Localization and expression of adrenocorticotropic hormone receptor mRNA in normal and neoplastic human adrenal cortex.

The recent cloning of the ACTH receptor (ACTH-R) gene allows investigation of the tissue localization and relative abundance of ACTH-R mRNA in normal and neoplastic adrenal cortex. Using in situ hybridization (ISH) we studied the expression of ACTH-R mRNA in four adult adrenals of brain-dead patients, two cortisol-producing adenomas (CPA), three aldosterone-producing adenomas (APA), one non-functional adenoma (NFA), and three carcinomas. The results were compared with the mRNA expression of key steroidogenic enzymes and of the glucocorticoid receptor (GR) mRNA using Northern blotting. In adult adrenals, messenger RNA encoding ACTH-R was localized in all three zones of the adrenal cortex, in accordance with the stimulatory role of ACTH on mineralocorticoid, glucocorticoid and adrenal androgen secretion. In comparison, expression of side-chain cleavage enzyme (P450scc) showed a similar tissue distribution with mRNA abundance in all three zones, whereas 17-hydroxylase/17-20 lyase (P450c17) mRNA expression was only detected in the zona fasciculata and zona reticularis. All CPAs and APAs expressed significant levels of ACTH-R mRNA whereas an NFA showed low expression of ACTH-R mRNA. Two of three adrenocortical carcinomas expressed ACTH-R mRNA. Northern analysis using dot blot was employed to quantify ACTH-R and GR mRNA expression and confirmed the ISH data: ACTH-R mRNA expression was high in CPAs (275 and 195% vs 100 +/- 25% in adult adrenals), APAs (127, 200 and 221%) and two carcinomas (99 and 132%), but low in the NFA (7%) and in an androgen secreting carcinoma (16%). GR mRNA expression was high in the NFA (195%) and in two of three carcinomas (93, 188, 227%). We conclude that ACTH-R mRNA is upregulated in functional adenomas by yet unidentified mechanisms. The tissue distribution of ACTH-R and P450 enzyme mRNA expression is highly variable in neoplastic adrenals and does not allow a clear differentiation between benign and malignant tumors.

Atypical findings in a patient with a renal milk-of-calcium cyst.

A case of an atypical renal milk-of-calcium cyst is presented. Although this cyst contained a colloidal suspension of calcium crystals, other signs and findings typical for a milk-of-calcium cyst were lacking. No connection of the cyst to the collecting system could be identified, no "half moon" phenomenon was found on upright and cross-sectional radiography, and the biopsies taken from the wall of the cyst showed sclerosis instead of urothelium. From the present case it was concluded that renal milk-of-calcium cysts may sometimes occur in the absence of findings that are typical of this particular entity. Therefore, this disease should be considered in the differential diagnosis of renal calcifications of unknown origin.

In-vivo stimulation of cell-proliferation of 2 human tumor xenograft lines by granulocyte-macrophage colony-stimulating factor (gm-csf).

In the present work the effect of a colony stimulating factor (CSFs), i.e. recombinant human granulocyte-macrophage colony stimulating factor (rhGMCSF), on tumor cell proliferation of a human renal cell carcinoma (RCC) and a squamous cell carcinoma (SCC) xenotransplanted into nude mice was studied. The measurement of the H-3-thymidine labeling index and the mitotic index of the tumor cells of both tumor lines as a function of the GM-CSF dose (0.05-1.00 mu g/g body weight) showed that the cell proliferation in both tumor types increases at low doses (p<0.05). Furthermore, the course of the dose dependent stimulation of cell proliferation is somewhat different for each tumor line. This possible growth stimulating effect of the rhGM-CSF found in the present work for both xenotransplanted tumor types should be considered, when this substance is applied within therapeutic regimens. Intertumoral differences should also be regarded.

Treatment results and long-term follow-up in stage I seminoma patients.

Between 1979 and 1992 seventy-nine patients with seminoma were treated at our institution, 62 of them with stage I. The mean follow-up time was 6.0 years (range: 36 months to 14 years). Preoperatively, serum beta human chorionic gonadotropin (beta-HCG) was elevated in 12 cases (19%) without prognostic significance. In addition to orchiectomy, 57 patients with stage I seminoma of the testis received adjuvant radiotherapy (mean dose: 33 Gy). Two patients were treated with primary retroperitoneal lymph node dissection (RPLND) and one patient with cisplatin-based chemotherapy. In 2 cases a surveillance strategy was used. Three patients (5%) had a relapse of the seminoma (2 in the retroperitoneum and one suprainguinally). The time interval between orchiectomy and relapse was 5 to 60 months. Salvage treatment consisted of chemotherapy and RPLND in 2 patients and chemotherapy and resection of the suprainguinal recurrent mass in one patient, and was successful in all 3 patients. A total of 60 patients evaluated (100%) are still alive with no evidence of disease. In conclusion, adjuvant radiotherapy is considered the routine treatment in seminomas stage I despite studies with a 'wait and watch' policy or a carboplatin monotherapy.

