Showing papers in "Journal of Neuro-oncology in 2005"
TL;DR: Brain metastases are the most common tumors of the central nervous system (CNS), but cancer databases are often incomplete leading to underestimation of the incidence of even symptomatic brain metastases, which may lead to the development of more efficient therapies to combat brain tumor growth.
Abstract: Metastases are the most common tumors of the central nervous system (CNS), but cancer databases are often incomplete leading to underestimation of the incidence of even symptomatic brain metastases. Brain imaging studies are not routinely performed on neurologically asymptomatic cancer patients and autopsy studies are outdated. Furthermore, while incidence rates for cancers are stable and mortality is decreasing due to earlier detection and better therapy, the incidence of brain metastases appears to be increasing. The pathophysiology of brain metastases is a complex multistage process, mediated by molecular mechanisms; from the primary organ, cancer cells must transform, grow and be transported to the CNS where they can lay dormant for various lengths of time before invading and growing further. Understanding the pathophysiology of brain metastases is of great importance, because it may lead to the development of more efficient therapies to combat brain tumor growth or to possibly make the CNS an undesirable environment for tumor progression.
791 citations
TL;DR: Pre-treatment MRI examinations of 100 immunologically competent patients with biopsy-proven PCNSL revealed a uniformly pathologic pattern of metabolite concentrations in all patients, and DW-MRI and proton spectroscopy may aid in differential diagnosis.
Abstract: To avoid an unnecessary extend of surgery in primary central nervous system lymphoma (PCNSL), the diagnosis should be suspected after MRI.
330 citations
TL;DR: Quality of life scores, reported by both survivors and their caretakers, were in the normal range, and severe neuropsychological and psychosocial deficiencies justify further attempts to reduce or delay the use of craniospinal radiation therapy for childhood medulloblastoma.
Abstract: Purpose: Survivors of medulloblastoma, the most frequently occurring malignant brain tumor of childhood, suffer neuropsychological damage in the first decade after diagnosis. Cognitive performance, psychosocial functioning and quality of life were assessed in medulloblastoma survivors in the second decade after diagnosis. Methods: Ten year survivors were evaluated with a battery of neuropsychological tests, and self-report questionnaires regarding quality of life and emotional functioning. Clinical variables examined included the patient’s age at diagnosis, duration since diagnosis, treatment, and complications. Results: Sixteen medulloblastoma survivors [mean age at diagnosis: 7.2 years, range: 1–15 years; 6 males] were tested at a mean age of 22.2 years [range: 13.6–27.9 years]. All survivors had been treated with craniospinal radiation therapy; nine were treated with chemotherapy. Significant impairments were identified in more than 50 of survivors on tests within all neuropsychological domains, including attention, memory, visuospatial abilities, motor functioning, language, and executive functioning. Significant impairments were also identified in all psychosocial domains examined, including employment, ability to drive an automobile, participation in normal education, independent living, and dating history. Most importantly, quality of life scores, reported by both survivors and their caretakers, were in the normal range. Conclusion: Survivors of childhood medulloblastoma frequently suffer severe persistent deficits in a wide-range of neuropsychological functional domains. Nevertheless, survivors and their families do not report impaired quality of life. These severe neuropsychological and psychosocial deficiencies justify further attempts to reduce or delay the use of craniospinal radiation therapy for childhood medulloblastoma.
203 citations
TL;DR: Clinically, the key feature is progressive ipsilateral involvement of cranial nerves and the overall prognosis is poor, with an overall median survival of about 2.5 years, probably because skull-base metastases appear late in the course of the disease.
Abstract: Metastasis to the skull-base particularly affects patients with carcinoma of the breast and prostate. Clinically, the key feature is progressive ipsilateral involvement of cranial nerves. Five syndromes have been described according to the metastatic site including the orbital, parasellar, middle-fossa, jugular foramen and occipital condyle syndromes. Magnetic resonance imaging (MRI) is nowadays the most useful examination to establish the diagnosis but plain films, CT scans with bone windows and isotope bone scans remain helpful to demonstrate bone erosion. Normal imaging studies do not exclude the diagnosis. The treatment depends on the nature of the underlying tumor. Radiotherapy is generally the standard treatment, while some patients with chemosensitive or hormonosensitive lesions benefit from chemotherapy or hormonotherapy and selected patients from surgical removal. Gamma Knife radiosurgery is sometimes a useful alternative, particularly for previously irradiated skull-base regions, and for small tumors (diameter < 30 mm). The overall prognosis is poor, with an overall median survival of about 2.5 years, probably because skull-base metastases appear late in the course of the disease.
