Prognostic features of Ewing's sarcoma on plain radiograph and computed tomography scan after initial treatment.
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Base Sequence↗
Biomedical subjects
W Winkelmann
Publications and source records attributed to W Winkelmann.
Diagnostic value of the molecular genetic detection of the t(11;22) translocation in Ewing's tumours.
One consistent feature of the Ewing's tumour family is the presence of a balanced translocation involving band q12 and band q24 of chromosome 22 and chromosome 11. Recent cloning of the chromosome breakpoint regions of t(11;22)(q24;q12) Ewing's sarcoma translocation has revealed that the breakpoints were localized within the Ewing's sarcoma gene (EWS gene) on chromosome 22 and the Fli-1 gene on chromosome 11. Molecular genetic techniques can thus be applied to the detection of the t(11;22) translocation in Ewing's tumours. By reverse transcription and polymerase chain reaction technique (RT-PCR) 11 Ewing's tumour derived cell lines, 12 primary Ewing's tumours, and 11 tumours after treatment were analysed for the occurence of the t(11;22) translocation. Furthermore, blood and bone marrow samples from 5 patients were available for RT-PCR. In 78% of the cell lines and 91% of the primary Ewing's tumours the t(11;22) translocation was detectable by RT-PCR. In bone marrow samples from a Ewing's sarcoma patient presenting in relapse tumour cells were detected by molecular genetic analysis. Our results indicate that molecular genetic detection of the t(11;22) translocation is valuable in the differential diagnosis of small round cell tumours and will provide important information for the staging and prognosis of Ewing's tumour.
Base Sequence↗
Case report 832. Solitary congenital or infantile (desmoid-type) fibromatosis of the proximal end of the tibia.
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Bone Neoplasms↗
[Molecular genetic detection of t(11;22)(q24;12) translocation in Ewing sarcoma and malignant peripheral neuroectodermal tumors].
Ewing's sarcomas and malignant peripheral neuroectodermal tumors (MPNTs) show very little evidence of differentiation and lack characteristic morphological features at the light-microscopic level. These malignancies have always presented a significant differential diagnostic challenge to the pathologist. Electron microscopy, immunohistochemical staining for neural antigens such as neuron-specific enolase (NSE), Leu 7, synaptophysin and, more recently, the detection of Mic-2 gene expression have been included in the routine histopathological diagnostic procedure. However, the expression of these antigens is not restricted to this entity. Thus, further modalities are required to prove diagnostic reliability. One consistent feature of the Ewing's sarcoma family is the presence of the reciprocal chromosomal t(11;22)(q24;q12) translocation. Recent cloning of the t(11;22) break point has led to the identification of the genes involved in this translocation. This provides the possibility of molecular genetic detection of the t(11;22) translocation in Ewing's sarcomas and MPNTs. We have established a method using reverse transcription and the polymerase chain reaction (RT-PCR) for the detection of the specific gene fusion transcript caused by the 11;22 translocation. The validity of our approach was proved by analyzing Ewing's tumor cell lines and tissue material obtained from primary biopsies and tumor resections. Molecular genetic detection of the 11;22 translocation by RT-PCR analysis should perhaps be included in the diagnostic work-up of suspected Ewing's sarcoma and MPNT.
Bone Neoplasms↗
The stress response to laparoscopic cholecystectomy: investigation of endocrine parameters.
Laparoscopic cholecystectomy, as a typical example of minimal invasive surgery, is associated with low complication rates and minimal patient discomfort, and provides the same safety as conventional cholecystectomy. In the present prospective observational study, endocrine parameters as indicators for stress response were measured. We investigated 53 patient with laparoscopy cholecystectomy and 12 patients with conventional cholecystectomy. Blood samples were taken pre-, peri-, and postoperatively for measurement of ACTH, cortisol, prolactin, and growth hormone. General anesthesia followed a standardized protocol. The increase in all stress hormones did not differ between patients in the two groups, and was comparable with that reported in the literature and the findings of our own previous studies in patients undergoing conventional cholecystectomy and elective colon resection. We conclude that laparoscopic cholecystectomy is associated with a pronounced endocrine stress response that does not account for the observed differences in the peri- and postoperative complication rate or patient comfort.
Adrenocorticotropic Hormone↗
Suramin in adrenocortical cancer: limited efficacy and serious toxicity.