Nobody needs "relative tumour sizes" to compare tumour growth curves.

Tumour growth curve experiments play an important role in experimental oncology and established methods exist for their unbiased interpretation. However, many authors till introduce systemic biases to their data by using the so-called "relative tumour size" transformation, inspite of wide awarance about the limitations of this latter method. With this communication and by using a fictive exaggeration of the problems connected with the application of this transformation we would like to appeal to both authors and reviewers likewise to ban this potential source of misinterpretation from the oncological literature.

Treatment with tumor necrosis factor alpha and interferon alpha of a human kidney cancer xenograft in nude mice: evidence for an anticachectic effect of interferon alpha.

Unfortunately the efficacy of the treatment of the metastatic or recurrent renal cell carcinoma (RCC) has not improved during the last few years. Recently effort has been put into the experimental and clinical evaluation of so-called "biological response modifiers" (BRM; cytokines and related peptides) as treatment modalities for RCC. The present results are, however, still disappointing. Since BRM, if applied alone, are largely ineffective as antineoplastic agents, more experimental studies are now necessary to test the antineoplastic value of their combinations, which seem to be more promising. In the present study, the in vivo effect of tumor necrosis factor a (TNF a) and/or interferon a (IFN a) on the macroscopic tumor growth (external caliper measurements of tumor size) and on the cell proliferation (in vivo 3H-thymidine labelling index, LI, and mitotic index, MI) of a human RCC xenograft line in nude mice has been investigated. Neither of these substances alone nor their combination was effective in changing the time course of the tumor sizes and the growth patterns of the treated tumors in a statistically significant manner as compared to the untreated controls. Also the cell kinetic parameters were only marginally affected by these treatments, whereby TNF a alone proved to be more effective than IFN a alone. However, compared to the effect of TNF alpha alone, the combination with IFN alpha leads to some amelioration of the cell kinetic perturbations and also to an appreciable shift in the growth patterns of the tumors from distinct Gompertzian (under TNF alpha alone) to near exponential (under the combination treatment; p < 0.05). As a consequence, the tumors grow more slowly under the combined treatment during the observation time, and on the other hand, their growth does not decelerate as much as under TNF alpha alone. Actually, if tumor growth continues in the same way, the extrapolation of the present data predicts smaller and greater tumors than the control tumors in the TNF alpha and in the combination treatment groups respectively. Notably, in the combination the effect of the IFN alpha seems to predominate. This is also seen in the effect of this combination on the cachexia of these tumor-bearing animals: either alone or in combination with TNF alpha, IFN alpha partially protects the animals from tumor-growth associated weight loss. Although the direct antineoplastic in vivo effect of the present cytokine combination against this human RCC xenograft line is rather limited, the potential antagonizing effect of IFN alpha on the development of cachexia should be further explored.

Expression of p53 and bcl-2 in primary locally confined renal cell carcinomas: no evidence for prognostic significance.

p53 tumor suppressor gene mutations are present in a wide variety of human cancers, and the bcl-2 gene product is considered to prevent apoptosis. However, the significance of these gene products for the aggressiveness of the tumor and correspondingly for the prognosis of patients with renal cell carcinoma (RCC) is unclear. The expression of p53 and bcl-2 gene products was studied immunohistochemically using formalin-fixed paraffinembedded tumor samples of 31 locally confined RCC of patients treated with radical nephrectomy. The significance of these 2 parameters, in addition to tumor stage and malignancy grade, was tested with regard to survival and time of no recurrence using Kaplan-Meier-plots by the log rank test or Tarone's test and the Cox multiple hazard regression analysis (mean follow-up 5.4 years). Only 5 of the 31 RCCs stained positively for p53 and only 2 showed positive bcl-2 staining of tumor cells. Tumor stage (P < 0.002) and malignancy grade (P < 0.007) were statistically significant prognostic parameters for both survival and disease-free period by univariate analysis. In contrast, the detection of either p53 (P > 0.67) or bcl-2 gene product (P > 0.28) had no prognostic impact. Also in the multivariate statistical analysis, neither of the 2 parameters i.e. p53 and bcl-2 expression significantly improved the prognostic impact of the conventional prognosticators stage and grade, if applied in addition. The expression of p53 and bcl-2 seems unimportant as a prognostic factor in locally confined RCCs.

