Biomedical subjects

N Sörensen

Publications and source records attributed to N Sörensen.

At least 19 recordsLinked to original sources

PubMed2006

Epigenetic repression of RASSF1A but not CASP8 in supratentorial PNET (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of childhood.

Supratentorial primitive neuroectodermal tumors (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of the CNS represent a biological and clinical enigma, despite advances in both molecular techniques and clinical management for these two rare embryonal brain tumors of childhood. Epigenetic changes hold great potential as possible disease mechanisms and may be manipulated therapeutically. We thus studied aberrant methylation of the genes RASSF1A and CASP8 and its consequence on expression in cell lines and primary tumors using a combination of semiquantitative methylation specific PCR (MSP), bisulfite sequencing and RT-PCR. In all, 17 samples of autopsy-derived normal appearing brain served as controls. Opposed to control tissues 19/24 sPNET and 4/6 AT/RT demonstrated aberrant methylation for the RASSF1A promoter region. Treatment of cell lines using 5-Aza-2'-deoxycytidine (5AZA) alone or in combination with trichostatin A (TSA) succeeded in re-establishing expression of RASSF1A in cell lines derived from a renal rhabdoid, an AT/RT and a medulloblastoma. A 5' CpG-rich region of CASP8 was methylated in normal tissues and in tumors. However, CASP8 showed inconsistent expression patterns in normal and tumor tissues. Our results indicate that aberrant methylation of the RASSF1A promoter region may be of importance in the origin and progression of sPNET and AT/RT while the analysed 5'-CpG rich region of the CASP8 gene does not seem to play an important role in these tumors. Further studies of epigenetic changes in these rare tumors are warranted as their biology remains obscure and treatment efforts have been rather unsuccessfull.

Adolescent↗

PubMed2006

Early periinsular hemispherotomy in children with Sturge-Weber syndrome and intractable epilepsy--outcome in eight patients.

BACKGROUND: Periinsular hemispherotomy is used to treat catastrophic epilepsy in hemispheric lesions. It avoids complications of tissue resection performed in other hemispherectomy procedures. We report on the effectiveness, complications, and neurological sequelae in patients with Sturge-Weber syndrome (SWS). METHODS: Eight patients (mean age at operation 15 months, mean surveillance time 7.1 years, 5 girls) were operated between 1994 and 2000, one with additional subpial resections of the insular cortex. Preoperatively hemiparesis was evident in all patients, mental retardation in six. Charts were reviewed for pre- and perioperative data. Outcome data were collected by structured telephone interview and questionnaires. RESULTS: No severe complications occurred. Five patients with unilateral angiomatosis were seizure-free without medication, rare non-disabling seizures occurred in one. Two patients with bilateral angiomatosis had seizure reduction of > 90%. Hemiparesis deteriorated in all patients with a marked deficit of hand function and less severe deficit in the lower extremity and trunk. Seven became ambulatory and achieved community language. Mental development improved with seizure control. Six patients have learning disability, two are mentally handicapped. CONCLUSION: Periinsular hemispherotomy is a valuable treatment modality in this patient group. The sequelae of hemiparesis, hemianopsia, and developmental delay must be seen in relation to the natural course in severe SWS.

Child↗

PubMed2006

Cerebral mass in a 13-year-old girl following long-term sojourn in the Tropics.

Cysticercosis of the central nervous system is the main cause of late-onset epilepsy in tropical countries. The case of a 13-year-old German girl with a generalized seizure following long-term sojourns in the Tropics is reported. Cranial imaging showed two cerebral lesions with central calcifications. Serological, molecular and cultural examination of cerebrospinal fluid and blood was negative for various parasites, fungi and bacteria including mycobacteria. Histopathological examination after neurosurgical resection revealed calcareous bodies pathognomonic for platyhelminths, in particular tapeworms. Taken together, the radiological and histopathological findings indicate infection with cysticerci, the larvae of Taenia solium.

Adolescent↗

PubMed2005

Cutaneous lesions in occult spinal dysraphism--correlation with intraspinal findings.

