NF-kappaB-independent sensitization of glioblastoma cells for TRAIL-induced apoptosis by proteasome inhibition.

The transcription factor nuclear factor-kappaB (NF-kappaB) is a key regulator of stress-induced transcriptional activation and has been implicated in mediating primary or acquired apoptosis resistance in various cancers. In the present study, we therefore investigated the role of NF-kappaB in regulating apoptosis in malignant glioma, a prototypic tumor refractory to current treatment approaches. Here, we report that constitutive NF-kappaB DNA-binding activity was low or moderate in eight different glioblastoma cell lines compared to Hodgkin's lymphoma cells, known to harbor aberrant constitutive NF-kappaB activity. Specific inhibition of NF-kappaB by overexpression of inhibitor of kappaB (IkappaB)alpha superrepressor did not enhance spontaneous apoptosis of glioblastoma cells. Also, overexpression of IkappaBalpha superrepressor had no significant impact on apoptosis induced by two prototypic classes of apoptotic stimuli, that is, chemotherapeutic drugs or death-inducing ligands such as TNF-related apoptosis inducing ligand (TRAIL), which are known to trigger NF-kappaB activation as part of a cellular stress response. Similarly, inhibition of NF-kappaB by the proteasome inhibitor MG132 did not increase doxorubicin (Doxo)-induced apoptosis of glioblastoma cells, although it prevented DNA binding of NF-kappaB complexes in response to Doxo. Interestingly, proteasome inhibition significantly sensitized glioblastoma cells for TRAIL-induced apoptosis. These findings indicate that the characteristic antiapoptotic function of NF-kappaB reported for many cancers is not a primary feature of glioblastoma and thus, specific NF-kappaB inhibition may not be effective for chemosensitization of glioblastoma. Instead, proteasome inhibitors, which enhanced TRAIL-induced apoptosis in an NF-kappaB-independent manner, may open new perspectives to increase the efficacy of TRAIL-based regimens in glioblastoma, which warrants further investigation.

Cervical spinal cord atrophy in the atraumatically born neonate: one form of prenatal or perinatal ischaemic insult?

After atraumatic birth, three neonates presented with muscle hypotonia and weakness. Flaccid paresis of the upper extremities, spasticity of the lower extremities, dissociate sensory loss and autonomic dysfunction developed later. This ruled out the initial, tentative diagnoses of cerebral palsy, spinal muscular atrophy or hereditary neuropathy. Diagnostic imaging revealed marked thinning of the cervical spinal cord in all patients. The possible aetiology of these lesions is considered. In all cases, an antenatal or perinatal infarction is thought to be the most probable cause. Different clinical pictures following intrauterine spinal cord ischemia are discussed. Spinal cord lesion must be considered even after atraumatic birth.

Clinical aspects and prognosis of ependymoma in infants and children. A single institution experience.

Thirty-two patients (22 boys and 10 girls) with a histologically confirmed diagnosis of ependymoma were treated between 1972 and 1999. A total macroscopic resection was achieved in 16 of these patients, whereas 15 resections were classified by the surgeon as subtotal. In 1 patient a ventriculostomy was created as part of a palliative strategy. All children over 3 years old were treated with postoperative radiotherapy. Chemotherapy consisted of procarbazine, ifosfamide, etoposide, methotrexate, cisplatin and cytosine arabinoside. There was 1 perioperative death. Twenty children developed a relapse of disease within 2 months to 13 years and 1 month after the initial therapy. A maximal number of five recurrences were seen in 1 patient. The value of adjuvant chemotherapy on the prognosis of children with ependymoma seems to be limited. With regard to the poor outcome, the advisability of further treatment after multiple recurrences is debatable.

Cerebral spinal fluid flow, venous drainage and spinal cord compression in achondroplastic children: impact of magnetic resonance findings for decompressive surgery at the cranio-cervical junction.