[Transvaginal closure of vesicovaginal fistulas]. / Transvaginaler Verschluss von vesikovaginalen Fisteln.

The surgical management of vesicovaginal fistulae (VVF) is a matter of controversy. This study deals with our experience with transvaginally treated patients suffering from VVF. Between 1966 and 1996, 64 patients with VVF were treated surgically. The VVF occurred in the course of hysterectomy in 54 patients, was due to radiotherapy in 7, was a result of obstetric complications in 2 patients, and occurred after colporrhaphy in 1 patient. In 60 of these 64 patients closure of the fistula was carried out transvaginally. Fourteen of these 60 patients (23%) had undergone prior surgical attempts to close the VVF (1 to 3 procedures). Transvaginal surgery was successful at first attempt in 55 of these 60 patients (92%). The other 5 patients were successfully treated by a second procedure (again transvaginal: n = 3; transabdominal: n = 2). In conclusion, the transvaginal approach to close VVF is of advantage, avoiding an abdominal incision and reducing postoperative morbidity. In the vast majority of the cases isolated VVF can be treated successfully by transvaginal repair.

[Molecular genetic and cell biology principles for the development of malignant tumors]. / Molekulargenetische und zellbiologische Grundlagen der Entstehung von malignen Tumoren.

The development of cancer is one of the most intensively studied areas of medical research resulting in an immense quantity of data. Therefore, the purpose of this article is to give an overview of the basic principles of cancer development. Key words such as multi-step carcinogenesis, cell cycle, protooncogene, tumor suppressor gene, DNA repair gene, apoptosis and telomeres are explained and described in examples. This paper aims to connect recent information of molecular and cellular biology in an overview of cancer origin and development.

[Conservative therapy of blunt kidney injuries]. / Konservative Therapie des stumpfen Nierentraumas.

Forty-two patients with blunt renal injuries were treated between 1984 and 1994 at our institution. Twenty-nine patients revealed a contusion (grade I injury), 10 showed lacerations (grade II), 1 a severe fracture (grade III), and 2 presented pedicle injuries (grade IV). All 10 patients with incomplete renal injuries (grade II) were treated conservatively, i.e. without primary surgery. One of these 10 patients required surgical intervention 3 months after the trauma due to a urinary obstruction. Two of the ten patients with grade II injuries suffered late complications, namely a contracted kidney in one case and hypertension in the other. This means that of 10 patients with conservatively treated grade II renal trauma, a loss of the function of the affected kidney occurred in only one. In 9 patients complete function of the kidney could be preserved. In conclusion, conservative management of incomplete blunt renal injuries is an effective treatment option with few complications.

[Pneumoscrotum. Case report and review of the literature]. / Pneumoskrotum. Fallbericht und Literaturübersicht.

The rare case of a pneumopenis and pneumoscrotum after a thoracic operation is reported. Two subtypes--pneumatocele and subcutaneous emphysema of the scrotum--are differentiated on the basis of anatomy. The cases reported in the literature so far are reviewed. A therapeutic regimen is recommended.

[Results of 15 years of radical prostatectomy]. / 15-Jahres-Ergebnisse der radikalen Prostatektomie.

From July 1969 to May 1994, radical prostatectomy was performed in 630 patients with clinically localized prostate cancer at the Department of Urology, University of Würzburg Medical School. These included 74 patients subsequently followed up for 15 years or more 15 years (15-23 years, mean 17.5 years), who were the subjects of the present study. Of these 74 patients 59 had pT2 tumors and 10 had pT3 tumors according to the staging criteria of the 1992 edition of the UICC TNM classification. The remaining 5 patients had microscopic lymph node metastases detected at staging pelvic lymphadenectomy (stage pT2-3pN1-2). Patients with lymph node involvement were treated by immediate orchiectomy. All other patients received no further treatment until progression occurred. The overall 15-year survival rate actually observed the 74 patients was 50% (37/74) and the disease-free survival rate was 43.2% (32/74 pts). Stage-related overall and disease-free survival rates were found to be 54.2% and 49.1%, respectively, for patients with pT2 tumors, 40% and 30% for those with pT3 tumors, and 20% and 0 for patients with lymph node metastases. Progression (either local recurrence or distant metastatic spread) was noted in 22 of the 74 patients (29.7%) within the 15-year period following radical prostatectomy. Mean time to progression was 7.9 years (3 months to 17 years). Within the follow-up period, 17 patients (23%) died of prostate cancer. These actual 15-year follow-up data show radical prostatectomy to be the most effective means of achieving long-term disease-free survival, if not cure, in patients with clinically localized prostate cancer.