OBJECTS: This study was conducted to investigate the frequency and type of cutaneous stigmata in different forms of occult spinal dysraphism (OSD) and their correlation to the underlying malformation. METHODS: Fourteen different forms of spinal malformations were identified in 358 operated patients with OSD. Most frequent findings (isolated or in combinations) were spinal lipoma, split cord malformation, pathologic filum terminale, dermal sinus, meningocele manqué, myelocystocele and caudal regression. Stigmata were present in 86.3% of patients, often in various combinations. Using a binary logistic regression analysis, significant correlations with distinct malformations were found for subcutaneous lipomas, skin tags, vascular nevi, pori, hairy patches, hypertrichosis, meningoceles and "cigarette burn" marks. CONCLUSIONS: Cutaneous markers in a high percentage accompany spinal malformations. Due to the correlations of different stigmata to distinct malformations, they can aid the clinician in further diagnostic and therapeutic work.

Adolescent↗

PubMed2005

Hydrocephalus in craniosynostosis: a review.

INTRODUCTION: Ventricular dilatation in the presence of primary craniosynostosis is a unique condition with respect to pathogenesis, clinical significance, and morphological appearance. It is rarely observed in nonsyndromic craniosynostosis, and in these cases usually attributable to coincidental disorders. Conversely, it is a common feature of syndromic craniosynostosis, affecting at least 40% of patients with Crouzon's, Pfeiffer's or the Apert syndrome. Shunt-dependent hydrocephalus is predominantly associated with Crouzon or Pfeiffer syndrome while in the Apert syndrome the usual finding is nonprogressive ventriculomegaly which, however, may also occur in some cases of Crouzon syndrome. PATHOGENESIS: The pathogenesis of progressive hydrocephalus remains somewhat obscure, a hypoplastic posterior fossa and a venous outlet occlusion at the skull base being the main causative factors discussed in literature. Ventriculomegaly may reflect primary brain maldevelopment or in some cases even a compensated state of increased cerebrospinal fluid (CSF) outflow resistance. CLINICAL EVALUATION: Clinical evaluation is mainly aimed at identifying progressive hydrocephalus, but diagnosis is hampered by the fact that classical clinical signs may be absent, and that ventricular dilatation will often become evident only after decompressive cranial surgery. Moreover, mild ventriculomegaly may in some cases coexist with intracranial hypertension from craniostenosis. Therefore, careful monitoring of intracranial pressure and ventricular size in the pre- and postoperative period is a diagnostic mainstay. CONCLUSION: In true hydrocephalus ventriculo-peritoneal shunting is currently the single promising mode of treatment.

Cranial Sutures↗

PubMed2005

AFP/beta-HCG secreting CNS germ cell tumors: long-term outcome with respect to initial symptoms and primary tumor resection. Results of the cooperative trial MAKEI 89.

PURPOSE: The aim of the present study was to evaluate survival and factors influencing long-term outcome of patients with AFP/beta-HCG secreting (non-seminomatous) central nervous system germ cell tumors (secCNSGCT), who were prospectively collected in the cooperative MAKEI (German: maligne Keimzelltumoren) 89 protocol. PATIENTS AND METHODS: Between January 1989 and January 1994, 28 patients with secCNS GCT were registered and treated according to the MAKEI 89 protocol. The protocol recommended, after a clinically or histologically proven diagnosis and cisplatin-based chemotherapy, a resection of residual tumor and craniospinal irradiation (30 Gy) with a tumor boost (20 Gy). RESULTS: The estimated (Kaplan-Meier) event-free survival (EFS) of protocol patients is 0.57 +/- 0.09 (n = 28) and the relapse-free survival (RFS) is 0.67 +/- 0.10 (at five and ten years). With respect to long-term survival, the combination of marked neurological symptoms at diagnosis along with primary tumor resection seem to be the main negative prognostic risk factors (Fisher exact test p < 0.05). CNS dissemination at diagnosis can also be considered as a negative risk factor as 3 of 5 patients with primary dissemination died of the disease. CONCLUSION: Cisplatin-based three agent chemotherapy followed by resection of the residual tumor and craniospinal irradiation (CSI) with tumor boost is a successful and well-tolerated treatment for secCNSGCTs. The possibility of a clinical diagnosis based on MRI and tumor markers together with the use of modern neurosurgical techniques gives us the chance to postpone or even avoid major surgery. This gives an additional chance to reduce acute morbidity and further decrease late effects.

Adolescent↗

PubMed2004

Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study.