OBJECTIVE: No satisfactory treatment for adrenocortical carcinoma (ACC) is available. We investigated the efficacy and toxicity of suramin in the treatment of metastatic ACC since suramin has been recently reported to be active as a single agent therapy for patients with ACC and prostatic carcinoma. DESIGN: We collected data on 9 patients with metastatic ACC treated with suramin in four centres in Germany between 1987 and 1992. PATIENTS: Nine patients (5 women, 4 men; age range 32-67 years) were included. Biochemical evidence of steroid excess was found in 6/9, in three leading to clinical symptoms (hypertension, hyperglycaemia, hirsutism, gynaecomastia). MEASUREMENTS: Tumour responses were assessed by radiological and biochemical evaluation. Other investigations included regular measurements of blood cell counts, coagulation, hepatic and renal function parameters, and serum suramin concentrations. RESULTS: The patients received cumulative doses ranging from 8.2 to 30.2 g suramin over periods of 1-15 months. 3/9 achieved a partial response, 2/9 disease stabilization and 4/9 experienced progressive disease. Tumour responses were transient. Suramin treatment was without direct influence on steroid excess. Serious side-effects included coagulopathy (6/9), thrombocytopenia (6/9), polyneuropathy (2/9) and allergic skin reactions (4/9); the death of two patients was possibly related to suramin therapy. Both toxicity and tumour response were strongly associated with serum level or cumulative dose of suramin. CONCLUSIONS: (1) Suramin is of antineoplastic efficacy in the treatment of metastatic adrenocortical carcinoma. (2) The clinical use of suramin is limited by a narrow therapeutic window with the risk of serious and possibly lethal toxicity at one extreme, and loss of efficacy at the other. Strict monitoring of suramin serum levels is mandatory aiming at levels between 200 and 250 mg/l. Suramin should not be considered as first-line treatment for metastatic adrenocortical carcinoma. (3) To improve treatment options in adrenocortical carcinoma as well as for further investigation on the usefulness of suramin, controlled prospective trials are urgently needed.
Adrenal Cortex Neoplasms↗
Impairment of adrenocortical function associated with increased plasma tumor necrosis factor-alpha and interleukin-6 concentrations in African trypanosomiasis.
African sleeping sickness (SS) is a severe, potentially lethal parasitic disease. The treatments of choice are the antiparasitic agents suramin, which is adrenotoxic, and/or melarsoprol. We evaluated the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis of patients with SS before, during, and after therapy with suramin and/or melarsoprol, in two sequential stages. First, we employed the standard adrenocorticotropic hormone (ACTH) 1-24 stimulation test (250 micrograms i.v.) to assess the maximal adrenocortical responsiveness of 69 patients with SS and 38 normal controls. We demonstrated paradoxically subnormal cortisol responses before suramin therapy [net cortisol response 60 min after stimulation: 10.5 +/- 2.9 (mean +/- SE) vs. 17.5 +/- 1.0 micrograms/dl for controls, p = 0.004], with 27% of the patients falling within the adrenal insufficiency range (stimulated cortisol concentration < 20 micrograms/dl). These responses subsequently and unexpectedly improved with suramin and/or melarsoprol therapy. Second, we performed a human corticotropin-releasing hormone (hCRH) test (100 micrograms i.v.) in 68 additional patients with SS and 14 control subjects to examine whether the glucocorticoid deficiency observed was primary and/or secondary. Compared to controls, the ACTH and cortisol responses to hCRH were blunted (ACTH after 60 min: 29 +/- 7 vs. 58 +/- 8 pg/ml in controls, p = 0.014; cortisol: 15.2 +/- 1.5 vs. 19.6 +/- 0.7 micrograms/dl, p = 0.018), suggesting the presence of secondary adrenal insufficiency. There was improvement of both ACTH and cortisol responsiveness to hCRH with therapy, with cortisol recovery occurring before ACTH, suggesting an additional primary component of adrenal dysfunction in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
[Detection of EWS-/FLI-1 gene fusion transcripts by RT-PCR as a tool in the diagnosis of tumors of the Ewing sarcoma group].
Recent cloning of the chromosome breakpoint regions of the reciprocal chromosomal t(11;22) (q24;q12) has revealed that the breakpoints were localized within the EWS gene (Ewings sarcoma gene) on chromosome 22 and the FLI-1 gene on chromosome 11. Thus, molecular genetic techniques were applicable for the detection of this genetic aberration, which occurs as a consistent feature of the Ewings tumor family. By reverse transcription and polymerase chain reaction technique (RT-PCR) in 78% of Ewings sarcoma derived cell lines, and in 91% of primary Ewings tumor tissue t(11;22) specific EWS/FLI-1 fusion transcripts were detected. Furthermore, in bone marrow samples from an Ewings sarcoma patient contaminating tumor cells could be shown by RT-PCR. Our results indicate that molecular genetic detection of the t(11;22) translocation opens a new modality for the differential diagnosis and the staging of Ewings tumor patients.
