatic vein is excised and the borders of dissection are defined. Via the ventral approach removal of retroaortic and retrocaval nodal tissue is technically not feasible. Therefore, in the second step, a lateral approach is used, which is the key to success because it permits straightforward transection of the lumbar vessels. Thus, complete lymph node dissection within the boundaries described by Weissbach can be achieved. Between August 1992 and March 1994, this procedure was performed in 15 patients. In 9 patients, the tumor was on the right side and in 6 it was on the left. RESULTS: Conversion to open surgery was necessary in 2 patients because of uncontrollable bleeding and a large metastasis. Microscopic metastasis were detected in 2 other patients. Apart from the bleeding just mentioned, no major complications occurred; no blood transfusions were required. CONCLUSIONS: The results obtained so far demonstrate that the technique is feasible and decreases postoperative morbidity. It therefore warrants further consideration.

Adult↗
PubMed1994

Laparoscopic repair of pediatric hydroceles.

An open processus vaginalis presenting as hydrocele was transected by means of laparoscopy in four boys aged between 2 and 5 years. In one boy, the internal ring was narrowed with one interrupted suture. In another, an asymptomatic indirect hernia was detected during laparoscopy, and herniorrhaphy was performed by suturing the internal oblique muscle to the inguinal ligament.

Child, Preschool↗
PubMed1994

[Laparoscopic interventions in pediatric urology].

Between January 1992 and June 1993 a total of 36 children underwent laparoscopic surgery in our department. On account of its superior validity, diagnostic laparoscopic surgery for nonpalpable testicles has become a viable alternative to the currently available imaging techniques. Furthermore, diagnostic laparoscopy has the benefit of enabling the surgeon to proceed directly with adequate therapy. Our results gained in 29 pediatric laparoscopic procedures for varicoceles show that it is a very efficient technique that entails few complications. The varicocele persisted in only 1 of the 29 children. In 2 patients laparoscopic nephrectomy was performed, which in technical terms turned out to be less complicated than in adults. Postoperatively, 1 patient developed an incarcerated hernia at the site of trocar insertion. In 2 patients a laparoscopic Lich-Gregoir procedure was performed for vesicoureteral reflux, which, however, cannot yet be considered a viable alternative to the conventional operative techniques.

Adolescent↗
PubMed1994

[Laparoscopic retroperitoneal lymph node excision in clinical stage I non-seminomatous testicular cancer].

Modified retroperitoneal lymph node dissection for stage I testicular tumors has been described by Weissbach. For performing laparoscopic retroperitoneal lymphadenectomy within these boundaries, we have developed a two-step procedure. In the first step, a ventral approach is used. The colon is dissected free, then the spermatic vein is excised, and the borders of dissection are defined. Removal of retroaortic and retrocaval nodal tissue is technically not feasible from the ventral approach. Therefore, in the second step, a lateral approach is employed, which is the key to success since it allows for easy transection of the lumbar vessels. Thus complete lymph node dissection can be realized. Between August 1992 and June 1993 this procedure was performed in 11 patients. In 7 patients, the tumor was on the right side and in 4 on the left. Conversion to open surgery was necessary in two patients because of uncontrollable bleeding and a large metastasis, respectively. Microscopic metastases were detected in two other patients. No major complications occurred; no blood transfusions were required. So far, the results have been encouraging.

Adult↗
PubMed1994

[Value of the neurovascular guide plate for pelvic surgery].

In the past few years great effort has been made to reduce the morbidity after oncologic operations in the small pelvis of the male. In this respect it is essential for urologic surgeons to orient themselves with the anatomic structures that mark the course of the important vessels and nerves. For this reason an anatomic study of the connective tissue in the male pelvis was performed in which dissections and serial sections were analyzed. The results show that the connective tissue in the male pelvis does not represent a monomorphic block but consists of several portions of varying density. The looser portions are also known as the "connective tissue spaces" of the pelvis. The comparatively dense portions--the so-called "vessel-nerve guiding plate" and its three "connective tissue pillars"--envelop the vessels and nerves supplying the corresponding pelvic organs. Therefore, they provide ideal landmarks for urologic surgery.