Patients with relapsed malignant glioma have a poor prognosis. We developed a strategy of vaccination using autologous mature dendritic cells loaded with autologous tumour homogenate. In total, 12 patients with a median age of 36 years (range: 11-78) were treated. All had relapsing malignant glioma. After surgery, vaccines were given at weeks 1 and 3, and later every 4 weeks. A median of 5 (range: 2-7) vaccines was given. There were no serious adverse events except in one patient with gross residual tumour prior to vaccination, who repetitively developed vaccine-related peritumoral oedema. Minor toxicities were recorded in four out of 12 patients. In six patients with postoperative residual tumour, vaccination induced one stable disease during 8 weeks, and one partial response. Two of six patients with complete resection are in CCR for 3 years. Tumour vaccination for patients with relapsed malignant glioma is feasible and likely beneficial for patients with minimal residual tumour burden.

Adjuvants, Immunologic↗

PubMed2004

No evidence for mutations or altered expression of the Suppressor of Fused gene (SUFU) in primitive neuroectodermal tumours.

The sonic hedgehog (Shh) and the Wnt signalling pathways are involved in the development of medulloblastomas (MBs), the most frequent malignant brain tumours in children. Components of these two developmental and cancer-associated pathways, including (Patched) PTCH, SMOH, adenomatous polyposis coli (APC), beta-catenin and AXIN1 show somatic mutations in sporadic MBs. In this study we analysed SUFU (human Suppressor of Fused), which acts as a negative regulator of both the Shh and Wnt signalling pathways and therefore represents a putative tumour suppressor gene, to find out if it is also involved in the pathogenesis of sporadic MBs. We screened 145 primitive neuroectodermal tumours (PNETs) including 90 classic MBs, 42 of the desmoplastic variant and two medullomyoblastomas as well as 11 MB cell lines for mutations using single-strand conformational polymorphism (SSCP) and sequencing analysis. 18% of the MBs exhibited allelic losses on chromosome 10q. In contrast to a previous report, in which truncating mutations of SUFU have been identified in 9% of MBs, we were not able to identify somatic mutations of SUFU in our large tumour panel. We uncovered single nucleotide polymorphisms (SNPs) in exon 4, 8, 11 and in intron 2 in the SUFU gene. Expression analysis by competitive reverse transcription-polymerase chain reaction (RT-PCR) revealed no difference in SUFU mRNA levels of both MB subtypes and normal foetal or adult cerebellar tissues. Our results indicate that genetic alterations of the SUFU gene, do not contribute significantly to the molecular pathogenesis of MBs.

Adolescent↗

PubMed2003

Volumetric bone mineral density in patients with childhood craniopharyngioma.

As the overall survival rate is high in patients with craniopharyngioma, the prognosis in survivors depends mainly on late effects. Late effects such as hypogonadism, growth hormone deficiency, glucocorticoid overreplacement and obesity have a strong impact on volumetric bone mineral density (vBMD). We analyzed vBMD and possible risk factors for reduced vBMD in 61 patients with childhood craniopharyngioma (29 f; 32 m) and in 14 weight, age, and sex-matched controls. VBMD was quantified by peripheral quantitative computed tomography (pQCT). Endocrine status, hormonal substitution therapy and calcium phosphate metabolism were evaluated. VBMD was in the lower normal range in 61 craniopharyngioma patients (total radial z-scores: median - 1.5; range - 3.1 to 1.4; trabecular z-scores: median - 0.4; - 2.4 to 2.3). 23 severely obese patients (body mass index [BMI] > 4 SD) had a higher total radial (p < 0.05) and trabecular (p < 0.05) vBMD when compared with 38 non-severely obese patients and 7 weight-matched controls. Although there was no gender difference in terms of obesity, endocrine substitution therapy or calcium phosphate metabolism, male patients had lower total radial (p < 0.01) and trabecular (p < 0.05) vBMD. Only in male patients' vBMD z-scores showed a positive correlation with BMI standard deviation score (SDS) (total radial z-score: Spearman r = 0.38, p = 0.03; trabecular z-score: Spearman r = 0.35, p = 0.04). We conclude that obesity has a major impact on vBMD in patients with craniopharyngioma. Lean male patients are at special risk for a lower vBMD, whereas female gender and severe obesity seem to have a protective effect regarding vBMD.

Adolescent↗

PubMed2003

Perioperative dexamethasone treatment in childhood craniopharyngioma--influence on short-term and long-term weight gain.

