Feasibility of intensive multimodal therapy in infants affected by rhabdoid tumors - experience of the EU-RHAB registry.

Rhabdoid tumors mainly affect infants and other very young children with a marked vulnerability towards intensive therapy such as invasive surgery, high dose chemotherapy (HDCT) and dose intense radiotherapy. Radiotherapy (RT) is a promising option in rhabdoid tumors but its application in infants remains controversial. Neurocognitive and vascular side effects occur even long after completion of therapy. Therapeutic recommendations suggested by the European Rhabdoid Registry including RT, high dose chemotherapy (HDCT) and methotrexate (MTX) were developed by a consensus committee. Unique to our EU-RHAB database is the ability to analyze data of 64 of 81 registered infants (under one year of age) separate from older children. 20 (age at diagnoses 2-12 months) of these had received radiotherapy. To our knowledge, this is the first report specifically analyzing treatment data of infants suffering from malignant rhabdoid tumors. Our results suggest that radiotherapy significantly increases the mean survival time as well as the 3 year overall survival in infants. We detected a doubling of survival times in infants who received RT. Overall, our results suggest that infants benefit from RT with tolerable acute side effects. Severe long term sequelae likely due to intraventricular MTX and/or RT were reported in 4 patients (leukoencephalopathy). No differences in chemotherapy-related toxicity were observed between infants and children. We suggest that a nihilistic therapeutic approach towards young infants is not warranted and that RT may not be a priori rejected as a therapeutic option in infants.

High-dose chemotherapy (HDCT) with auto-SCT in children with atypical teratoid/rhabdoid tumors (AT/RT): a report from the European Rhabdoid Registry (EU-RHAB).

A retrospective analysis of data from the European Rhabdoid Registry (EU-RHAB) was performed to describe the outcome of children with atypical teratoid/rhabdoid tumors (AT/RT) who underwent high-dose chemotherapy (HDCT) with auto-SCT. Nineteen patients (male, n=15; median age at diagnosis 21 months) were identified. Nine patients presented with metastatic disease at diagnosis. A partial or subtotal resection was achieved in 11, a total resection in five and a biopsy in three patients. Patients received a median of six chemotherapy cycles prior to HDCT. Additional radiotherapy was performed in 14 patients (first-line, n=9; following progression, n=5). Six patients underwent tandem auto-SCT. Disease status before HDCT was CR in six, PR in eight, stable disease in two and progressive disease (PD) in two patients (data missing, n=1). With a median follow-up of 16 months, 14 patients progressed. Estimated progression-free and OS at 2 years were 29% (±11%) and 50% (±12%), respectively. At last follow-up, eight patients were alive (first CR, n=4; second CR, n=2; PR, n=1; PD, n=1). Eleven patients died of PD. Median time-to-progression was 14 months. Selected patients with AT/RT might benefit from HDCT with radiotherapy. The definitive impact of this treatment modality has to be evaluated prospectively in a randomized trial.

Bone involvement in atypical teratoid/rhabdoid tumors of the CNS.

SUMMARY: Destruction of the bony structures of the skull is rare in primary tumors of the CNS. In low-grade gliomas, modeling of the skull is caused by slow growth and chronic pressure. Bony destruction is exceptional even in highly malignant gliomas. Atypical teratoid/rhabdoid tumors of the CNS are highly malignant neoplasms diagnosed with an increasing frequency, mainly in young children. On imaging, these tumors exhibit distinct though not specific morphologic features including peripheral cysts, bleeding residues, and a distinct bandlike, wavy pattern of enhancement. A combination of these single characteristics together with a predilection for young age is suggestive of an atypical teratoid/rhabdoid tumor. We present 5 children with an atypical teratoid/rhabdoid tumor affecting the adjacent bone. These 5 patients were collected in our imaging data base for childhood atypical teratoid/rhabdoid tumor consisting of 91 children at the time of this evaluation and thus representing 6.6%. The mean age of children with bone involvement (4.8 years) was above the average age (2 years) of all children in the data base. We add this rare feature to the list of typical features in MR imaging and CT morphology of atypical teratoid/rhabdoid tumor.

