Relapse patterns in pediatric embryonal central nervous system tumors

To evaluate in a single center retrospectively the efficacy and tolerability of a weekly regimen, which alternates temozolomide (TMZ) in patients with recurrent or progressive high-grade glioma (HGG). From January 2005 until June 2011, 54 patients with recurrent or progressive HGG were treated with TMZ 150 mg/m²/day on days 1–7 and 15–21 of a 28-day cycle (“one week on–one week off” scheme; TMZ 7/14) with individual dose adjustment depending on toxicity. The majority of patients (n = 48, 89 %) was treated at first tumor recurrence or progression. All patients had received prior radiotherapy with or without concomitantly administered TMZ and, optionally, adjuvant chemotherapy. After initiation of TMZ 7/14, MRI was obtained every 8–12 weeks. Tumor response or progression was assessed according to Macdonald criteria. Blood examinations were performed weekly. Toxicity was evaluated according to Common Terminology Criteria for Adverse Events (CTCAE; version 3.0). A total of 434 treatment weeks with TMZ 7/14 were delivered. The median number of treatment weeks was 7 (range, 1–41 weeks). No grade 4 hematological toxicity and no opportunistic infections occurred. Patients with neutropenia were not observed. Two patients developed grade 3 and 4 patients grade 2 leukocytopenia. Thrombocytopenia grade 3 and grade 2 occurred in 4 patients and 6 patients, respectively. The progression-free survival (PFS) rate at 6 months was 43 %. Median PFS from treatment initiation was 18 weeks (95 % CI, 14–22 weeks) and median overall survival (OS) was 37 weeks (95 % CI, 31–42 weeks). The rates for PFS and OS at 1 year were 24 and 28 %, respectively. Our data suggest that treatment with TMZ 7/14 is safe and effective in patients with recurrent or progressive HGG.     

Differentiation in embryonal neuroepithelial tumors of the central nervous system.

Ninety-six embryonal neuroectodermal tumors were studied histologically and immunohistologically with a panel of antibodies including glial, neuronal, epithelial, mesodermal, and myelin markers. In 71 tumors there was glial and neuronal differentiation and expression both of an S (photoreceptor) antigen and vimentin. In five tumors there was only glial differentiation and in 20 tumors only neuronal differentiation. No reactivity for myelin and epithelial markers was found. Histologic and immunohistologic findings identified various degrees of differentiation in different tumors, which was bipolar (glial and neuronal) in most tumors and unipolar in the remainder. The authors suggest that their findings may be the result of normal or aberrant oncogenic differentiation, agreeing with the nomenclature of the World Health Organization classification for these tumors with and the inclusion of a category for ependymoblastoma.     

Liposomal cytarabine for central nervous system embryonal tumors in children and young adults

To assess the tolerability and efficacy of liposomal cytarabine (LC), an encapsulated, sustained-release, intrathecal (IT) formulation of cytosine arabinoside, in de novo and relapsed central nervous system (CNS) embryonal tumors in children and young adults. We studied retrospectively all patients less than age 30 at our institution treated consecutively with LC for medulloblastoma (MB), primitive neuroectodermal tumor (PNET), and atypical teratoid rhabdoid tumor (ATRT). Seventeen patients received LC (2 mg/kg up to 50 mg, every 2 weeks to monthly) at diagnosis of high-risk CNS embryonal tumor (2 PNET, 3 ATRT) or relapse of MB (12 MB; 9 had leptomeningeal metastases). Sixteen patients received concurrent systemic chemotherapy. A total of 108 doses were administered (IT 82, intraventricular 26) with a mean of six (range 1–16) treatments per patient. Only three administrations were associated with adverse effects of arachnoiditis or headache. None developed malignant cerebrospinal fluid (CSF) cytology while receiving LC. All the six evaluable patients with malignant CSF cytology and treated with at least two doses cleared their CSF (mean 3 doses, range 1–5). Median overall survival in relapse patients was 9.1 months. Five patients (4 de novo and 1 relapsed) remain alive in complete remission for a median 26.8 months from first LC. Liposomal cytarabine is an easily administered, well-tolerated, and active drug in patients with high-risk embryonal neoplasms. One-third of our cohort remains in remission from otherwise fatal diagnoses. Our findings warrant a phase II trial of LC in newly diagnosed or recurrent CNS embryonal tumors.     

