Relative survival of patients with non-malignant central nervous system tumours: a descriptive study by the Austrian Brain Tumour Registry.

BACKGROUND: Unlike malignant primary central nervous system (CNS) tumours outcome data on non-malignant CNS tumours are scarce. For patients diagnosed from 1996 to 2002 5-year relative survival of only 85.0% has been reported. We investigated this rate in a contemporary patient cohort to update information on survival. METHODS: We followed a cohort of 3983 cases within the Austrian Brain Tumour Registry. All patients were newly diagnosed from 2005 to 2010 with a histologically confirmed non-malignant CNS tumour. Vital status, cause of death, and population life tables were obtained by 31 December 2011 to calculate relative survival. RESULTS: Overall 5-year relative survival was 96.1% (95% CI 95.1-97.1%), being significantly lower in tumours of borderline (90.2%, 87.2-92.7%) than benign behaviour (97.4%, 96.3-98.3%). Benign tumour survival ranged from 86.8 for neurofibroma to 99.7% for Schwannoma; for borderline tumours survival rates varied from 83.2 for haemangiopericytoma to 98.4% for myxopapillary ependymoma. Cause of death was directly attributed to the CNS tumour in 39.6%, followed by other cancer (20.4%) and cardiovascular disease (15.8%). CONCLUSION: The overall excess mortality in patients with non-malignant CNS tumours is 5.5%, indicating a significant improvement in survival over the last decade. Still, the remaining adverse impact on survival underpins the importance of systematic registration of these tumours.

RNA-based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference.

Heterozygous germline mutations in one of the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 cause hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, a dominantly inherited cancer susceptibility syndrome. Recent reports provide evidence for a novel recessively inherited cancer syndrome with constitutive MMR deficiency due to biallelic germline mutations in one of the MMR genes. MMR-deficiency (MMR-D) syndrome is characterized by childhood brain tumors, hematological and/or gastrointestinal malignancies, and signs of neurofibromatosis type 1 (NF1). We established an RNA-based mutation detection assay for the four MMR genes, since 1) a number of splicing defects may escape detection by the analysis of genomic DNA, and 2) DNA-based mutation detection in the PMS2 gene is severely hampered by the presence of multiple highly similar pseudogenes, including PMS2CL. Using this assay, which is based on direct cDNA sequencing of RT-PCR products, we investigated two families with children suspected to suffer from MMR-D syndrome. We identified a homozygous complex MSH6 splicing alteration in the index patients of the first family and a novel homozygous PMS2 mutation (c.182delA) in the index patient of the second family. Furthermore, we demonstrate, by the analysis of a PMS2/PMS2CL "hybrid" allele carrier, that RNA-based PMS2 testing effectively avoids the caveats of genomic DNA amplification approaches; i.e., pseudogene coamplification as well as allelic dropout, and will, thus, allow more sensitive mutation analysis in MMR deficiency and in HNPCC patients with PMS2 defects.

Histopathological prognostic factors in medulloblastoma: high expression of survivin is related to unfavourable outcome.

Standard postoperative treatment of medulloblastoma consists of craniospinal irradiation and chemotherapy. Currently, only clinical factors are used for therapy stratification. To optimise treatment and patient outcome, biological prognostic markers are needed. In the present study we tested the prognostic influence of four histopathological parameters considered in recent publications as prognostic factors in medulloblastoma. We analysed a series of 82 Austrian medulloblastoma patients who were treated according to the consecutive HIT protocols for medulloblastoma conducted by the German Society of Paediatric Haematology and Oncology. Histological subtype and immunohistochemical expression of erbB-2, TRKC, and survivin were determined on paraffin embedded tumour tissue and correlated with patient outcome. Statistical analysis showed a significant correlation of high expression levels of survivin with decreased survival. None of the other investigated histopathological factors correlated significantly with patient outcome. Our data indicate that high survivin expression is related to unfavourable clinical outcome in medulloblastoma patients.

myc gene amplification and expression in primary human neuroblastoma.