UNLABELLED: In order to investigate the diagnostic properties of MRI of the brain and spine in achondroplastic children with regard to decompressive surgery, 25 patients were examined by conventional morphological and by "functional" imaging of CSF flow and magnetic resonance angiography (MRA) of the veins and sinuses at the cranial base following a special protocol. The results were compared to those from age-matched controls and were correlated with each other and retrospectively with the neurological findings. Measurements of distances and angulations at the cranio-cervical junction (CCJ) from MR scans showed similar values to those from conventional radiographs and CTs and thus can be used without correction for spatial distorsion. Signs of cervical medullary compression, myelomalacia and intramedullary cyst formation were found in six, seven and three children respectively. These alterations correlated significantly with each other (P < 0.05). Semiquantitative evaluation of CSF flow demonstrated interruption of CSF pathways at the CCJ, which correlated with CCJ narrowing (P < 0.05). MRA showed a significant narrowing of the jugular foramina with a variable compensatory enlargement of the emissary veins and a significant reduction of the total outflow area (P < 0.01). There were no significant correlations between these MR changes and neurological deficits. CONCLUSION: Due to this unexpectedly poor correlation between magnetic resonance and clinical findings in achondroplastic children, the present role of magnetic resonance in the clinical setting is limited to the demonstration of spinal cord compression in individual cases. In three of our patients with prominent neurological abnormalities, the severe changes demonstrated by magnetic resonance imaging strongly supported the indication for surgical decompression.

Anderson-Fabry disease: clinical manifestations of disease in female heterozygotes.

Anderson-Fabry disease is a rare, X-chromosomal lipid storage disorder caused by a deficiency of lysosomal alpha-galactosidase A. Clinical manifestations of Anderson-Fabry disease include excruciating pain in the extremities (acroparaesthesia), skin vessel ectasia (angiokeratoma), corneal and lenticular opacity, cardiovascular disease, stroke and renal failure, only renal failure being a frequent cause of death. Heterozygote female carriers have often been reported as being asymptomatic or having an attenuated form of the disease. To evaluate the spectrum of clinical signs in heterozygotes, a comprehensive clinical examination was performed on 20 carriers of Anderson-Fabry disease. This revealed that, in addition to the skin manifestation, various other clinical manifestations of the disease are present, including acroparaesthesia, kidney dysfunction, cerebrovascular disease, and gastrointestinal and heart problems. It therefore appears that Anderson-Fabry disease affects both hemizygotes and heterozyotes and therefore should be considered to be an X-linked dominant disease.

Abnormal somatosensory evoked potentials indicate compressive cervical myelopathy in mucopolysaccharidoses.

Compressive myelopathy at the cranio-cervical junction is a complication of mucopolysaccharidoses (MPS). To detect cervical myelopathy we recorded median and posterior tibial nerve SEPs in 15 patients aged 2.4-33.4 years (median 8.8 years) with MPS I-S (n = 3), MPS IVA (n = 8) and MPS VI (n = 4). In addition to the cortical waveforms we recorded the subcortical median nerve SEPs N13b and P13 generated near the cranio-cervical junction and the lemniscal P30 after posterior tibial nerve stimulation. MRI studies in 13 subjects revealed spinal cord compression at the cranio-cervical junction in 10 patients; 5 patients had an increased signal intensity on the T2-weighted initial MRI indicating high cervical myelomalacia and 4 patients had clinical signs of cervical myelopathy. We did not find a relationship between the SEPs and spinal cord compression. Abnormal SEPs were found in the patients with MRI evidence of myelomalacia (sensitivity 1.0, specificity 1.0) and correspondingly in the patients with clinical signs (sensitivity 1.0, specificity 0.91). The SEPs consequently deteriorated in 2 subjects of 7.3 and 10.3 years of age. Abnormal SEPs indicated subclinical cervical myelopathy in 3 subjects. Cervical cord compression may be present before occurrence of clinical or electrophysiological evidence of myelopathy. However, we feel that the SEP analysis is useful to detect functional impairment of the cervical cord in patients with MPS.

Long-term outcome in patients with advanced hilar bile duct tumors undergoing palliative endoscopic or percutaneous drainage.