Role of surgery, radiotherapy and chemotherapy in papillary tumors of the pineal region: a multicenter study.

Papillary tumor of the pineal region (PTPR), recently described as a distinct clinicopathological entity, can show aggressive biological behavior. The optimal therapeutic approach of PTPR has not been well defined. The role of surgery, radiotherapy, and chemotherapy in the treatment of PTPR was analyzed in a large multicenter series. In order to determine factors that influence prognosis, outcome data of a series of 44 patients with histopathologically proven PTPR were retrospectively analyzed. Of the 44 patients, 32 were still alive after a median follow-up of 63.1 months. Twelve patients experienced progressive disease, with seven undergoing two relapses and five more than two. Median overall survival (OS) was not achieved. Median progression-free survival (PFS) was 58.1 months. Only gross total resection and younger age were associated with a longer OS, radiotherapy and chemotherapy having no significant impact. PFS was not influenced by gross total resection. Radiotherapy and chemotherapy had no significant effect. This retrospective series confirms the high risk of recurrence in PTPR and emphasizes the importance of gross total resection. However, our data provide no evidence for a role of adjuvant radiotherapy or chemotherapy in the treatment of PTPR.

PAX2 is an antiapoptotic molecule with deregulated expression in medulloblastoma.

PAX2 is a paired box transcription factor possessing a fundamental role in the embryogenesis of hindbrain and urinary tract. PAX genes are proto-oncogenes, PAX2 expression may contribute to the pathogenesis of renal cell carcinoma. Because of the expression of PAX2 in the developing hindbrain and its essential role in cerebellar development, it has been hypothesized that PAX2 may also be involved in medulloblastoma tumorigenesis. We investigated the expression pattern of PAX2 and various genes of the neuronal lineage in medulloblastoma and glioma cell lines. We found high expression of PAX2 mRNA and PAX2 protein in medulloblastoma cells and some glioma cell lines independent of their neuronal lineage gene expression signature. Gene suppression of PAX2 decreased the expression of the PAX2 transcriptional target GDNF in Daoy cells and had a profound cytotoxic effect in vitro on Daoy medulloblastoma and T98G glioma cells. Expression of PAX2 was then assessed in two separate medulloblastoma tissue microarrays with a total of 61 patient samples by immunohistochemistry. PAX2 expression was detected in the majority of medulloblastoma samples and correlated with less differentiated histology. Therefore, PAX2 is a biomarker for a more aggressive medulloblastoma phenotype and may represent a novel therapeutic target.

BRAF-KIAA1549 fusion transcripts are less frequent in pilocytic astrocytomas diagnosed in adults.

AIM: Duplication of 7q34 resulting in generation of BRAF-KIAA1549 fusion transcripts is a characteristic event in pilocytic astrocytoma that may also aid distinction from diffuse astrocytic tumours. As data on BRAF-KIAA1549 fusion transcript status remain mainly limited to children, we aimed to examine the diagnostic value of BRAF-KIAA1549 fusion transcripts across all age groups. METHODS: BRAF-KIAA1549 fusion transcript status was examined using reverse transcription polymerase chain reaction on formalin-fixed paraffin-embedded samples of 105 primary pilocytic astrocytomas [median patient age: 17 years (1-74 years)]. RESULTS: Informative results (distinct wildtype BRAF bands detectable) were obtained in 105/124 cases (85%). Fusion transcripts were detected in 53 of cases (51%). They were more often encountered in tumours of infratentorial location [42/67 (63%) vs. 11/38 (29%)] and comprised KIAA1549-Ex16_BRAF-Ex9 (32 cases), KIAA1549-Ex15_BRAF-Ex9 (14 cases) and KIAA1549-Ex16_BRAF-Ex11 (seven cases). Fusion transcripts were present in 79% of tumours diagnosed in the first decade of life, but only in 51% of patients aged 11-20 years, 42% of patients aged 21-30 years, 30% of patients aged 31-40 years and 7% of patients older than 40 years. On multivariate logistic regression analysis, the association of fusion transcript status and age was confirmed adjusting for tumour location (P = 0.006). CONCLUSIONS: The frequency of BRAF-KIAA1549 fusion transcripts is significantly lower in adult patients with pilocytic astrocytoma, weakening the sensitivity of this specific diagnostic marker in that age group.