Although N-myc amplification in neuroblastomas correlates with poor prognosis, not all neuroblastomas which fail to respond to therapy have N-myc amplification. To determine whether other modes of myc gene activation underlie progression of some neuroblastomas, 45 were analyzed for amplification of N-myc, c-myc and L-myc and 26 were studied for transcription of these oncogenes. N-myc amplification was found in 6 of 45 tumors; no tumor had amplification of c-myc or L-myc. Transcription of both N-myc and c-myc occurred in 21 of 26 neuroblastomas. No tumor without N-myc amplification had a level of N-myc expression near that of a tumor or cell line with amplification. One tumor with N-myc amplification was the only specimen with N-myc but not c-myc expression. Five samples had c-myc but not N-myc expression; all had histological features of ganglioneuroma. DNA index did not correlate with myc gene amplification or expression. It is concluded that N-myc and c-myc are commonly expressed in primary untreated neuroblastomas, but in the absence of N-myc amplification, expression of these genes does not appear to correlate with disease progression.

miR-200a-mediated suppression of non-muscle heavy chain IIb inhibits meningioma cell migration and tumor growth in vivo.

miR-200a has been implicated in the pathogenesis of meningiomas, one of the most common central nervous system tumors in humans. To identify how miR-200a contributes to meningioma pathogenesis at the molecular level, we used a comparative protein profiling approach using Gel-nanoLC-MS/MS and identified approximately 130 dysregulated proteins in miR-200a-overexpressing meningioma cells. Following the bioinformatic analysis to identify potential genes targeted by miR-200a, we focused on the non-muscle heavy chain IIb (NMHCIIb), and showed that miR-200a directly targeted NMHCIIb. Considering the key roles of NMHCIIb in cell division and cell migration, we aimed to identify whether miR-200a regulated these processes through NMHCIIb. We found that NMHCIIb overexpression partially rescued miR-200a-mediated inhibition of cell migration, as well as cell growth in vitro and in vivo. Moreover, siRNA-mediated silencing of NMHCIIb expression resulted in a similar migration phenotype in these cells and inhibited meningioma tumor growth in mice. Taken together, these results suggest that NMHCIIb might serve as a novel therapeutic target in meningiomas.

Immunity against vaccine-preventable potentially neurotropic diseases in children treated for malignant brain tumours with HIT-91 chemo- and radiotherapy.

Following surgery, chemotherapy and/or irradiation, patients with malignant brain tumours are at risk of neurotropic diseases, although these are partly vaccine-preventable. In a retrospective, controlled, observational study, the impact of the German-Austrian chemo- and radiotherapy protocol (HIT-91) on antibody concentrations against vaccine-preventable diseases and on vaccination behaviour was analysed. A significant level of seronegativity for measles- and mumps-IgG, and a reduced protection induced by inactivated vaccines was observed after HIT-91 therapy. Failure of seroconversion following measles and mumps live vaccinations was assessed in the HIT-91-treated group and in a group with benign brain tumours (BBT). Analysis of cellular immunological parameters revealed significant aberrations in the HIT-91-treated group 36 months after completion of HIT-91 therapy. A retrospective analysis of the patient's vaccination history revealed an incorrect risk perception concerning the choice of vaccinations. We therefore recommend clinical vaccination with serosurveillance in patients who have undergone treatment for brain tumours.

DNA topoisomerase IIalpha expression in optic pathway gliomas of childhood.

DNA topoisomerase IIalpha (Topo IIalpha) is linked to tumour cell growth and chemoresistance. We examined immunohistochemically Topo IIalpha expression levels in a series of 36 consecutive paediatric optic pathway glioma (OPG) patients. Topo IIalpha labelling index (LI) ranged from 0.0 to 11.6 and was significantly associated with patient age, with higher levels of Topo IIalpha in children < or = 3 years (P=0.031). Topo IIalpha expression did not correlate with patient survival. Topo IIalpha LI was not significantly increased in specimens of repeat surgery. Topo IIalpha LI closely correlated with MIB-1 LI (R=0.781, P<0.001). We conclude that Topo IIalpha expression correlates with tumour cell proliferation in paediatric OPGs. Assessment of cell proliferation, however, does not assist in refining prognostic predictions. Enhanced Topo IIalpha expression in children < or = 3.0 years suggests that Topo IIalpha-interfering anticancer compounds for adjuvant treatment of OPGs may be of particular benefit to young children.

Combined postoperative irradiation and chemotherapy for anaplastic ependymomas in childhood: results of the German prospective trials HIT 88/89 and HIT 91.