OBJECTIVE: Advanced tumors of the hepatic duct bifurcation (Klatskin tumors) present problems to the endoscopist in deciding which procedure to use for palliative treatment of the resulting cholestasis--endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic biliary drainage (PTBD), or both. There are technical difficulties with all forms of treatment for stenoses in the hilar region and intrahepatic bile ducts, and there are as yet no clear data on which type of drainage is feasible or preferable. SUBJECTS: 59 consecutive patients (30 men, 29 women; mean age 71 years) underwent palliative treatment for malignant hilar bile duct tumors of Bismuth stages II-IV during a three-year period (1992-94). METHOD: A retrospective analysis was carried out, and long-term follow-up data were obtained from telephone interviews with the patients, relatives, or referring physicians. RESULTS: The 59 patients were treated using ERCP (n = 20) or PTBD (n = 39). Three died within 30 days, and six were lost to follow-up. Clinically adequate drainage was achieved in 78% (n = 46) of the total patient group. Patient survival was a median of six months (range 0.5-38), and was slightly longer when the primary drainage procedure was successful (7.5 months). Initial complications occurred in 11% after ERCP and in 33% after PTBD, with a 30-day mortality of 5%. After the initial intervention, five patients who received ERCP treatment had to be switched to PTBD during the longer-term course. Three of these five patients died within 30 days of the PTBD insertion. CONCLUSIONS: Palliative treatment in patients with advanced Klatskin tumors is still suboptimal, even when combined endoscopic and percutaneous techniques are used in the same institution, allowing treatment to be tailored to the individual patient's needs. There is therefore a need for improvements in existing forms of treatment, as well as for the development of new forms of treatment.

Early diffuse leptomeningeal primitive neuroectodermal tumors can escape detection by magnetic resonance imaging.

Primitive neuroectodermal tumors are easily detected by neuroradiologic imaging, as a rule. We report on two patients with early diffuse leptomeningeal primitive neuroectodermal tumors which escaped detection by contrast-enhanced magnetic resonance imaging.

Long-term results of endoscopic and percutaneous transhepatic treatment of benign biliary strictures.

BACKGROUND AND STUDY AIMS: Benign biliary strictures, mostly associated with biliary surgery, are of growing importance for the therapeutic endoscopist. In the short term, endoscopic therapy has success rates similar to those of surgery. With regard to the long-term results, fewer data are available, particularly concerning forms of treatment including percutaneous transhepatic biliary drainage (PTBD) as an additional tool. The present study was aimed at allowing evaluation of the short and long-term results of endoscopic and percutaneous treatment in patients with benign biliary strictures. PATIENTS AND METHODS: The charts of 40 consecutive patients treated during the period 1992-1994 (12 men, 28 women; median age 60.5 years, range 24-86) were analyzed retrospectively. Long-term follow-up was carried out by direct contact. In almost all of the cases, the endoscopic treatment consisted of papillotomy and stenting (single stent treatment 10 or 11.5 Fr); Yamakawa-type prostheses (14 or 16 Fr) were used in the PTBD patients. RESULTS: The primary treatment was successful in 37 of the 40 patients, including nine of 21 patients (43 %) treated endoscopically and 28 of 31 patients (90%) treated using the percutaneous approach. The complication rates after endoscopic retrograde cholangiopancreatography (ERCP) were 14%, compared with 26% after PTBD. Relief of the stricture was achieved in 25 patients after a median period of stent treatment of nine months (range 3-44), while recurrences were seen in six patients with stents in place for only 4.5 months (range 1-8), and in one patient with a metal stent. Therapy failed in two patients, and three were lost to follow-up. Serious long-term complications were rare, but there was a fatal complication in one patient with metal stents. The follow-up period was 44 months (range 11-66). Three patients underwent successful primary surgery, and three more underwent successful surgery after stricture recurrence; all were free of complaints after 49 months (range 40-44). CONCLUSIONS: Endoscopic and percutaneous treatment of benign biliary strictures is not only a short-term treatment, but also an adequate long-term therapeutic alternative to surgery, with tolerable complication rates. The period of stenting appears to influence the outcome, and the diameter of the stents used also probably plays a role. Prospective studies are required for further evaluation of these observations.

Abnormal subcortical somatosensory evoked potentials indicate high cervical myelopathy in achondroplasia.