The substitution of dexamethasone during and after surgery of childhood craniopharyngioma is necessary in order to treat and/or prevent brain edema and adrenal insufficiency. Early post-operative weight gain is a predictor for severe obesity during long-term follow-up. In a retrospective analysis of 60 patients with childhood craniopharyngioma we inquired whether dose and duration of perioperative dexamethasone therapy (n = 68) had influence on short-term post-operative weight gain and long-term development of severe obesity. The median follow-up period was 4.2 years, ranging from 1 to 9 years. 24 patients (14 f/10 m) developed severe obesity (BMI > 3 SD). 28 patients (10 f/18 m) retained normal weight (BMI < 2 SD). Eight patients presented with a BMI between 2 and 3 SD at the final visit. Differences in terms of age at surgery or follow-up period were non-detectable between the analyzed groups of craniopharyngioma patients. Duration and cumulative dexamethasone doses (mg/m2 BSA) for perioperative dexamethasone therapy were similar for severely obese patients (duration: 8.7 d; 4.5 - 17 d, cumulative dose: 74; 42 - 177 mg/m2 BSA) and normal weight patients (duration: 10.0 d; 1 - 41 d; dose: 76; 9 - 390 mg/m2 BSA). Whereas cumulative dexamethasone doses positively (p < 0.01; rho: 0.424) correlated with weight gain during the first year following surgery, long-term development of severe obesity was not influenced by dose and duration of perioperative dexamethasone treatment. Patients who developed severe obesity during follow-up had a higher (p < 0.001) BMI already at the time of diagnosis. We conclude that dose and duration of perioperative dexamethasone treatment had short-term effects on post-operative weight gain, but not on the development of long-term severe obesity. The results of our retrospective analysis are currently tested in a prospective surveillance study Kraniopharyngeom 2000 (www.kraniopharyngeom.com).

Adolescent↗

PubMed2002

Human medulloblastomas lack point mutations and homozygous deletions of the hSNF5/INI1 tumour suppressor gene.

Medulloblastomas (MBs) are malignant primitive neuroectodermal tumours (PNETs) of the cerebellum occurring predominantly in childhood. The association of monosomy of chromosome 22 with MB is controversial. Atypical teratoid/rhabdoid tumours (AT/RTs) of the brain share clinical and histological features with MBs and supratentorial PNETs (sPNETs). In particular, AT/RTs can be misdiagnosed as MBs and sPNETs because AT/RTs frequently contain areas of primitive neuroepithelial cells similar to PNETs. Recently, mutations of the tumour suppressor gene hSNF5/INI1, located on 22q11.23, have been described in AT/RTs, MBs and sPNETs, with conflicting data on the prevalence of hSNF5/INI1 mutations in the latter entities. Therefore, we screened MBs for point mutations and homozygous deletions of the hSNF5/INI1 tumour suppressor gene. In 90 MBs, no mutations of the hSNF5/INI1 gene were identified. Thus, our study virtually rules out hSNF5/INI1 as a tumour suppressor gene involved in the pathogenesis of medulloblastoma.

Adolescent↗

PubMed2001

Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas.

Medulloblastoma (MB) represents the most frequent malignant brain tumor in children. Most MBs appear sporadically; however, their incidence is highly elevated in two inherited tumor predisposition syndromes, Gorlin's and Turcot's syndrome. The genetic defects responsible for these diseases have been identified. Whereas Gorlin's syndrome patients carry germ-line mutations in the patched (PTCH) gene, Turcot's syndrome patients with MBs carry germ-line mutations of the adenomatous polyposis coli (APC) gene. The APC gene product is a component of a multiprotein complex controlling beta-catenin degradation. In this complex, Axin plays a major role as scaffold protein. Whereas APC mutations are rare in sporadic MBs, a hot-spot region of beta-catenin (CTNNB1) mutations was identified in a subset of MBs. To find out if Axin is also involved in the pathogenesis of sporadic MBs, we analyzed 86 MBs and 11 MB cell lines for mutations in the AXIN1 gene. Using single-strand conformation polymorphism analysis, screening for large deletions by reverse transcription-PCR, and sequencing analysis, a single somatic point mutation in exon 1 (Pro255Ser) and seven large deletions (12%) of AXIN1 were detected. This indicates that AXIN1 may function as a tumor suppressor gene in MBs.

Adolescent↗

PubMed2001

Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors.