Adult↗
PubMed1994

[Report of experience in reconstruction of the lower urinary tract in the man and woman].

For some decades uretero(ileo) cutaneostomy and ureterosigmoidostomy were the methods of choice for urinary diversion in cystectomized patients. In recent years, lower urinary tract reconstruction with an anastomosis from an intestinal urinary reservoir to the urethra has established itself as an alternative for male patients undergoing cystectomy. We present the results obtained in 35 patients (32 men, 3 women) who chose to have a ureteroileal urethrostomy to the residual urethra after radical cystectomy for bladder cancer. These patients were followed up by clinical, serologic, radiographic, and urodynamic evaluation conducted at short intervals according to a strict protocol. There was no perioperative mortality, and the early postoperative complication rate was 17% (6/35 patients). For all patients, including those followed only for 3 months so far, the diurnal continence rate was 87% and the nocturnal continence rate was 78%. In every patient, male and female, the maximum urethral pressure (average value in the urethra pressure profile 50.8 cm H2O) was higher than the average resting intraluminal pressure in the pouch (average 12 cm H2O) with physiologic capacity (250-550 ml) of the urinary bladder. Patient acceptance, measured on a numerical self-rating scale, was high (average value 8.75 out of 10).

Adult↗
PubMed1993

Psychosocial effects of unrelated bone marrow donation: experiences of the National Marrow Donor Program.

In this study, we investigated the psychosocial effects of unrelated marrow donation. Survey questionnaires were administered pre-donation, shortly post-donation, and 1 year post-donation to all donors through the National Marrow Donor Program over a 3-year period. Univariate, bivariate, and multivariate analyses were then performed. Donors were generally quite positive about the donation 1 year post-donation: 87% felt it was "very worthwhile" and 91% would be willing to donate again in the future. Marrow donors were more likely than kidney donors to feel better about themselves as a result of the donation (P < .001). Donors with longer collection times, in general, had less positive psychosocial outcomes from the donation. Donors who experienced lower back pain or difficulty walking as a result of the donation were more likely to experience the donation as more stressful and painful than expected, but no more likely to experience it as less positive emotionally than donors who did not experience these side effects.

Anesthesia↗
PubMed1993

Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program.

BACKGROUND AND METHODS: Allogeneic bone marrow transplantation is curative in a substantial number of patients with hematologic cancers, marrow-failure disorders, immunodeficiency syndromes, and certain metabolic diseases. Unfortunately, only 25 to 30 percent of potential recipients have HLA-identical siblings who can act as donors. In 1986 the National Marrow Donor Program was created in the United States to facilitate the finding and procurement of suitable marrow from unrelated donors for patients lacking related donors. RESULTS: During the first four years of the program, 462 patients with acquired and congenital lymphohematopoietic disorders or metabolic diseases received marrow transplants from unrelated donors. The probability of engraftment by 100 days after transplantation was 94 percent, although 8 percent of patients later had secondary graft failure. The probability of grade II, III, or IV acute graft-versus-host disease was 64 percent, and the probability of chronic graft-versus-host disease at one year was 55 percent. The rate of disease-free survival at two years among patients with leukemia and good prognostic factors was 40 percent and among patients at higher risk, 19 percent. Twenty-nine percent of the patients with aplastic anemia were alive at two years, and the rate of two-year disease-free survival among patients with myelodysplasia was 18 percent. For patients with congenital immunologic or nonimmunologic disorders, the probability of survival was 52 percent. CONCLUSIONS: The National Marrow Donor Program has benefited a substantial number of patients in need of marrow transplants from closely HLA-matched unrelated donors and has facilitated the recruitment of unrelated donors into the donor pool and the access to suitable marrow.