Inhibitors of histone deacetylases as potential therapeutic tools for high-risk embryonal tumors of the nervous system of childhood

The origin of malignant embryonal tumors is incompletely understood and certain risk groups remain difficult to treat. The epigenetic structure of DNA and its lesions play a role in the origin of these neoplasms. Manipulation of the epigenome may offer novel treatment options. The authors evaluated the cytotoxicity of histone deacetylase inhibitors (HDI) [MS-275, SAHA, TSA, M344, M360, D85, SW55, SW187 and valproic acid (VPA)] on 13 embryonal tumor cell lines [4 medulloblastomas, 5 neuroblastomas, 2 atypical teratoid/rhabdoid tumors (AT/RT), and 2 malignant rhabdoid tumors of the kidney (RTK)] in MTT assay. In addition, HDI effects on hyperacetylation, reexpression of growth regulatory genes and apoptosis were characterized by Western analysis, RT-PCR and annexin-V staining. All HDI inhibited cell proliferation in a time- and dose-dependent manner. VPA was least cytotoxic with GI50 values after 72 hr ranging from 53.6 to 332.9 microM, while TSA was most efficient with GI50 values after 72 hr ranging from 0.01 to 8.8 microM. M344 and M360 were also highly effective. Western blot revealed hyperacetylation of histone H4 after HDI treatment. Reactivation of several genes including the proapoptotic CASP8 was identified by RT-PCR. Annexin-V staining demonstrated a dose and time dependent induction of apoptosis. HDI inhibited the growth of medulloblastoma, neuroblastoma and rhabdoid tumors in vitro. Treatment with HDI induced the reactivation of growth regulatory genes and consequently apoptosis. Our results warrant further studies and may help in the design of new protocols geared at the treatment of high risk embryonal tumors.     

Evaluation of osteopontin as biomarker for pancreatic adenocarcinoma.

OBJECTIVES: Pancreatic adenocarcinoma is a deadly disease with an overall 5-year patient survival of less than 5%. This dismal prognosis of pancreatic cancer is largely due to the advanced stage of the disease at presentation. If pancreatic cancer could be diagnosed more readily and accurately using serum markers, patient survival could theoretically be improved by enabling more patients to avail of surgical resection. One candidate tumor marker recently identified by global gene expression analysis of pancreatic cancer is the secreted glycophosphoprotein osteopontin (OPN). In this study, we evaluate OPN as a serum marker of pancreatic adenocarcinoma. METHODS: In situ hybridization for OPN was performed on a pancreatic adenocarcinoma tissue microarray. Serum OPN levels were determined in preoperative sera from 50 patients with pancreatic cancer and 22 healthy control individuals by competitive ELISA. RESULTS: In situ hybridization for OPN performed on a tissue microarray revealed strong OPN mRNA signal in tumor-infiltrating macrophages in 8 of 14 pancreatic adenocarcinomas. In contrast, OPN expression was not seen in the pancreatic cancer cells themselves, nor was it seen in normal pancreatic tissue or in the macrophages distant from the infiltrating cancer. Serum OPN levels, as measured by ELISA, were elevated in the sera of 50 patients with resectable pancreatic adenocarcinoma compared to 22 healthy control individuals (mean +/- SD for OPN was 482 +/- 170 ng/ml and 204 +/- 65 ng/ml, respectively; P < 0.001). Using a cutoff level of 2 SD above the mean for healthy individuals, elevated OPN had sensitivity of 80% and specificity of 97% for pancreatic cancer. In contrast, only 62% of these patients with resectable pancreatic cancer had elevated CA19-9. CONCLUSIONS: Serum OPN may have utility as a diagnostic marker in patients with pancreatic cancer.     