[Surgical treatment of metastases in renal cell carcinoma]. / Metastasenchirurgie beim Nierenzellkarzinom.

The aim of the present study was to investigate the efficacy of surgical excision of metastases in patients with renal cell carcinoma (RCC). Eighteen patients with metastatic RCC underwent resection of metastases between 1988 and 1994 (pulmonary: n = 6; skeletal: n = 6; cerebral: n = 3; local relapse: n = 3). Two patients suffered from synchronous appearance of metastases, whereas in 16 cases a metachronous occurrence was observed. In 12 out of a total of 18 patients metastases were completely resected. These patients survived longer than patients in whom metastases were incompletely resected (30 vs. 12 months). Six out of these 12 patients with a complete resection of metastases are presently free of disease for a mean duration of 24 months (10-34 months). The resection of lung metastases seems to be associated with longer survival times. In conclusion, surgical resection of metastases--solitary or single organ site--especially in the lung appears to be justified in patients with RCC. The surgical excision of skeletal metastases at least improves quality of life.

[Cosmetic and functional long-term outcome after operation of Fournier gangrene]. / Kosmetische und funktionelle Langzeitergebnisse nach Operation einer Fournier-Gangrän.

The study documents the long-term cosmetical and functional sequelae in 12 patients treated for Fournier's gangrene after an average of 5 years follow-up. Only 50% of the patients were free of pain. In the majority of cases, the sexual function was impaired by penile deviation or penile torsion as well as by a loss of sensitivity of the penile skin or pain during erection. Two patients suffered from temporary stool incontinence. Despite major complaints due to extensive scarring, most (10 of 12) patients considered their cosmetic result as well as their quality of life to be satisfactory.

[Colony stimulating factors in polychemotherapy of testicular tumors. A comparison between G-CSF and GM-CSF]. / Koloniestimulierende Faktoren bei der Polychemotherapie von Hodentumoren. Ein Vergleich zwischen G-CSF und GM-CSF.

Colony-stimulating factors (CSF) are frequently used in cases of cytostatic therapy of patients with testicular cancer assuming that they support hematopoietic recovery and, thus, shorten duration of neutropenia as well as reduce infections. Currently, G-CSF and GM-CSF are clinically used. In the present study efficacy and toxicity of these two drugs were investigated and compared in patients with testicular cancer treated by standard chemotherapy. Studying 83 chemotherapy cycles applied to 31 patients with advanced germ cell tumors the effectivity and the side effects of the two CSF were examined by questioning, clinical evaluation, and blood chemistry studies. G-CSF (480 micrograms subcutaneously (s.c.)) were used in 55 and GM-CSF (400 micrograms s.c.) in 28 chemotherapeutic cycles. The indications consisted in the treatment of leukocytopenia on the one hand and in the prophylaxis in subsequent cycles on the other hand. No difference between the two CSF could be found either with regard to postponement of the next cycle (G-CSF: 6.8 vs. GM-CSF: 7.3 days), or to the number of injections per cycle (G-CSF: 8 vs. GM-CSF: 12.5), or to the leukocyte (G-CSF: 2.1 vs. GM-CSF: 1.6 x 10(3)/microliter) or platelet nadir (G-CSF: 0.5 vs. GM-CSF: 0.5 x 10(5)/microliter; mean values of all cycles, respectively). Both CSF did not seem to influence the production of platelets. However, a difference between the two CSF was demonstrated with respect to the toxicity. Frequency (G-CSF: 38.5% vs. GM-CSF: 69.3%) as well as intensity of side effects causing a change of the drug (G-CSF: n = 1 vs. GM-CSF: n = 7) were lower in the case of G-CSF. In conclusion, these data demonstrate no difference was seen between G-CSF and GM-CSF with respect to the efficacy in patients with testicular cancer treated by standard chemotherapy. However, the use of G-CSF seems to be associated with lower toxicity.

[Radical prostatectomy as primary monotherapy in capsule penetrating prostatic carcinoma. 15 years outcome]. / Radikale Prostatektomie als primäre Monotherapie bei kapselüberschreitendem Prostatakarzinom. 15-Jahres-Ergebnisse.