203 citations
TL;DR: For the first time, the presence of MRP3 and MRP5 is detected on glioma specimens – both in tumor and endothelial cells – and an expression profile of chemoresistance proteins in gliomas is delineated.
Abstract: Chemotherapy in glioma is poorly effective: the blood-brain barrier and intrinsic and/or acquired drug resistance of tumor cells could partly explain this lack of major effect We investigated expression of P-glycoprotein (Pgp), multidrug resistance protein (MRP) 1, MRP3, MRP5 and glutathione-S-transferase pi (GST-pi) in malignant glioma patients Cytofluorimetric analysis of 48 glioma specimens and 21 primary cultures showed high levels of MRP1, moderate levels of MRP5 and low levels of Pgp, GST-pi and MRP3 Immunohistochemistry (25 glioma specimens) showed expression of GST-pi (667% of cases), MRP1 (513%), MRP5 (458%), Pgp (348%) and MRP3 (299%) in tumor cells Moreover, analysis of tumor samples by real time quantitative PCR showed mRNA expression of all investigated genes Tumor vasculature, analyzed in glioma specimens and in tumor derived endothelial cells, showed expression of all investigated proteins Non-tumor brain samples (from a patient with arteriovenous malformation and from one with epilepsy), normal human astrocytes and cultured endothelial cells were also analyzed: astrocytes and endothelial cells expressed the highest levels of the investigated proteins, mainly MRP1 and MRP5 No significant differences in proteins expression were detected between primary or recurrent gliomas, suggesting that glioma chemoresistance is mostly intrinsic Therefore, we detected, for the first time, the presence of MRP3 and MRP5 on glioma specimens--both in tumor and endothelial cells--and we delineated an expression profile of chemoresistance proteins in glioma The possible association of inhibitors of drug efflux pumps with chemotherapy could be investigated to improve drugs delivery into the tumor and their cytotoxic effects
196 citations
TL;DR: Results indicate that AED influence the pharmacokinetics of chemotherapeutic drugs in patients with GBM, and valproic acid might be responsible for increasing haematotoxicity.
Abstract: The co-administration of antiepileptic drugs (AED) and chemotherapeutic agents in patients with glioblastoma multiforme (GBM) is common. Interactions of chemotherapeutic agents and AED have not been investigated sufficiently. The purpose of this study is to evaluate the effects of enzyme inducing (EI-AED) and non-EI-AED in patients with GBM treated with standard chemotherapeutic agents on survival and haematotoxicity. One hundred and sixty eight glioblastoma patients with standard treatment including surgery, radiotherapy and chemotherapy were retrospectively analysed. Patients were separated into three groups: Group A patients without AED (n=88), Group B patients with EI-AED (n=43), and Group C patients with non-EI-AED (n=37). CCNU was the most frequently used first-line drug in all three groups (Group A: 77%; Group B: 81%; Group C: 78%). Second line treatment, mainly temozolomide, was applicated in 58 of patients and third-line treatment in 9. Carbamazepine was the most frequently administered AED in Group B (81%) and valproic acid in Group C (85%). For statistical analysis, only patients with CCNU first line treatment were calculated. A significant difference regarding survival was detected between Group B (10.8 month) and Group C (13.9 month), as well as increased haematotoxicity for Group C. These results indicate that AED influence the pharmacokinetics of chemotherapeutic drugs in patients with GBM. Valproic acid might be responsible for increasing haematotoxicity. Whether the difference regarding survival between Group B and Group C is due to a decrease of efficacy of chemotherapeutic agents by EI-AED, or due to increased efficacy of chemotherapeutic agents caused by the enzyme inhibiting properties of valproic acid, has to be evaluated in future studies.