Neuroimaging for central nervous system tumors

Advances in neuroimaging techniques have now provided clinicians with the ability to detect CNS neoplasms at an earlier stage and to measure responses to therapy. However, errors in performing or interpreting these studies can lead to erroneous conclusions that may subsequently influence therapeutic decisions. The exact delineation of areas of tumor involvement in the brain has improved with newer imaging techniques, but this too is problematic in some patients. Evaluations of response to treatment can also be complicated by technical artifacts that can lead to inadequate differentiation of tumor from non-neoplastic tissues. Nevertheless, MRI and CT have helped clinicians to redefine the natural history of CNS tumors, reach earlier diagnoses, improve the accuracy of radiotherapy, explain adverse treatment responses, and exclude conditions that are not related directly to the tumor but that can be responsible for clinical deterioration. Newer tests that have the ability to assess tumor metabolism will further increase our understanding of these pathological processes.     

Current immunotherapeutic strategies for central nervous system tumors

Immunotherapy has emerged as a promising tool in the management of malignant central nervous system tumors. Despite improvement in patient survival, traditional approaches, which consist mostly of surgery, radiotherapy, and chemotherapy, have been largely unsuccessful in permanently controlling these aggressive tumors. Immunotherapeutic strategies offer not only a novel approach but also an advantage in a way other modalities have been failing. Specifically, the capabilities of the immune system to recognize altered cells while leaving normal cells intact offer tremendous advantage over the conventional therapeutic approaches. This article summarizes our current understanding of immunotherapeutic treatment modalities used in clinical trials for management of malignant central nervous system tumors.     

Glioneuronal tumors of the central nervous system

Advances in the immunohistochemical detection of neuron-specific and neuronal-associated antigens have resulted in the discovery of neuronal elements in certain primary human brain tumors. The results have been not only to expand what neuropathologists commonly recognize as gangliogliomas, including the tumors now known as glioneurocytic tumor with neuropil rosettes and papillary ganglioneuroma, but also to expand the spectrum of tumor types to now include tumors such as central neurocytoma, dysembryoplastic neuroepithelial tumor, and desmoplastic infantile ganglioglioma. These discoveries have helped us to better understand the biology of these tumors and to refine our classification of them. Distinctions among these tumors include sites of predilection, such as the temporal lobe with the dysembryoplastic neuroepithelial tumors, and a spectrum of clinical aggressiveness that spans indolent “quasihamartomatous” lesions, such as the dysembryoplastic neuroepithelial tumor, to high-grade, highly aggressive tumors, such as the supratentorial primitive neuroectodermal tumor (World Health Organization Grade IV). Many of these tumors also commonly exhibit a glial component, as determined by both their histologic appearance and their immunoreactivity for glial fibrillary acidic protein. This review covers these recently described lesions, including the desmoplastic infantile ganglioglioma, the dysembryoplastic neuroepithelial tumor, the papillary glioneuronal tumor, the glioneuronal tumor with neuropil rosettes, and the mixed glioblastoma-cerebral neuroblastoma (supratentorial primitive neuroectodermal tumor), as well as the known tumors, ganglioglioma, medulloepithelioma, and medulloblastoma. For pathologists confronted by this growing array of tumors and subtypes, it is appropriate to focus on them and understand the differential diagnosis to be considered when confronted by them.     

Chemotherapy for metastatic tumors to the central nervous system

Management of patients with central nervous system metastases poses numerous challenges. This review focuses on the use of chemotherapy in these patients, addressing treatment difficulties such as drug resistance and possible solutions. The impact of the blood-brain barrier is considered less of a limitation than once thought. The advent of targeted signal transduction inhibitors is noted in this context. The current efficacy of chemotherapeutic agents and combinations is also discussed, with results from large studies highlighting a positive survival trend for chemotherapy in selected tumor histologies.     