Primitive neuroectodermal tumors (PNETs) represent the most frequent malignant brain tumors in childhood. The majority of these neoplasms occur in the cerebellum and are classified as medulloblastomas (MB). Most PNETs develop sporadically; however, their incidence is highly elevated in patients carrying germline APC gene mutations. The APC gene encodes a central component of the WNT/wingless developmental signaling pathway. It regulates the levels of cytoplasmic beta-catenin protein that plays a central role in neural development and cell proliferation. We analyzed 87 sporadic PNETs and 10 PNET cell lines for mutations of the APC gene and beta-catenin (CTNNB1) gene using single strand conformational polymorphism (SSCP) and sequencing analysis. We examined the mutation cluster region of APC (codons 1255--1641) for germline variants and somatic mutations. The medulloblastoma cell line MHH-MED-2 carried a Glu1317Gln missense germline variant and a sporadic MB sample showed a somatic Pro1319Leu substitution. Mutational analysis of exon 3 of CTNNB1 uncovered 4 PNETs (4.8%) with somatic missense mutations. These mutations caused amino acid substitutions in 3 of 80 medulloblastomas (Ser33Phe, Ser33Cys and Ser37Cys) and 1 of 4 supratentorial PNETs (Gly34Val). All mutations affected GSK-3 beta phosphorylation sites of the degradation targeting box of beta-catenin and resulted in nuclear beta-catenin protein accumulation. Deletions of CTNNB1 were not detected by PCR amplification with primers spanning exons 1--5. Our data indicate that inappropriate activation of the WNT/wingless signaling pathway by mutations of its components may contribute to the pathogenesis of a subset of PNETs.

Adenomatous Polyposis Coli Protein↗

PubMed2001

[Current and future strategies in interdisciplinary treatment of medulloblastomas, supratentorial PNET (primitive neuroectodermal tumors) and intracranial germ cell tumors in childhood].

BACKGROUND: The chances for cure in medulloblastoma, supratentorial primitive neuroectodermal tumors (stPNET) and intracranial germ cell tumors have decisively improved within the last decades. Today long-term survival in the range between 60% and 80% and more than 90%, respectively, can be achieved. The low incidence of brain tumors in childhood and the necessity for optimal patient care has led to the fact that more than 90% of children are treated within national and international controlled studies today in order to assure a constant improvement of therapeutic outcome. Recent developments in neurosurgery achieved complete tumor resections in the majority of children at a low risk for morbidity and mortality. METHODS: Systemic irradiation of neuroaxis is an essential part in the management of medulloblastoma, stPNET and intracranial germ cell tumors. The introduction of quality assurance programs in radiooncology assures a precise radiotherapy of target volumes and is a prerequisite to improve survival. RESULTS: Hyperfractionated radiotherapy has the potential of increasing dose to tumor more safely without increasing the risk for late adverse effects. Pilot studies revealed excellent tumor control in medulloblastoma with acceptable acute toxicity and a long-term survival of up to 96%. In medulloblastoma stereotactic radiation techniques reveal an acceptable toxicity and promising results in tumor control in recurrent disease or as primary treatment. They are now part of future treatment protocols in case of persisting residual tumor. Radiotherapy alone in pure germinoma is continuously yielding high cure rates. In secreting germ cell tumors cisplatin containing chemotherapies in conjunction with radiotherapy achieve a long-term survival rate of 80% today. Especially in high risk medulloblastoma and secreting germ cell tumors chemotherapies are playing an increasingly important role in the interdisciplinary management. It can be expected that future developments of chemotherapeutic protocols and the introduction of new cytostatic substances will further improve the therapeutic outcome. CONCLUSIONS: The therapeutic endeavors of all those caring for children are aiming to study modifications of the therapeutic components in the interdisciplinary approach in order to optimize the therapeutic strategies. In future the affected children and young adolescents should be accrued for the forthcoming cooperative, prospective trial HIT 2000 and ongoing trial SIOP CNS GCT 96, respectively, in order to provide the body of data supporting the selection of novel and optimized approaches for future treatment strategies.

Adolescent↗

PubMed2001

Indications for a tumor suppressor gene at 22q11 involved in the pathogenesis of ependymal tumors and distinct from hSNF5/INI1.