PURPOSE: To evaluate the outcome in children with anaplastic ependymomas after surgery, irradiation, and chemotherapy; and to identify prognostic factors for survival. METHODS AND MATERIALS: Fifty-five children (n = 27 girls, 28 boys; median age at diagnosis, 6.2 years) with newly diagnosed anaplastic ependymomas were treated in the multicenter, prospective trials HIT 88/89 and HIT 91. Macroscopic complete resection was achieved in 28 patients; 27 patients underwent incomplete resection. All patients received chemotherapy before (n = 40) or after irradiation (n = 15). The irradiation volume encompassed either the neuraxis followed by a boost to the primary tumor site (n = 40) or the tumor region only (n = 13). No radiotherapy was administered in two patients. RESULTS: Median follow-up was 38 months. The overall survival rate at 3 years after surgery was 75.6%. Disease progression occurred in 25 children with local progression occurring in 20. The median time to disease progression was 45 months. The only significant prognostic factor was the extent of resection (estimated progression-free survival [EPFS] after 3 years was 83.3% after complete resection and 38.5% after incomplete resection) and the presence of metastases at the time of diagnosis (0% vs. 65.8% 3-year EPFS in localized tumors). Age, sex, tumor site, mode of chemotherapy, and irradiation volume did not influence survival. CONCLUSIONS: Treatment centers should be meticulous about surgery and diagnostic workup. Because the primary tumor region is the predominant site of failure it is important to intensify local treatment. Dose escalation by hyperfractionation or stereotactic radiotherapy might be a promising approach in macroscopically residual disease. The role of adjuvant chemotherapy requires further study.

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.

Hyaluronidase additional to standard chemotherapy improves outcome for children with malignant brain tumors.

Ex vivo experiments with vital brain tumor samples show that hyaluronidase enhances the permeation of carboplatin into tumor tissue with a matrix rich in hyaluronic acid. We achieved long-lasting second remissions for children with relapsed malignant brain tumors treated with carboplatin, etoposide and this enzyme. Thereafter, we initiated a pilot study where we added hyaluronidase to the first line standard therapy to prevent the deadly relapses right from the beginning. All 19 patients with malignant brain tumors admitted to our pediatric neurooncological center from 1992 to 1994 were included in the study. Kaplan-Meier estimation of event-free survival and overall survival after 3 years follow-up indicates a significantly better outcome for the hyaluronidase-treated group. The children receiving supportive hyaluronidase suffered significantly less relapses (P = 0.034) and had a significantly better chance for survival (P = 0.045) compared to the historical control of 21 children treated with the same standard regimen but without supportive hyaluronidase (product limit analysis and the log-rank test, P < 0.05). Children aged >3 years receiving hyaluronidase together with primary treatment seemed to gain the most benefit.

Anesthetic management of marrow harvesting from a 7-week-old premature baby.

Bone marrow was harvested from a 3.95 kg premature 7-week-old female baby for donation to a 13 kg HLA-identical sister with severe aplastic anemia. Two hundred ml of donor bone marrow were aspirated, containing a calculated dose of 3 x 10(8)/kg nucleated bone marrow cells for the recipient. This was equivalent to two-thirds of the donor's calculated blood volume (320 ml). Peri-operative care included invasive monitoring of intravascular pressures, arterial blood gas analysis, careful temperature control and the infusion of 150 ml of packed red cells, 150 ml of colloid and 50 ml of crystalloid. Rapid engraftment occurred. There were no complications and both donor and recipient are healthy 12 months later.

Endocrine function after bone marrow transplantation without the use of preparative total body irradiation.

Ten children who underwent allogeneic (n = 5) or autologous (n = 5) bone marrow transplantation (BMT) for chronic myelogenous leukaemia (n = 2), acute lymphoblastic leukaemia (n = 1), acute myelogenous leukaemia (n = 2), severe aplastic anaemia (n = 2), malignant histiocytosis (n = 1), neuroblastoma (n = 1) and teratoma (n = 1) were assessed for endocrinological function. Transplant preparative regimens consisted of high-dose cyclophosphamide, high-dose cyclophosphamide in combination with high-dose busulphan, high-dose melphalan as well as BACT (BCNU, cytarabine, cyclophosphamide and 6-thioguanine) chemotherapy. None of the patients received total body irradiation (TBI). Median survival following BMT was 37 months (range 7-115). Growth hormone deficiency was present in only one patient; none of the patients had abnormal thyroid or adrenocortical function. This is in contrast to previous reports in which growth hormone deficiency and abnormal thyroid and adrenocortical function occurred in a much higher percentage of patients after BMT conditioned with TBI.