Clinical epidemiology for childhood primary central nervous system tumors

This work was conducted by the French Brain Tumor Data Bank (FBTDB) and aims to prospectively record all primary central nervous system tumors (PCNST), in France, for which histological diagnosis is available. Results concerning children are presented. This study analyzes the childhood cases (0–19 years) of newly diagnosed and histologically confirmed PCNST (during the years 2004–2006) which have been recorded by the FBTDB. All French neuropathology and neurosurgery departments participated in this program. Neurosurgeons and neuropathologists completed a data file containing socio-demographic, clinical, radiologic and anatomopathologic information. The Tumor Registry from Herault was authorized to compile the data files with personal identifiers. About 1,017 cases (533 boys and 484 girls) of newly diagnosed childhood PCNST have been recorded (gliomas: 52%, all other neuroepithelial tumors: 31%, craniopharyngioma: 5%, germ cell tumors, meningioma and neurinoma: approximately 3% each, all histological subtypes have been detailed). Tumor resections were performed in 83.3%, and biopsies in 16.7%. The distributions by histology, cryopreservation of the samples, age, sex, tumor site and surgery have been detailed. To our knowledge, this work is the first databank in Europe dedicated to PCNST that includes the collection of clinical, radiological and histological data (including cryopreservation of the specimen). The long term goals of the FBTDB are to create a national registry and a network to perform epidemiological studies, to implement clinical and basic research protocols, and to evaluate and harmonize the healthcare of children and adult patients affected by PCNST. Luc Bauchet, Valérie Rigau are equally contributed to this work.     

Circulating U2 small nuclear RNA fragments as a novel diagnostic biomarker for primary central nervous system lymphoma

Background

Primary central nervous system lymphomas (PCNSLs) are highly aggressive tumors. Chemotherapy has improved prognosis significantly; however, early diagnosis is crucial for effective treatment. Presently, the diagnosis of PCNSL depends on histopathology of tumor biopsies. We have previously demonstrated differential expression of microRNAs in cerebrospinal fluid (CSF) samples from patients with PCNSL. Based on promising findings about circulating U2 small nuclear RNA fragments (RNU2-1f) as novel blood-based biomarkers for pancreatic, colorectal, and lung cancer, we investigated RNU2-1f in the CSF of PCNSL patients.

Methods

CSF was collected from patients with PCNSL (n = 72) and control patients with various neurologic disorders (n = 47). Sequential CSF samples were collected from 9 PCNSL patients. RNU2-1f levels were measured by real-time polymerase chain reaction.

Results

Measurement of RNU2-1f levels in CSF enabled the differentiation of patients with PCNSL from controls with an area under the curve (AUC) of 0.909 with a sensitivity of 68.1% and a specificity of 91.4%. The diagnostic accuracy was further improved by combined determination of RNU2-1f and miR-21, resulting in AUC of 0.987 with a sensitivity of 91.7% and a specificity of 95.7%. In consecutive measurements of RNU2-1f, which were performed in 9 patients at different stages of the disease course, RNU2-1f CSF levels paralleled the course of the disease.

Conclusions

Our data suggest that the measurement of RNU2-1f detected in CSF can be used as a diagnostic marker and also as a possible marker for treatment monitoring. These promising results need to be evaluated within a larger patient cohort.     

Primary central nervous system germ cell tumors

Opinion statement The prognosis of primary germ cell tumors (germinal neoplasms) of the central nervous system varies, depending on the histology and size of tumor and the extent of disease at diagnosis. Although some patients receive therapy without a tissue diagnosis, it is strongly recommended that tumor tissue samples be obtained for accurate histologic diagnosis. Modern neurosurgical navigation techniques have made tissue sampling by stereotactic biopsy a safe and rapid method of determining tumor histology. Depending on tumor location, open surgical biopsy may be required in some patients. Typically, germinomas are exquisitely radiosensitive, although pre-irradiation chemotherapy reduces the total radiation exposure and may increase the cure rate. Induction cisplatin-based chemotherapy, followed by low-dose involved field radio-therapy, has excellent overall and relapse-free survival rates and is the optimal treatment for patients with germinomas. This combined chemoradiotherapy approach is associated with minimal endocrinopathy and minimal neurocognitive dysfunction. Patients with relapses after low-dose radiation therapy can respond well to salvage therapy (chemotherapy or chemoradiotherapy) without significant sequelae. Patients with nongerminomas respond best to chemotherapy combined with radiation, although the response and cure rates are lower compared to germinomas. Patients with residual masses and normal tumor markers after primary therapy should have a second-look resection because most patients have residual teratoma or necrotic tissue and can be spared additional chemotherapy or radiation. Pure mature teratomas are cured only by surgical extirpation. Immature central nervous system teratomas appear to benefit from radical surgical resection, but higher doses of locally directed radiotherapy are required with no benefit from the usual chemotherapy.     