Base Sequence↗
Reconstructive vascular surgery in rotationplasty for malignant tumors of the femur.
The rotationplasty procedure of the femur, as first described by Borrgreve, is the functional improvement of an abnormally shortened lower limb. In the last 15 years this procedure has been used in its original form and as modification for tumors of the femur and proximal tibia. The reconstruction of the femoral vessels as an important part of the operation has not enough been accentuated. Principally two types of reconstructions can be performed: the vessels are dissected in the adductor canal or a segmental resection and reanastomosis are performed. Between January 1990 and April 1993 classical and modified rotationplasties were performed for malignant tumors in 34 patients in our institution. In all cases a segmental femoral vessel resection with end-to-end anastomosis were performed. No intra- and postoperative vascular related complications occurred. The authors emphasize the advantage of this method: reanastomosing resected femoral vessels by experienced vascular surgeons is a save, time-saving method. In addition, the radicality of the operation increases in order to obtain excellent long term results.
Adolescent↗
[MRI in soft tissue tumors].
MRI has been shown to be very useful in the diagnostic work-up of soft tissue masses. Because of its multiplanar capability and excellent contrast resolution, MRI is the method of choice for identification of tumour extent and follow-up examinations of soft tissue lesions. Due to the unspecific appearance of most soft tissue tumours, MRI cannot replace biopsy for definitive determinations of the nature of the lesion (benign vs malignant) in the majority of cases.
Diagnosis, Differential↗
The application of modern imaging methods in orthopedic surgery.
In this paper the application of ultrasonography, computed tomography, magnetic resonance imaging and bone scintigraphy in the diagnosis of orthopedic diseases is discussed. Because of the advances in the diagnosis made possible by these investigations, diagnosis is often made earlier with the consequence that therapeutic modalities can be used in a better way. As a result, late complications of orthopedic diseases can be influenced in a positive way.
Bone Diseases↗
[Pulmonary valve endocarditis and atrial fibrillation].
A 61-year-old man became ill with a fever of 39.4 degrees C, decreased exercise tolerance and headache as well as chest pain. Physical examination 3 weeks after the onset of symptoms merely revealed irregular heart rate at 100 beats/min. Erythrocyte sedimentation rate was increased (30/61 mm), as were serum bilirubin, lactate dehydrogenase, alkaline phosphatase, gamma-GT and C-reactive protein. The ECG showed atrial fibrillation with a rapid and irregular ventricular rate, as well as ventricular extrasystoles (Lown type IIIA), there were no abnormal findings on either the chest radiography or transthoracic echocardiography. Antiarrhythmic treatment brought about atrial flutter with 4:1 a-v conduction. Transoesophageal echocardiography now revealed vegetation on the pulmonary valve and microthrombi in the left atrial appendage. Ten days after starting intravenous penicillin G (10 mega units four times daily), gentamycin (60 mg three times daily) and heparin (30,000 units over 24 h) sinus rhythm was restored, the vegetation had got smaller and no thrombi were demonstrated. After 27 days antibiotic treatment was changed to oral penicillin V. After 4 weeks the patient was discharged symptom-free.
Atrial Fibrillation↗
Intraoperative, probe-guided curettage of osteoid osteoma.
The only curative approach for osteoid osteoma is operative removal of the nidus, but intraoperative detection of the nidus is difficult even when an X-ray amplifier is used. A simple probe-guided operative procedure using technetium-99m methylene diphosphonate is described, and the results and follow-up in 12 patients are reported. In addition physical properties of the probe have been evaluated by phantom measurements.
Adolescent↗
Chondromyxoid fibroma of the sternum. Case report.
We report the second case of chondromyxoid fibroma (CMF) of the sternum, documented in the literature. In this case, only histology of the biopsy was useful in diagnosing CMF before definitive surgery. A wide subtotal resection of the sternum and reconstruction with a Gore-Tex soft tissue patch was performed.
Adult↗
High malignant surface osteosarcoma arising at the site of a previously treated aneurysmal bone cyst.