Ependymomas account for approximately 9% of all neuroepithelial tumors and represent the most frequent neuroepithelial tumors of the spinal cord. In adults, allelic loss of chromosome arm 22q occurs in up to 60% of the cases studied. Some of these tumors show an altered neurofibromatosis type 2 (NF2) gene; in others, NF2 appears to be unaffected, indicating the involvement of another tumor suppressor gene. Recently, the tumor suppressor gene hSNF5/INI1, located on 22q11.23, has been shown to contribute to the pathogenesis of renal and extrarenal rhabdoid tumors. In addition, this gene may be responsible for a new hereditary syndrome predisposing to a variety of tumors designated "rhabdoid predisposition syndrome." In the present study, we analyzed a series of 53 ependymal tumors of 48 patients [4 myxopapillary ependymomas (WHO grade I), 3 subependymomas (WHO grade I), 18 ependymomas (WHO grade II), 21 anaplastic ependymomas (WHO grade III) and 2 ependymoblastomas (WHO grade IV)] for mutations and homozygous deletions in the coding region of the hSNF5/INI1 gene and for allelic loss of its flanking chromosomal regions in 39 ependymal tumors of 35 patients. Allelic loss was detected in 11 of 35 informative primary ependymal tumors (31%) with a common region of overlap covered by the markers D22S257 and D22S310 on 22q11 including the marker D22S301. However, a detailed molecular analysis of 53 ependymal tumors for mutations and homozygous deletion of the hSNF5/INI1 gene revealed no alterations. We conclude that the hSNF5/INI1 gene is not involved in the pathogenesis of human ependymal tumors with allelic loss on chromosome arm 22q and an intact NF2 locus. In addition, our study localizes a putative ependymoma tumor suppressor gene(s) to a domain of chromosome arm 22q flanked by the microsatellite markers D22S257 and D22S310.

Adolescent↗

PubMed2001

Intra-operative electromyographic monitoring of the lower cranial motor nerves (LCN IX-XII) in skull base surgery.

The functional preservation of lower (motor) cranial nerves (LCN) is endangered during skull base surgery. Intra-operative EMG monitoring of the LCN IX-XII was investigated in 78 patients undergoing 80 operations on various skull base tumors with regard to technical feasibility and clinical efficacy. Ongoing 'spontaneous muscle activity' (SMA) and 'compound muscle action potentials' (CMAP) following supramaximal bipolar stimulation were intra-operatively recorded applying needle electrodes into the soft palate (CN IX: n=76), the vocal cord (CN X: n=72), the trapezius muscle (CN XI: n=18), and the tongue (CN XII: n=71). From 24/22/8 cases with LCN IX/X/XII deficits (despite monitoring) only 5/6/4 remained unchanged (3-6 months postoperative). An irreversible plegia of the LCN IX/X/XII occurred in three (1/1/1) patients. In 7/6/1 patients postoperative (3-6 months) LCN IX/X/XII function was better than preoperatively. In all patients accessory nerve function remained unchanged. 'Pathological' SMA of the LCN IX/X/XII occurred in 12/16/8 cases, but in only 6/5/3 cases corresponded to postoperative LCN deficits. Corresponding 'pathological' SMA patterns were found in 18/17/5 out of 24/22/8 cases with postoperative LCN IX/X/XII dysfunction. Reproducible CMAP of LCN IX/X/XI/XII could be recorded in 59/56/11/32 patients. Approximate 'normal' values were calculated and compared to (very few) data so far given in the literature. Electromyographic monitoring proved to be a safe tool for the intra-operative identification and localization of the LCN contributing to their anatomical and functional preservation. The predictive value of standard neurophysiological parameters for functional outcome, however, is limited.

Adolescent↗

PubMed2001

Surgical management of tethered spinal cord in adults: report of 54 cases.