Intraarterial chemotherapy and osmotic blood-brain barrier disruption for patients with embryonal and germ cell tumors of the central nervous system

BACKGROUND: The rate of durable responses in embryonal and certain germ cell tumors of the central nervous system (CNS) is unsatisfactory. Intraarterial chemotherapy and osmotic blood-brain barrier disruption (IA/BBBD) increases drug delivery to the CNS. METHODS: Data of patients treated with carboplatin or methotrexate-based IA/BBBD on prospective phase 2 trials conducted at 3 centers were collected. Study outcomes included overall survival (OS), time to progression (TTP), and toxicity. RESULTS: Fifty-four patients were treated. Twenty-seven patients received IA/BBBD as salvage treatment. The median OS was 2.8 years for all patients, 2.5 years for supratentorial and disseminated primitive neuroectodermal tumors (PNETs, n = 29), 1.7 years for medulloblastomas (n = 12), and 5.4 years for germ cell tumors (n = 13). OS and TTP for all patients were better with a Karnofsky Performance Status > or =70% (P = .0013 and .0070) and IA/BBBD as first-line treatment (P = .0059 and .029). In PNETs, OS was higher with pineal location (P = .045) and IA/BBBD as first-line treatment (P = .0036), and TTP was improved with radiotherapy before IA/BBBD (P = .036) and IA/BBBD as first-line treatment (P = .0079). Seventeen of 54 patients (31%) are alive, and 16 are alive at 4+ to 18+ years. Three survivors were not treated with radiotherapy and 4 were treated with focal radiotherapy only. The patients who were not irradiated did not develop dementia. CONCLUSIONS: Survival and toxicity data appear promising, considering the cohort's adverse prognostic profile. A plateau in survival curves suggests a cure for some patients. Long-term survival may be achieved with focal or reduced-dose radiotherapy in some IA/BBBD patients.     

High-dose chemotherapy with autologous stem cell transplantation in adults with recurrent embryonal tumors of the central nervous system

BACKGROUND: Embryonal central nervous system (CNS) tumors (medulloblastoma, cerebral neuroblastoma, pineoblastoma, and primitive neuroectodermal tumors) are rare in adults. Recurrent disease has an extremely poor outcome. The use of high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has demonstrated promising results in children with recurrent disease, but there are only limited data regarding its role in adults. The purpose of the current study was to evaluate adult patients with embryonal CNS tumors who were treated with HDC with ASCT and compare their outcomes with those of patients who received conventional-dose chemotherapy. METHODS: The authors reviewed the medical records of 23 adult patients (age >or= 18 years) who were treated at the Mayo Clinic for recurrent embryonal CNS tumors between 1976 and 2004. The authors compared treatment with HDC with ASCT (10 patients) with an historic control of patients treated with conventional-dose chemotherapy (nitrosourea based, cisplatin based, or both) (13 patients). RESULTS: HDC with ASCT was associated with increased survival (P= .044) and a longer time to disease progression (TTP) (P= .028). The conventional-dose chemotherapy group had a median TTP of 0.58 years and a median survival of 2.00 years. The HDC with ASCT group had a median TTP of 1.25 years and a median survival of 3.47 years. When restricted to patients receiving ASCT after first disease recurrence, the median TTP was 2.5 years and the median survival was 4.16 years. Toxicities were similar in both groups. CONCLUSIONS: Improvements in the median TTP and survival noted with the administration of HDC with ASCT, as well as the acceptable toxicity of this regimen, supports consideration of its use in adults with recurrent embryonal CNS tumors.     