[Severe aseptic leucoencephalopathy. Manifested as immune reconstitution inflammatory syndrome in Caucasian and African patients]. / Schwere Leukenzephalopathie. Manifestationsform des aseptischen Immune-reconstitution-inflammatory-Syndroms bei Kaukasiern und Afrikanern.

BACKGROUND: We hypothesize that CNS immune reconstitution inflammatory syndrome (IRIS) after highly active antiretroviral therapy (HAART) in HIV-1-positive patients may become manifest without any opportunistic infection as an aseptic leucoencephalopathy. This opens a window of opportunity for successful treatment with corticosteroids. DESIGN: We describe a case series of immunocompromised HIV-1-positive patients who were started on HAART. All of them had clinical laboratory follow-up tests and cerebral MRI in order to investigate the course and the underlying pathophysiology of this aseptic form of IRIS. One African patient died and we performed a neuropathological examination. RESULTS: No infectious agent was detected before and during HAART. Three of four immunocompromised patients were successfully treated with corticosteroids while HAART was never interrupted and have survived up to now. One African patient died within 2 days despite intensive care due to cerebral oedema. CONCLUSIONS: Starting HAART, HIV-1-positive patients may develop an aseptic type of IRIS of the CNS without any detectable opportunistic infection, a finding that has not yet been published. This makes them susceptible for successful treatment with corticosteroids. Perhaps IRIS has a higher incidence in African patients and the patients have a poorer outcome than Caucasians.

[Molecular diagnostic testing in gliomas]. / Molekulare Diagnostik von Gliomen.

Glial tumours represent the majority of central nervous system tumours. Even though current therapy guidelines do not advocate the routine use of molecular markers for treatment decisions, the identification of prognostic markers and patient subgroups that may especially benefit from novel therapeutic options becomes increasingly important also outside the setting of clinical trials. This review summarizes methods and rationale for the use of the determination of 1p/19q loss, MGMT promoter methylation and tyrosine kinase receptor expression as diagnostic, prognostic and predictive markers in gliomas.

Stem cell protein BMI-1 is an independent marker for poor prognosis in oligodendroglial tumours.

AIMS: The polycomb factor BMI-1 has recently been implicated in tumorigenesis of the central nervous system in several experimental animal models. However, the significance of BMI-1 in human glioma has not been investigated. Here we describe expression of the polycomb protein BMI-1 and its downstream targets p16(Ink4a) and MDM2 in both high- and low-grade human glioma. METHODS: Tumour samples were collected from 305 adult patients treated for primary grades 2-4 gliomas between 1980 and 2006 in Finland and Germany. BMI-1, p16 and MDM2 expression was evaluated using immunohistochemistry in representative paraffin-embedded tumour tissue. The significance of observed immunoreactivity, age at onset, gender, histopathological findings and proliferative index was analysed in univariate and multivariate survival models. RESULTS: BMI-1 was expressed in all histologic types of diffuse gliomas. We found a significant correlation (P = 0.007) between the frequency of BMI-1 immunoreactive tumour cells and poor survival in World Health Organization grades II-III oligodendrogliomas and oligoastrocytomas (n = 62). The median survival of patients grouped by low, intermediate or high frequency of BMI-1 immunoreactive tumour cells was 191 months, 151 months and 68 months, respectively. This association was also significant in the Cox multivariate regression model. Nuclear p16 immunopositivity predicted better survival in astrocytomas and an inverse correlation between p16 expression and the Ki-67 mitotic index was also observed. CONCLUSIONS: BMI-1 is found in all histological types of gliomas and the relative protein expression of BMI-1 is a novel independent prognostic marker in oligodendroglial tumours.