OBJECT: The clinical features specific to tethered cord syndrome (TCS) in adults as well as factors determining outcome and prognosis have rarely been addressed systematically. The authors studied 56 patients, 54 of whom were treated surgically over the last 16 years. METHODS: In 17 patients who had been asymptomatic during childhood, TCS was diagnosed 8 years after onset of symptoms. Tethered cord syndrome was diagnosed 4 years after worsening in 39 patients with neurological signs or symptoms since childhood. The patients were followed for an average of 8 years. Features specific to adult-age presentation included nondermatomal pain aggravated by movement in 34 patients and conditions such as pregnancy and childbirth (in five of 11 pregnant patients). The most frequent tethering lesions were lipoma in 32, tight terminal filum in 28, and split cord malformation and secondary adhesions in 12 patients, respectively. Improvement or stabilization of symptoms at 6 months after surgery was noted in 46 (85%) of 54 patients. Improvement in pain status was most frequent (86%) followed by improvements in spasticity (71%), bladder dysfunction (44%), and sensorimotor deficits (35%). Factors associated with adverse outcome included preoperative duration of neurological deficits more than 5 years and incomplete untethering. On average, 8 (80%) of 10 patients with incomplete untethering developed recurrent symptoms 5 years after surgery compared with only seven (16%) of 44 patients in whom complete untethering was achieved. Seven patients underwent reoperation and in five of them stabilization of symptoms was attained. At a mean follow up of 8 years, 46 (85%) of the 54 surgically treated patients were in stable neurological condition, including those in whom reoperation was performed. CONCLUSIONS: Surgery for TCS is as beneficial in adults as it is in children. Its success depends on early diagnosis and complete untethering of the spinal cord.

Adolescent↗

PubMed2000

Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91.

PURPOSE: The German Society of Pediatric Hematology and Oncology (GPOH) conducted a randomized, prospective, multicenter trial (HIT '91) in order to improve the survival of children with medulloblastoma by using postoperative neoadjuvant chemotherapy before radiation therapy as opposed to maintenance chemotherapy after immediate postoperative radiotherapy. METHODS AND MATERIALS: Between 1991 and 1997, 158 patients were enrolled and 137 patients randomized. Seventy-two patients were allocated to receive neoadjuvant chemotherapy before radiotherapy (arm I, investigational). Chemotherapy consisted of ifosfamide, etoposide, intravenous high-dose methotrexate, cisplatin, and cytarabine given in two cycles. In arm II (standard arm), 65 patients were assigned to receive immediate postoperative radiotherapy, with concomitant vincristine followed by 8 cycles of maintenance chemotherapy consisting of cisplatin, CCNU, and vincristine ("Philadelphia protocol"). All patients received radiotherapy to the craniospinal axis (35.2 Gy total dose, 1.6 Gy fractionated dose / 5 times per week followed by a boost to posterior fossa with 20 Gy, 2.0 Gy fractionated dose). RESULTS: During chemotherapy Grade III/IV infections were predominant in arm I (40%). Peripheral neuropathy and ototoxicity were prevailing in arm II (37% and 34%, respectively). Dose modification was necessary in particular in arm II (63%). During radiotherapy acute toxicity was mild in the majority of patients and equally distributed in both arms. Myelosuppression led to a mean prolongation of treatment time of 11.5 days in arm I and 7.5 days in arm II, and interruptions in 35% of patients in arm I. Quality control of radiotherapy revealed correct treatment in more than 88% for dose prescription, more than 88% for coverage of target volume, and 98% for field matching. At a median follow-up of 30 months (range 1.4-62 months), the Kaplan-Meier estimates for relapse-free survival at 3 years for all randomized patients were 0.70+/-0.08; for patients with residual disease: 0.72+/-0.06; without residual disease: 0.68+/-0.09; M0: 0.72+/-0.04; M1: 0.65+/-0.12; and M2/3: 0.30+/-0.15. For all randomized patients without M2/3 disease: 0.65+/-0.05 (arm I) and 0.78+/-0.06 (arm II) (p < 0.03); patients between 3 and 5.9 years: 0.60+/-0.13 and 0.64+/-0.14, respectively, but patients between 6 and 18 years: 0.62+/-0.09 and 0.84+/-0.08, respectively (p < 0.03). In a univariate analysis the only negative prognostic factors were M2/3 disease (p < 0.002) and an age of less than 8 years (p < 0.03). CONCLUSIONS: Maintenance chemotherapy would seem to be more effective in low-risk medulloblastoma, especially in patients older than 6 years of age. Neoadjuvant chemotherapy was accompanied by increased myelotoxicity of the subsequent radiotherapy, causing a higher rate of interruptions and an extended overall treatment time. Delayed and/or protracted radiotherapy may therefore have a negative impact on outcome. M2/3 disease was associated with a poor survival in both arms, suggesting the need for a more intensive treatment. Young age and M2/3 stage were negative prognostic factors in medulloblastoma, but residual or M1 disease was not, suggesting a new stratification system for risk subgroups. High quality of radiotherapy may be a major contributing factor for the overall outcome.

Adolescent↗