Successful treatment of CMV retinitis with ganciclovir after allogeneic marrow transplantation.

Cytomegalovirus (CMV) infection of the retina is a well recognized complication in patients with the acquired immune deficiency syndrome but is rarely seen after bone marrow transplantation (BMT). Among a variety of drugs ganciclovir so far appears to be the most effective therapy for CMV retinitis, but in previous studies relapses occurred in all patients in whom ganciclovir was interrupted. We report the clinical findings in a 22-year-old BMT recipient who developed bilateral exudative CMV retinitis 64 days after BMT despite prophylactic treatment with high-titer CMV-immunoglobulins and transfusions of CMV-negative blood products and donor bone marrow. During a 12 day course of treatment with 7.5 mg/kg/day of ganciclovir the CMV retinitis improved and viruria ceased on day 4 of therapy. In contrast to the previous reports, CMV retinitis in this patient continued to improve even after ganciclovir was stopped and eventually complete healing of all intraretinal lesions as well as total reconstitution of the visual acuity was achieved. He is now free of disease and without relapse of CMV retinitis more than 1 year after transplantation.

Busulfan/cyclophosphamide plus bone marrow transplantation is not sufficient to eradicate the malignant clone in juvenile chronic myelogenous leukemia.

Bone marrow transplantation plays an essential role in the successful treatment of both juvenile and adult chronic myelogenous leukemia. Recently, it has been reported that conditioning with high doses of busulfan can successfully replace total body irradiation (TBI), in patients with acute myelogenous leukemia as well as adult chronic myelogenous leukemia. We report here the case of a 29-month-old boy with juvenile chronic myelogenous leukemia (JCML) transplanted with HLA-identical bone marrow after conditioning with busulfan, etoposide and cyclophosphamide. Successful engraftment was followed by early relapse on day 67. A second HLA-identical transplant was performed following myeloablative treatment with TBI. Engraftment was once again successful and the patient remains free of disease more than 24 months after transplantation. We conclude that busulfan is insufficient in eradicating JCML and that TBI is required prior to transplantation.

MR findings in methotrexate-induced CNS abnormalities.

MR of the brain was performed in eight patients (mean age, 14.9 years) with osteogenic sarcoma during or after IV treatment with high-dose methotrexate. MR detected brain abnormalities in four patients, three of whom had concomitant neurologic dysfunction. Pathologic findings demonstrated on MR were (1) chronic brain edema, demonstrable over a period of 3-14 months (proved by autopsy in one patient); (2) multifocal white matter necrosis; and (3) deep brain atrophy. MR appears to be valuable in the detection of abnormalities induced by treatment with high-dose methotrexate.

[Use of autologous bone marrow transplantation in pediatric malignant diseases--results and conclusions]. / Die Anwendung der autologen Knochenmarkstransplantation (AKMT) bei pädiatrischen malignen Erkrankungen--Ergebnisse und Schlussfolgerungen.

Ultrahigh-dose myeloablative antineoplastic therapy followed by autologous bone marrow transplantation (ABMT) has become an attractive therapeutic option for patients without HLA compatible bone marrow donors. Autologous bone marrow was harvested in 9 patients. In four cases the bone marrow was also treated ex vivo with a stable derivative of 4-hydroperoxycyclophosphamide, ASTA-Z 7654, to eliminate residual tumour cells. Altogether 5 patients, namely a patient with metastatic neuroblastoma, a patient with malignant histiocytosis, a patient with recurrent sacrococcygeal malignant teratoma and two patients with acute myelogenous leukaemia in first remission are in continuous remission so far from 125 + to 821 + days (median 657 + days). These patients were transplanted at the time of minimal tumour load (first remission) and in good clinical condition 3-7 months after diagnosis, while 3 of the four patients who died were transplanted in first or repeated relapse after one to several years of chemotherapy. It is concluded that the earliest possible recognition of a refractory therapeutic situation is of utmost importance for successful ABMT. Patients with an unfavourably responding neoplasm should, therefore, be already primary candidates for ABMT.

[High-dose busulfan with subsequent bone marrow transplantation in poor-risk forms of leukemia]. / Hochdosiertes Busulfan mit anschliessender Knochenmarkstransplantation bei ungünstigen Leukämieformen.