Intramedullary spinal cord metastasis as initial presentation of systemic cancer--report of a rare case.

We report the rare case of a 74-year-old man who was admitted to our hospital with rapid progression of tetraparesis, which was most apparent in the lower right limb, sensory disturbances from C3 to S1 on the left side and recent onset of constipation and urinary retention. There was no known history of cancer. As MRI of the neck disclosed a cervical intramedullary mass lesion at C 4/5 level suspicious for a primary glial tumour, the patient underwent surgery. After microsurgical excision the histological analysis of the lesion unexpectedly revealed an intramedullary spinal cord metastasis (ISCM) of a poorly differentiated carcinoma, immunohistochemically consistent with a bronchial carcinoma. As intramedullary spinal cord metastases are generally associated with poor survival, a palliative irradiation of the levels C1-6 was additionally performed. Unfortunately tetraparesis and numbness remained. The very rare occurrence of intramedullary spinal cord metastasis and the absence of pathognomonic symptoms often lead to a delay until an underlying malignancy is discovered. Although rare, intramedullary spinal cord metastasis should be considered as a differential diagnosis of a spinal intramedullary lesion. Surgery and radiation are both options in the controversially discussed treatment of ISCM.

Immunohistochemical profile and chromosomal imbalances in papillary tumours of the pineal region.

The histopathology of papillary tumours of the pineal region (PTPR) closely resembles that of ependymomas and choroid plexus tumours. Therefore, immunohistochemical staining profiles were investigated in a series of 15 PTPR. In addition to cytokeratin, synaptophysin and glial fibrillary acidic protein expression, PTPR were examined for the presence of dot- or ring-like epithelial membrane antigen (EMA) immunoreactivity typically encountered in ependymoma, staining for inwardly rectifying potassium channel Kir7.1 and stanniocalcin-1 (specifically expressed in choroid plexus tumours) as well as microtubule-associated protein-2 (MAP-2). Furthermore, comparative genomic hybridization was performed in five PTPR. Cytokeratin was expressed in all PTPR examined, whereas glial fibrillary acidic protein and synaptophysin staining were absent. Dot- or ring-like EMA immunoreactivity was only observed in 1 out of 15 PTPR. Membranous Kir7.1 and cytoplasmic stanniocalcin-1 staining were present in the minority of PTPR (3/15 and 4/15, respectively). In contrast, MAP-2 immunoreactivity was encountered in 13 out of 15 PTPR, but was significantly less frequently observed in a series of choroid plexus tumours (7/37). PTPR mainly presented with chromosomal losses affecting chromosomes 10 (4/5 cases) and 22q (3/5 cases) as well as gains on chromosomes 4 (4/5 cases), 8 (3/5 cases), 9 (3/5 cases) and 12 (3/5 cases). To conclude, the majority of PTPR can be distinguished from ependymomas and choroid plexus tumours by absent staining for epithelial membrane antigen, Kir7.1 and staniocalcin-1 as well as the presence of distinct MAP-2 immunoreactivity. Antibodies directed against these antigens are thus expected to be valuable markers in the diagnosis of papillary tumours located in the vicinity of the third ventricle.

Cellular and reticular variants of haemangioblastoma revisited: a clinicopathologic study of 88 cases.