A patient who developed a high malignant surface osteosarcoma at the site of a previously treated aneurysmal bone cyst is reported. The patient developed the osteosarcoma 4 years after complete curettage and bone-grafting of the cyst. The clinical, radiological and light microscopic features of this case are described. A causal relationship between the preexisting aneurysmal bone cyst and osteosarcoma is discussed, but seems to be unlikely.
Adult↗
Interferon gamma and tumour necrosis factor alpha induce a synergistic antiproliferative response in human Ewing's sarcoma cells in vitro.
Three human cell lines derived from Ewing's sarcoma (RM-82, VH-64, and WE-68) were investigated to establish the influence of recombinant human interferon gamma (rhIFN gamma) and tumour necrosis factor alpha (rhTNF alpha) on cell proliferation and survival and to characterize IFN gamma and TNF alpha receptor expression. Incorporation of [3H]thymidine into cells was inhibited by rhIFN gamma after 24 h of incubation. Half-maximal inhibition was observed with 10-80 U/ml rhIFN gamma. A maximal effect (50%-70% inhibition of cell proliferation) was achieved by treatment of cells with 250 U/ml rhIFN gamma. The influence of rhTNF alpha on proliferation was found to differ among cell lines and varied with the concentration and the duration of exposure of cells to this cytokine. In WE-68 and VH-64 cells [3H]thymidine incorporation was not affected by rhTNF alpha up to 2000 U/ml after 96 h of incubation, whereas in RM-82 cells the incorporation was inhibited by 35% after 48 h of incubation with 100 U/ml rhTNF alpha. However, all cell lines showed a synergistic antiproliferative response to the combination of rhIFN gamma and rhTNF alpha after 24 h of incubation. The human recombinant cytokines interleukin(IL)-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-6 and granulocyte/macrophage-colony-stimulating factor, tested alone and in combination with rhIFN gamma and rhTNF alpha, had no influence on cell proliferation. Binding studies in the cell lines with 125I-rhIFN gamma revealed a dissociation constant (Kd) of 160-306 pM and approximately 8000-13,500 receptors/cell. Binding experiments with 125I-rhTNF alpha indicated 430-1250 receptors/cell with Kd ranging from 13 pM to 162 pM. These data indicate that, among various cytokines, only IFN and TNF alpha are capable of potently reducing Ewing's sarcoma cell growth in vitro. Our data suggest that IFN alone or in combination with TNF alpha may be useful in the design of novel strategies in Ewing's sarcoma therapy.
Antineoplastic Combined Chemotherapy Protocols↗
Thyroid dysfunction in African trypanosomiasis: a possible role for inflammatory cytokines.
OBJECTIVE: Sleeping sickness (African trypanosomiasis) is an anthropozoonosis transmitted by the tsetse fly. The treatments of choice are the antiparasitic agents suramin and/or melarsoprol. Experimental infection of animals with Trypanosoma brucei results in inflammatory lesions in the pituitary and/or the thyroid gland. In biochemical terms, these animals have hypothyroidism. We evaluated the functional integrity of the hypothalamic-pituitary-thyroid axis in patients with African trypanosomiasis before, during and after specific therapy. DESIGN: Prospective, controlled, cross-sectional study. PATIENTS AND MEASUREMENTS: Sixty-five patients with sleeping sickness (31 female, 34 male; aged 18-66; 32 with haemolymphatic sleeping sickness receiving suramin i.v., 33 with cerebral sleeping sickness receiving melarsoprol) and 13 control subjects (6 female, 7 male; aged 21-60) were enrolled in a cross-sectional study after giving informed consent. Fourteen patients were studied shortly after admission for sleeping sickness, 19 in the middle of the course of treatment, 18 at the end of the 5-week treatment period, and 14 patients after cure. All subjects underwent a TRH stimulation test at 1200 with bolus injection of 400 micrograms TRH i.v. Blood was drawn for determination of fT3, fT4, TSH, rT3, TNF-alpha, IL-1 and IL-6 at 0 minutes and TSH at 60 minutes. All hormones and cytokines were determined by RIA or