Adolescent↗
PubMed1993

Unrelated donor marrow transplantation therapy for chronic myelogenous leukemia: initial experience of the National Marrow Donor Program.

In the interval from December 1987 to November 1990, 196 consecutive patients with chronic myelogenous leukemia (CML) received unrelated donor marrow transplantation using marrow procured by the National Marrow Donor Program (NMDP) at 21 NMDP-affiliated marrow transplant centers. Baseline donor and recipient data as well as follow-up data were obtained systematically in all cases by the NMDP. The median interval from the initiation of a search for an unrelated donor to bone marrow transplantation was 8.4 months (range, 1.7 to 34.6 months). Median age of the recipients was 33.3 years (4.5 to 54.5 years). Seventy-five recipients were female and 121 were male. At time of transplant, 115 patients were in chronic phase, 51 in accelerated phase, 14 in blast crisis, and 16 in a second or subsequent chronic phase. In 133 cases, donors and recipients were identical at the HLA A, B, and DR loci using standard serologic typing, and in 63 cases, there was nonidentity at one HLA locus. Patients were prepared for transplantation with a combination of high-dose chemotherapy and total body irradiation (N = 169) or with high-dose chemotherapy only (N = 27). Thirty-five patients received marrow depleted ex vivo of T lymphocytes, whereas 161 patients received non-T-depleted marrow. One hundred seventy-four of 196 patients engrafted (absolute neutrophil count > or = 500/mm3 for 3 consecutive days). The median time to engraftment was 22 days (6 to 69 days). Twenty-two patients failed to engraft, and an additional 10 patients experienced late graft failure. The incidence of grades III or IV acute graft-versus-host disease (GVHD) was 0.54 +/- 0.10, and that of extensive chronic GVHD was 0.52 +/- 0.12. A lower incidence of both grades III and IV acute GVHD (P = .0003) and of extensive chronic GVHD (P = .01) were independently associated with use of T-depleted marrow. The actuarial incidence of hematologic relapse at 2 years is 0.11 +/- 0.06. The 2-year actuarial incidence of disease-free survival for patients transplanted in first chronic phase within 1 year of diagnosis is 0.45 +/- 0.21, in chronic phase more than 1 year from diagnosis is 0.36 +/- 0.11, in accelerated phase is 0.27 +/- 0.12, in second or subsequent chronic phase is 0.22 +/- 0.21, and in blast crisis is 0. Fifteen of 55 patients transplanted at 40 to 50 years of age survive.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Disease↗
PubMed1993

DNA sequence of the androgen receptor in prostatic tumor cell lines and tissue specimens assessed by means of the polymerase chain reaction.

Essentially all prostatic carcinomas relapse to an androgen-independent stage during androgen ablation therapy. The underlying genetic changes are still unclear. Such changes are suspected to affect the androgen-signalling pathway as well as growth promoting and inhibiting factors. This study was undertaken to test for structural changes of the androgen receptor in prostatic tumor cell lines and primary tumors. Complementary DNA (cDNA) fragments of the androgen receptor (AR) were isolated from the cell lines LNCaP, PC-3, and DU 145, ten tissue specimens obtained by radical prostatectomy, and five fine-needle biopsies by means of the polymerase chain reaction (PCR) technique. Fragments encoding the hormone- and DNA-binding domains were analyzed by DNA sequencing. The PCR technique is highly sensitive and especially recommended for the analysis of small tissue samples, such as those obtained by fine-needle aspiration. No alterations were detected in the tissue specimens and the five fine-needle aspirates. In the three tumor cell lines that represent late stages of prostatic tumor, different findings were obtained. The androgen-independent DU 145 cells did not express androgen receptors, whereas the PC-3 cells, which are also androgen-independent, expressed very low levels of normal AR. In contrast to this, the androgen-dependent LNCaP cells expressed high levels of structurally abnormal androgen receptors. These results suggest that androgen receptor mutations are probably uncommon molecular events in the early stages of prostatic cancer. Qualitative and quantitative changes, however, seem to occur in advanced prostatic cancer.