The presence of histological variants of haemangioblastoma is well established, but data on the prognostic implications of histological subtyping are missing. We thus characterized clinical factors associated with histological subtypes, that is, of the cellular and reticular variant of haemangioblastoma, in a series of 88 consecutive primary haemangioblastomas of the central nervous system. Ten haemangioblastomas were classified as 'cellular' according to Cushing and Bailey. As compared to the more common 'reticular' variant (n = 78), the proportion of tumours containing glial fibrillary acidic protein-positive tumour cells (80% vs. 7%), as well as median Ki67 (MIB1) proliferation indices [4% (quartiles: 1-8%) vs. < 1% (<1-2%)], was significantly higher in cellular haemangioblastomas (P < 0.01). Recurrences were more frequent in the cellular variant [2/8 (25%) vs. 4/51 (8%)]. Kaplan-Meier analysis confirmed a significantly higher probability of recurrence in the cellular variant (Log-Rank test P < 0.01). Cox regression analysis not only confirmed the well established association of von Hippel-Lindau disease with tumour recurrence (P < 0.01), but also revealed an independent effect of histological subtype on the probability of recurrence (P < 0.05), whereas no significant influence of age, sex or tumour location was observed. To conclude, the results from this retrospective study suggest that histological subtyping of haemangioblastomas has prognostic implications and might contribute to identify patients at risk for recurrence.

Haematological abnormalities in early abstinent alcoholics are closely associated with alterations in thrombopoietin and erythropoietin serum profiles.

Numerous reports exist on haematological pathology in alcoholism. However, no data are available regarding a potential involvement of haematopoietic growth factors in the recovery from alcohol-induced haematological abnormalities upon abstinence. Therefore, thrombopoietin (TPO) and erythropoietin (EPO) serum levels along with haematological and other routine laboratory parameters were closely followed in 14 thoroughly characterized male alcoholic patients over one to five months of controlled abstention from alcohol. Haematological changes in these early abstinent alcoholics consisted predominantly of (a) the well known rebound surge of platelets, (b) an early reticulocyte peak, and (c) persistently low haematocrit levels over months without signs of recovery. Observations on EPO and TPO during early abstinence can be summarized as follows: (1) Increased TPO levels precede the rebound thrombocytosis by several days, (2) both EPO and TPO concentrations are higher in anaemic than in nonanaemic alcoholics, with (3) nonanaemic subjects exhibiting levels of TPO in the range of healthy controls but levels of EPO below controls and (4) TPO concentrations show a stronger correlation with initial haematocrit values than with thrombocyte counts. To conclude, haematological recovery in early alcohol abstinence appears to be, at least in part, growth factor-driven, involving both TPO and EPO, and may reflect an intense interaction of erythro- and thrombopoiesis.

ET(A) and ET(B) specific ligands synergistically antagonize endothelin-1 binding to an atypical endothelin receptor in primary rat astrocytes.

Using a whole-cell binding procedure with long incubations at low temperature and subsequent acid stripping, we have characterized an atypical endothelin (ET) receptor in primary rat cortical astrocyte cultures. We found the following: (a) no competition for 125I-ET-1 binding by the ET(A) antagonists BQ-123 and LU 135252 or the ET(B) agonist IRL 1620; (b) weak competition by the ET(B) antagonist BQ-788 and by the predominant ET(B) ligand ET-3; (c) potent synergistic competition of ET(A) and ET(B) ligands in combination for 125I-ET-1 binding; (d) potent competition of ET-1 with any of the radioligands used, 125I-ET-1, 125I-IRL 1620, and [3H]BQ-123; (e) lack of competition of IRL 1620 and BQ-123 with the respective other radioligand; (f) shifting of the amount of acid-strippable 125I-ET-1 binding from 20 to 80% by ET(B) ligands and to 4% by ET(A) ligands; and (g) as a control, typical ET(A) and ET(B) binding characteristics of the RAT-1 fibroblast and the U373MG astrocytoma cell line, respectively, under our assay conditions. The unusual binding properties of astrocytic ET receptors described in this study appear to be the result of several binding sites in the receptor for different ET ligands or ligand epitopes.