ELISA. RESULTS: Baseline TSH concentrations (mean +/- SEM) were elevated in unmedicated patients with sleeping sickness compared to normal subjects (2.6 +/- 0.4 vs 1.4 +/- 0.2 mU/l; P = 0.01), whereas fT3 (2.7 +/- 0.5 vs 5.8 +/- 0.3 pmol/l; P = 0.0002) and fT4 concentrations (10.3 +/- 1.2 vs 15.4 + 0.8 pmol/l; P = 0.007) were low. Stimulated TSH concentrations did not significantly differ from normal controls. Reverse T3 concentration in patients with sleeping sickness were normal (2.2 +/- 0.3 vs 2.4 +/- 0.2 nmol/l; P = NS). During the course of treatment, baseline TSH, fT3 and fT4 concentrations slowly returned to normal and were indistinguishable from controls after cure. Plasma concentrations of TNF-alpha (16.0 +/- 4.1 vs 2.9 +/- 1.4 ng/l in controls; P = 0.003) and interleukin-6 (19.2 +/- 7.3 vs 1.3 +/- 0.2 ng/l; P = 0.0001), but not interleukin-1 beta (2.0 +/- 0.2 vs 0.9 +/- 0.2, ng/l P = NS), were elevated, when thyroid function impairment and disease activity were at their maximum, but gradually decreased into the normal range with therapy. We found a negative correlation between baseline cytokine concentrations and fT3 concentrations (TNF-alpha: r = -0.34, P = 0.003; IL-6: r = -0.43, P = 0.0001). CONCLUSIONS: We conclude that unmedicated sleeping sickness is associated with significant impairment of thyroid function, which is reversed with specific therapy. Elevated TSH concentrations and low fT3 and fT4 concentrations suggest primary hypothyroidism in patients with sleeping sickness. However, an additional pituitary and/or hypothalamic component cannot be excluded. This impairment may be due to the elevated plasma cytokine concentrations found in these patients or may be the result of parasitic thyroiditis.
Adolescent↗
The hypothalamic-pituitary-adrenal axis in critical illness: response to dexamethasone and corticotropin-releasing hormone.
Plasma ACTH and cortisol concentrations are frequently elevated in patients in intensive care units (ICU). To examine the functional integrity of the hypothalamic-pituitary-adrenal axis during critical illness, we evaluated prospectively 53 ICU patients in a general medical ICU. Thirty-one patients and 7 normal controls underwent an overnight dexamethasone suppression test (3 mg dexamethasone, orally, at 2300 h). Plasma ACTH and serum cortisol were measured at 0900 h. In a separate experiment, 22 patients and 7 control subjects underwent a CRH stimulation test [100 micrograms human (h) CRH, iv]. ACTH and cortisol concentrations were determined from -15 to 120 min. Compared to normal controls, plasma ACTH and serum cortisol concentrations were not fully suppressible by dexamethasone [mean +/- SEM: plasma ACTH, 21 +/- 4 vs. 3 +/- 0.5 pg/mL (4.7 +/- 0.9 vs. 0.7 +/- 0.1 pmol/L); serum cortisol, 13.9 +/- 1.9 vs. 1.5 +/- 0.3 micrograms/dL (390 +/- 50 vs. 40 +/- 10 nmol/L); P = 0.0001], demonstrating an altered glucocorticoid feedback in the ICU patients. Patients undergoing hCRH stimulation had clearly elevated mean baseline plasma ACTH and serum cortisol concentrations [ACTH, 78 +/- 20 pg/mL vs. 15 +/- 3 in controls (17.2 +/- 4.4 vs. 3.4 +/- 0.7 pmol/L; P = 0.007); cortisol, 36.8 +/- 3.4 micrograms/dL vs. 9.6 +/- 1.2 (1020 +/- 80 vs. 260 +/- 30 nmol/L; P = 0.0001)]. Despite elevated baseline glucocorticoid concentrations, stimulation with hCRH resulted in significantly higher peak plasma ACTH concentrations 15 min after hCRH than in controls [134 +/- 31 vs. 48 +/- 9 pg/mL (29.5 +/- 6.8 vs. 10.6 +/- 2.0 pmol/L); P < 0.05]. Serum cortisol concentrations in ICU patients were significantly elevated throughout the test period (P = 0.0001) and rose to a peak of 43.9 +/- 3.5 micrograms/dL compared to 18.2 +/- 2.0 micrograms/dL in controls (1210 +/- 70 vs. 500 +/- 60 nmol/L). We conclude that ICU patients have a markedly altered responsiveness of their pituitary corticotroph to suppression with dexamethasone and stimulation with hCRH. These findings may be explained by altered pituitary glucocorticoid feedback and/or hypersecretion of peptides with CRH-like activity (vasopressin and cytokines) during critical illness.
Adrenal Glands↗