UNLABELLED: Children with achondroplasia may have high cervical myelopathy due to stenosis of the cranio-cervical junction resulting in neurological disability and an increased rate of sudden death. To detect myelopathy we recorded somatosensory evoked potentials (SEPs) after median nerve stimulation in 30 patients with achondroplasia aged 13 months to 18 years (mean 6 years). In addition to the conventional technique of recording the cortical N20 and the central conduction time (CCT), we employed a noncephalic reference electrode recording the subcortical waveforms N13b and P13. generated near the cranio-cervical junction. The findings were related to the clinical status and MRI results. Eighteen patients had MRI evidence of spinal cord compression with indentation or narrowing of the upper cervical cord, and 13 showed signs of myelomalacia. Seven patients had neurological abnormalities. The sensitivities of the SEPs were 0.89 for cervical cord compression, 0.92 for myelomalacia and 1.0 for the clinically symptomatic patients. There were no false-positive results. The subcortical SEPs were more sensitive than the conventional recordings. However, the conventional SEPs were highly specific in the most severely affected patients; here the specificity was 1.0 for patients with myelomalacia and 0.96 for symptomatic patients. Postoperative SEPs improved after occipital decompression in two children. CONCLUSION: The analysis of somatosensory evoked potentials, in particular of subcortical tracings, is useful in the detection of early cervical myelopathy in children with achondroplasia. Early neurosurgical decompression may prevent irreversible damage.

Long-term results of endoscopic treatment of biliary duct obstruction due to pancreatic disease.

BACKGROUND/AIMS: Endoscopic stenting has become an established method of providing palliative treatment in cases of malignant biliary obstruction, as well as in benign biliary stenosis. Several problems associated with the types of stent used have not yet been resolved, and an ideal stent has yet to be designed. Observation of the clinical course for patients with biliary obstruction of various etiologies, and evaluation of the results with various treatment methods are the aims of this study. METHODOLOGY: In 1993 and 1994, biliary obstruction was treated endoscopically in 47 patients with a malignant pancreatic tumor and in 18 patients with chronic pancreatitis. The primary intervention was assessed retrospectively on the basis of the patients' records, and information concerning the clinical course was obtained by contacting the patients or their relatives or general practitioners. RESULTS: Primary endoscopic drainage was successful in all cases. Only one of the patients with pancreatic tumors is still alive; survival after stent placement averaged 6.2 months. Metal stents remained patent significantly longer than plastic stents and percutaneous transhepatic biliary drains (PTBDs)(8.2 versus 3.5 or 1.9 months; p < 0.001). In cases of chronic pancreatitis, three of the nine patients who received only endoscopic treatment, without stenting, were able to continue without stents in the longer term, whereas seven of the nine who underwent surgery had no further problems. CONCLUSIONS: Endoscopic drainage of biliary obstruction provides excellent short-term results. In long-term treatment for purely palliative purposes, metal stents remain patent for longer than plastic stents. In chronic pancreatitis, surgical treatment clearly seems to provide better long-term results than endoscopic therapy.

Cerebral haemorrhage in long-term survivors of childhood acute lymphoblastic leukaemia.

Modern treatment of childhood acute lymphoblastic leukaemia (ALL) has dramatically improved the prognosis for children with this disease. Therapeutic approaches consist of multimodal chemotherapy and radiotherapy with significant long-term side-effects. We report on 4 children out of a group of 120 newly diagnosed patients with ALL, who survived the disease for more than 2 years and developed a cerebral haemorrhage after chemotherapy and fractionated cranial irradiation. Following a period of 2-12 years the four children presented with acute neurological signs and symptoms. i.e. seizures, ataxia and hemiparesis. CT and MRI revealed intracerebral mass lesions, interpreted as haemorrhage. After neurosurgery the patients neurological state improved. Histological examination confirmed the suspected diagnosis of bleeding cavernous haemangioma or capillary telangiectases. There are two possibilities to explain these rare alterations: they may be pre-existent to the disease and therapy or they may be caused by irradiation. CONCLUSION Acute neurological symptoms in patients treated for ALL may be caused by spontaneous cerebral haemorrhaging of cavernous haemangiomas or capillary telangiectases induced by chemotherapy and/or radiotherapy.

[Direct antibiotic sensitivity testing in the treatment of urinary tract infections in a nursing home]. / Directe gevoeligheidsbepaling voor antibiotica bij de behandeling van urineweginfecties in een verpleeghuis.