Twenty-five patients with locally advanced prostate cancer (stage pT3pN0) underwent pelvic lymphadenectomy and radical prostatectomy and were followed up thereafter for at least 15 years. No hormonal treatment was given prior to tumor progression. Overall and disease-free 15-year survival rates were observed to be 44 and 24%, respectively. These data suggest that a cure from prostate cancer by radical prostatectomy can be expected in a quarter of patients with capsular penetration. From our results, no justification can be derived to exclude radical prostatectomy from the spectrum of treatment options for patients with capsular penetration of prostate cancer. More detailed analysis of the results depending on the local extent of the tumor and histological grade revealed distinct differences with respect to the risk of progression. Histological grade was the single most predictive parameter of progression. Out of all subgroups of patients with capsular penetration of prostate cancer, those with a poorly differentiated tumor showed the shortest progression-free interval after surgery, the highest level of overall progression and the largest proportion of tumor-related deaths. By contrast, the prognosis was only slightly influenced by the presence or absence of seminal vesicle involvement. The role of adjuvant treatment after radical prostatectomy for patients with stage pT3pN0 prostate cancer or for subgroups of them remains to be determined within the scope of prospective randomized trials.

[Lipoma of the adrenal gland. Case report and review of the literature]. / Lipom der Nebenniere. Fallbericht und Literaturübersicht.

Adrenal lipomas are extremely rarely occurring benign tumors being hormonally inactive. The patient described in this report underwent surgical excision of an adrenal lipoma because of the associated hypertension. The blood pressure decreased postoperatively to normal levels. This case report and the review of the literature consider diagnosis and therapy of the adrenal lipomas.

[Value of transrectal ultrasound in determining the T-stage of prostate cancer]. / Wertigkeit der transrektalen Sonographie bei der Beurteilung des T-Stadiums des Prostatakarzinoms.

Accurate preoperative staging of prostate adenocarcinoma is especially important before radical prostatectomy. The purpose of this prospective study was to investigate the staging accuracy of transrectal ultrasonography in prostatic adenocarcinoma. The results of the preoperative staging evaluation in 126 patients with endorectal ultrasound were compared with the histopathologic findings after radical prostatectomy. Correct staging by transrectal sonography was possible in 82 of 126 patients (65%). For stage pT3 tumors, sensitivity, specificity and positive predictive value were 69%, 51% and 82% respectively.

[Results of low dosage cyclic interferon-gamma therapy of metastatic renal cell carcinoma]. / Ergebnisse der niedrig dosierten zyklischen Interferon-Gamma-Therapie beim metastasierten Nierenzellkarzinom.

A total of 24 patients with metastatic renal cell carcinoma were treated with a low-dose cyclic regimen of interferon-gamma (IFN-gamma). The dosage was 50 micrograms IFN-gamma s.c. per day for 5 days every 4 weeks. In 16 of the 24 patients nephrectomy had preceded this treatment. Another immunotherapy had already been performed in 13 of the 24 cases. No complete remission was achieved in any of the patients, all of whom were evaluable. One patient with pulmonary metastases achieved partial response. Stable disease lasting 2 to 12+ months was seen in 5 cases. Tumour progression was observed in 18 patients. Only slight side-effects were noted. Patient selection could be one reason for the wide range of response rates reported for IFN-gamma treatment in the literature.

[Surgical interventions of the adrenal gland. Diagnosis and results of treatment]. / Operative Eingriffe an der Nebenniere. Diagnostik und Behandlungsergebnisse.

From 1982 to 1992, 33 patients underwent adrenalectomy for disease of the adrenal gland: 18 patients with adrenal cortex adenoma or hyperplasia (Cushing's syndrome n = 11, Conn's syndrome n = 6, adrenogenital syndrome n = 1), 3 with pituitary-dependent Cushing's disease, 7 with pheochromocytoma (malignant n = 1), 2 with a metastasis of lung cancer and 1 with cystic adrenal necrosis. Multiple endocrine neoplasia existed in four cases. Various preoperative symptoms were noted, including complaints typical of the respective syndromes and general abdominal symptoms. Other patients were symptom-free with incidental findings. An intercostal approach was used in 30 cases, a transabdominal approach in 3 cases. In 6 cases bilateral and in 27 cases unilateral adrenalectomy was performed. In two cases additional nephrectomy became necessary because of extensive adhesions. Intraoperatively, one patient suffered a blood pressure crisis. 31 patients are still alive and symptom-free after a mean follow-up of 5.4 years (range 1-11 years). Two patients have died (one with benign pheochromocytoma and one with a metastasis of lung cancer). Detailed preoperative hormone analysis and adequate preoperative medication substantially lowers the risk involved in adrenal surgery. However, the indications for surgical treatment of hormonally inactive, symptom-free adrenal tumors that are found incidentally remain controversial, and surgery should perhaps be restricted to large tumors.