MicroRNAs in cerebrospinal fluid as biomarker for disease course monitoring in primary central nervous system lymphoma

Diagnosis of primary lymphomas of the central nervous system (PCNSL) largely depends on histopathology of tumor biopsies. Recently, we identified miRNAs detected in the CSF of PCNSL patients as novel non-invasive biomarkers for this disease. In combined analyses of miR-21, miR-19b, and miR-92 CSF levels, it was possible to differentiate PCNSL from other neurological disorders. In the current study, we first confirmed our previous findings in an enlarged PCNSL cohort (n?=?39; sensitivity 97.4?%). Also, we sought to establish the potential role of CSF miRNAs as biomarkers for disease course monitoring. In sequential miRNA measurements in CSF derived from nine patients with different disease courses, an intriguing correlation of miRNA levels and PCNSL status during treatment and/or disease follow-up was demonstrated. Finally, we demonstrated that miRNA levels in serum of PCNSL patients (n?=?14) were not elevated as compared to controls. In summary, this study provides the first evidence that CSF miRNAs have the potential as biomarkers for treatment monitoring and disease follow-up of patients with PCNSL.     

Immunology of tumors of the central nervous system

Central nervous system (CNS) tumours possess special immunological features resulting from their development in an organ having a privileged immunological status. The following review gives a summary of actual data concerning their tumour-associated antigens, the immunological responses of their hosts and the mechanisms permitting them to escape from these responses. There is presently no proof of the existence of tumour-specific antigens on spontaneous glial tumours. Much progress has been made in this area with the development of monoclonal antibodies technology which mainly disclosed the profound antigenic heterogeneity of brain tumours. This heterogeneity could favour the escape of brain tumours from immunosurveillance; furthermore, it represents a major limitation to the use of monoclonal antibodies for diagnosis or therapy. Regarding the immunological responses of brain tumour patients, the main feature is a profound depression of cellular immunity creating an anergic state toward a large number of antigens. In vitro, it concerns specifically T4 helper lymphocytes: their mitogenic responses and secretion of interleukin-2 after antigenic stimuli are drastically reduced. Three phenomena have also been incriminated to explain the defect of immunosurveillance in brain tumour patients: 1) the synthesis by tumour cells of a protective mucopolysaccharidic coat, 2) the secretion by these cells of specific immunosuppressive factors related to cytokines, 3) the isolation of CNS maintained by the blood-brain barrier which regulates the circulation of immunocompetent cells between the intra- and extracerebral compartments. Currents efforts are focused on the individualization of therapy based on these biologic principles.     

Pediatric central nervous system germ cell tumors: a review

Central nervous system (CNS) germ cell tumors (GCTs) represent approximately 3% of primary pediatric brain tumors and encompass a wide pathologic spectrum. CNS GCTs are most commonly located in the pineal and suprasellar regions of the brain and can be divided into major groups including germinomas and nongerminomatous GCTs (NGGCTs), with teratomas often considered a separate category. The clinical presentation varies by location and size, and it frequently includes endocrine abnormalities, visual changes, and signs of increased intracranial pressure. Neuroimaging studies cannot differentiate GCTs from other tumors, and therefore, the diagnosis usually requires histologic confirmation. The rare exceptions are the cases where characteristic elevations of tumor markers, including alpha-fetoprotein and/or beta-human chorionic gonadotropin are documented in the serum and/or cerebrospinal fluid. In these cases, the imaging findings along with the tumor marker elevation may be diagnostic in themselves without the need for tissue confirmation. Treatment and prognosis differ greatly between groups. Germinomas have a superior prognosis than NGGCTs. Five-year overall survival rates >90% were reported initially with the use of craniospinal irradiation. More recently, the use of chemotherapy in addition to radiation therapy has afforded the ability to decrease the dose and volume of radiation therapy without affecting survival rates. NGGCTs are less radiosensitive than germinomas, but the use of adjuvant chemotherapy has improved survival rates in this group as well. The standard management for CNS GCTs remains controversial. Treatment regimens aimed to improve progression-free and overall survival times are ongoing.