Urinary tract infections occur frequently in nursing homes. Treatment is usually empiric without microbiological investigation. Because there is widespread resistance to the most frequently used antibiotics, we tested a relatively simple method (direct sensitivity testing for 7 antibiotics) to get information about the antibiotic resistance. The results, with 49 urine samples in the evaluation, showed a concordance of our direct sensitivity test with conventional culture (the golden standard) of 89.8% (35/342 evaluations were not in concordance). The concordance for the result 'sensitive' was 98.8% (3/240 results showed 'false-sensitive'), and the the result 'resistant' 68.6% (32/342 results showed 'false-resistant'). Urinary tract infections in the nursing home can be treated more quickly and more adequately with antibiotics with the information obtained by direct sensitivity testing. This method can be recommended as an alternative to empiric treatment.

[Rhabdomyosarcoma of the orbits in childhood]. / Rhabdomyosarkom der Orbita im Kindesalter.

BACKGROUND: Rhabdomyosarcoma is the most common malignant orbital tumor in children. Treatment modalities (individualized therapy or study protocol) have been changed radically. Surgery was supplemented by radiation therapy and chemotherapy. The objective of our retrospective analysis was to define the prognosis in correlation to changes of treatment in an unselected patient group of a single institution. PATIENTS AND METHODS: Between 1954 and 1995, 18 patients (age at presentation 1 month to 17 years, 11 male and 7 females) with orbital rhabdomyosarcoma were diagnosed and treated at our institution. RESULTS: The 5-year survival rate was 76%. Primary exenteration was replaced by tumor resection (microsurgery), radiation therapy and chemotherapy. Favorable outcome in the precytostatic era (with permanent loss of function) was not significantly improved by polychemotherapy. Microsurgery seems to increase the risk of recurrence. CONCLUSION: Considering the high risk of recurrence, primary exenteration in selected patients with expanded primary tumor is still a therapeutic option.

Long-term follow-up of endoscopic therapy in patients with post-surgical biliary leakage.

BACKGROUND/AIMS: Leakage is a rare complication of biliary surgery which is thought to follow a benign course after appropriate treatment. However there is a paucity of long-term follow-up data. PATIENTS AND METHODS: In this retrospective analysis, we present our experience with 21 patients in whom a biliary leakage was diagnosed following conventional and laparoscopic cholecystectomy (n = 14) or other types of biliary surgeries such as liver transplantation or segmental liver resection. Long-term follow-up (mean: 15.5 months) was obtained by telephone contact with patients, families or referring physicians. RESULTS: Endoscopic therapy was primarily successful in 20 of 21 patients and failed in 1 case with complete common bile duct dissection. Closure of the leakage was achieved by placement of nasobiliary tubes or endoprostheses with (n = 16) or without (n = 4) endoscopic papillotomy. Despite successful endoscopic therapy 3 patients died, 1 unrelated to the intervention, and 2 due to prolonged biliary sepsis (mortality: 9.5%; 30 day: 4.8%). Long-term follow-up in the surviving 18 patients showed them to be free of biliary complaints. CONCLUSION: ERCP is the primary modality to diagnose and treat post-operative biliary leakages. Despite rapid healing of the leakage in all 20 successfully treated cases, complications-related mortality was higher than previously suspected.

Clinical and neuroradiological findings in classic infantile and late-onset globoid-cell leukodystrophy (Krabbe disease).

In the present study the clinical course and imaging of early and late-onset forms of Krabbe disease are analyzed. We report on 11 patients with a biochemical diagnosis of galactosyl ceramide beta-galactoside deficiency. Two presented as the classic infantile form and died within the second year of life. In 9 children the first clinical signs, such as gait difficulties and visual failure, started after age 2 years. All these patients developed slow regression of motor and mental capacities, and most of them died within their first decade. In patients of both groups computed tomography (CT) and magnetic resonance imaging (MRI) were performed. In the late-onset form, hypodensities of the central white matter and pyramidal tracts were the leading radiological signs, whereas in the early-onset form, hyperdensities and cerebellar white matter lesions were also detected. From our results it becomes clear that variability of Krabbe disease refers not only to clinical manifestation but also to CT and MRI findings. Better knowledge of phenotypic and radiological diversity will help to understand the pathogenesis of the disease.