Base Sequence↗
PubMed1993

Characterization of two point mutations in the androgen receptor gene of patients with perineoscrotal hypospadia.

Perineoscrotal hypospadia is a major sign of sexual ambiguity due to inadequate androgen action in genetic and gonadal males. In patients showing these symptoms we have detected two androgen receptor gene mutations. In consequence we characterized the properties of the mutant receptors with respect to hormone-binding, transactivation and DNA-binding. An amino acid substitution alanine-596-->threonine in the D-box of the androgen receptor was detected in 3 and 2 brothers, respectively. This mutant receptor, AR-thr596, bound ligand in a normal fashion. It showed a promoter-dependent defect of transactivation and was unable to induce transcription of a promoter containing one androgen responsive element but showed almost wild-type transactivation of a promoter containing two closely spaced androgen-responsive elements. The complex promoter of the human prostate-specific antigen gene was induced with intermediate efficiency. In electrophoretic mobility shift assays AR-thr596 was unable to form a complex with oligonucleotides containing 1 or 2 androgen responsive elements, however its DNA-binding activity was restored by an anti-androgen receptor antibody in the presence of ligand. A point mutation which caused substitution of serine-703 in the hormone-binding domain with glycine was detected in a new-born male with ambiguous genitalia. This mutant receptor, AR-gly703, showed a reduced ligand affinity. The total amount of specific androgen binding sites in genital fibroblasts of the patient was reduced. Transactivation activity of AR-gly703 was dependent on hormone concentration. It was inactive at low levels of androgens but was fully activated in the presence of high androgen concentrations. The nature of the promoter had no effect on transactivation properties of this mutant androgen receptor. Its DNA-binding activity in gel shift experiments was normal.

Base Sequence↗
PubMed1993

Management of benign prostatic hyperplasia with particular emphasis on aromatase inhibitors.

The pathogenesis of human benign prostatic hyperplasia (BPH) has not been fully elucidated. There is, however, evidence that estrogens--besides other factors--might play an important role for the growth of the prostate. Consequently, estrogen deprivation might be a new, useful principle for a conservative treatment of BPH. Atamestane, a new, highly selective steroidal aromatase inhibitor has been proven to be successful in antagonizing experimentally-induced estrogen-related stromal overgrowth of the prostate in dogs and monkeys. Double-blind placebo controlled studies are now underway in Europe and the U.S.A. It is anticipated that these studies will give us a definite answer of the clinical validity of this concept in BPH patients in the near future. However, it is very important to take into consideration that for an effective treatment of BPH, a reduction of both the glandular and stromal elements has to be achieved. In other words, both androgens and estrogens seem to be involved in the regulation of (over)growth of the prostate. Therefore, a combination of an androgen and estrogen deprivation might be a more promising approach than any single treatment.

Androstenedione↗
PubMed1993

Posterior hypospadias: long-term followup after reconstructive surgery in the male direction.

Posterior hypospadias with a scrotal or perineal meatus results from a defect in step 3 of male sexual differentiation. The different etiological factors underlying this condition result in a broad spectrum of presentations ranging from the isolated form to complex ambiguity of the external genitalia, such as male pseudohermaphroditism. Between 1952 and 1988 a total of 92 patients with posterior hypospadias underwent a 2-stage reconstruction at our department. A retrospective study was performed with the aim of evaluating the long-term results in these patients. Our special interest focused on the functional and cosmetic results, exocrine and endocrine functions, as well as the sexual lives of the patients. While satisfactory results were obtained in two-thirds of the 42 male patients available for long-term followup, there were 13 patients who at followup still presented with complex sexual ambiguity. In 6 of these patients androgen receptor defects were detected by means of biochemical as well as molecular-biological investigations. Our data emphasize the importance of androgen metabolism for male sexual development and underline the necessity of careful evaluation in these children.

Adolescent↗