The toxicity and potential late side effects of total body irradiation, especially in children, have caused the evaluation of alternative myeloablative agents. We report the results obtained in 4 patients with acute myelocytic leukaemia, 2 patients with acute lymphocytic leukaemia and 1 patient with chronic myelocytic leukaemia who received high-dose busulfan followed by bone marrow transplantation (4 times allogeneic, 3 times autologous), according to the protocol published by G. W. Santos. 4 patients have survived 708+, 413+, 313+ and 234+ days, respectively, to date, 3 patients died, two of whom had acute myelocytic leukaemia in relapse and died of cardiac and combined organ failure 9 and 10 days post transplantation, respectively, without evidence of leukaemic cells in the bone marrow. One patient with acute lymphocytic leukaemia (T-All) in second remission died of an extramedullary relapse 485 days after bone marrow transplantation. We report our experience in the use of busulfan before transplantation not only in patients with acute myelocytic leukaemia, but also in patients with acute lymphocytic leukaemia and chronic myelocytic leukaemia and discuss the effectiveness and toxicity of high-dose busulfan as alternative to total body irradiation.

[Infections in the neutropenic phase following bone marrow transplantation: comparison of laminar airflow isolation with conventional isolation]. / Infektionen während der neutropenischen Phase nach Knochenmarktransplantation: Vergleich einer laminaren Air-flow-Isolation mit einer konventionellen Isolation.

From May 1978 to September 1989 45 patients underwent 25 allogeneic and 21 autologous bone marrow transplantations (BMT) and 1 peripheral stem cell transplantation for the following indications: severe aplastic anemia (n = 4), hematological malignancies (n = 28), malignant solid tumours (n = 12) and sideroblastic anemia (n = 1). The first group of 20 patients was isolated in a conventional hospital room, while management of the aplastic phase in the second group of 25 patients was performed in a laminar air flow (LAF) unit. All patients received total decontamination. In a retrospective analysis the number of positive blood cultures during the neutropenic period was 85% in the first group, as compared with 40% in the second group, and the number of febrile episodes was 85% versus 64%, respectively. Despite the fact that the septic morbidity was lower in the LAF group, mortality during the neutropenic period (15% in group I versus 16% in group II) was unaffected and survival rate (45% in group I versus 36% in group II) did not improve. We conclude that LAF protection will only have a positive impact on survival rate if the incidence of non-infectious complications of BMT, such as organ toxicity or graft-versus-host disease, is likewise reduced.

ABO-incompatible bone marrow transplantation: prevention of hemolysis by alkaline hydration with mannitol diuresis in conjunction with red cell reduced buffy coat bone marrow.

Bone marrow transplantation (BMT) in the presence of major ABO incompatibility presents the risk of a potentially fatal hemolytic transfusion reaction at the time of marrow infusion. We describe the use of a forced alkaline hydration/mannitol diuresis regimen in combination with red blood cell (RBC) reduced bone marrow given as buffy coat in 5 patients undergoing allogeneic BMT from ABO incompatible donors. Three patients had ABO antibody titers of 1:32 and were not subjected to antibody removal procedures. Two patients with respective antibody titers of 1:512 and 1:128 underwent plasmapheresis to reduce the antibody titers to below 1:64. The forced diuresis/mannitol regimen was well tolerated. Although the RBC content was still high in the buffy coat preparation a significant hemolytic transfusion reaction was successfully prevented. No patient had back pain, hyperbilirubinemia or renal impairment despite clinical and laboratory evidence of hemoglobinuria. These data indicate that patients with antibody titers below 1:64 might be spared the risks and cost associated with plasmapheresis or complete RBC depletion of the bone marrow transplant.

[Immunosuppressive treatment of severe aplastic anemia with high-dose methylprednisolone and antithymocyte globulin in 2 patients]. / Immunosuppressive Behandlung der schweren aplastischen Anämie mit hochdosiertem Methylprednisolon und Antithymozytenglobulin bei 2 Patienten.

This article describes the treatment of two patients with severe aplastic anaemia (SAA) by means of high-dose methylprednisolone ( HDMP ) and antithymocyte globulin (ATG). A complete normalization of the haematological data was obtained in one patient, which has persisted now for 10 months. ATG and HDMP seem to provide an alternative mode of treatment of SAA to bone marrow transplantation if there is no histocompatible bone marrow donor available.