178 citations
TL;DR: Observations raise the possibility that the heterogeneity in glucose metabolism and, in particular, the sole expression of LDH-B, might identify an important biological marker of glioma cells that is critical for their progression and that might afford a new target for anticancer drugs.
Abstract: The current study examined specific bioenergetic markers associated with the metabolic phenotype of several human and mouse glioma cell lines. Based on preliminary studies, we hypothesized that glioma cells would express one of at least two different metabolic phenotypes, possibly acquired through progression. The D-54MG and GL261 glioma cell lines displayed an oxidative phosphorylation (OXPHOS)-dependent phenotype, characterized by extremely long survival under glucose starvation, and low tolerance to poisoning of the electron transport chain (ETC). Alternatively, U-251MG and U-87MG glioma cells exhibited a glycolytic-dependent phenotype with functional OXPHOS. These cells displayed low tolerance to glucose starvation and were resistant to a ETC blocker. Moreover, these cells could be rescued in low glucose conditions by oxidative substrates (e.g., lactate, pyruvate). Finally, these two phenotypes could be distinguished by the differential expression of LDH isoforms. OXPHOS-dependent cells expressed both LDH-A and -B isoforms whereas glycolytic-dependent glioma cells expressed only LDH-B. In the latter case, LDH-B would be expected to be essential for the use of extracellular lactate to fuel cell activities. These observations raise the possibility that the heterogeneity in glucose metabolism and, in particular, the sole expression of LDH-B, might identify an important biological marker of glioma cells that is critical for their progression and that might afford a new target for anticancer drugs.
171 citations
TL;DR: A sub-group of patients, tentatively defined here, may benefit from an aggressive treatment that relies mainly on focal irradiation and intrathecal or systemic chemotherapy and studies using other therapeutic approaches such as new biological or cytotoxic compounds are ongoing.
Abstract: Leptomeningeal metastases (LMM) consist of diffuse involvement of the leptomeninges by infiltrating cancer cells. In solid tumors, the most frequent primary sites are lung and breast cancers, two tumors where the incidence of LMM is apparently increasing. Careful neurological examination is required to demonstrate multifocal involvement of the central nervous system (CNS), cranial nerves, and spinal roots, which constitute the clinical hallmark of the disease. Cerebro-spinal fluid (CSF) analysis is almost always abnormal but only a positive cytology or demonstration of intrathecal synthesis of tumor markers is diagnostic. T1-weighted gadolinium-enhanced sequence of the entire neuraxis (brain and spine) plays an important role in supporting the diagnosis, demonstrating the involved sites and guiding treatment. Radionuclide CSF flow studies detect CSF compartmentalization and are useful for treatment planning. Standard therapy relies mainly on focal irradiation and intrathecal or systemic chemotherapy. Studies using other therapeutic approaches such as new biological or cytotoxic compounds are ongoing. The overall prognosis remains grim and quality of life should remain the priority when deciding which treatment option to apply. However, a sub-group of patients, tentatively defined here, may benefit from an aggressive treatment.
147 citations
TL;DR: The frame-based approach, however, required significantly less anesthesia resources, less operating room time and shorter hospital stays, and thus should still be considered a first-line approach for stereotactic brain biopsy.
Abstract: Object: As the availability of image-guided surgical navigation systems has increased, the application of frame-based biopsy has declined at our institution, despite equivalent accuracy and safety. There are several cost issues separating the use of surgical navigation systems and stereotactic frames for simple biopsy which may have implications in this era of health care cost control. We retrospectively reviewed the UCSF experience with stereotactic brain biopsy from a 9 year period. Methods: Data were collected for 213 consecutive stereotactic brain biopsies performed at UCSF (139 frame-based and 74 frameless). There were no significant differences between the frame-based and frameless biopsy groups with regard to patient demographics, overall histopathology, proportion of nondiagnostic biopsies, or incidence of complications. General anesthesia was used for 9 (6%) and 70 (95%) of the frame-based and frameless biopsy cases, respectively. Frame-based biopsies required a mean of 114 ± 3 min of operating room time, while frameless biopsies required 185 ± 6 min (P < 0.0001). For patients admitted to our neurosurgery service who underwent frame-based (n=110) or frameless (n=52) biopsy within 24 h of admission, the mean lengths of hospital stay were 1.8 ± 0.2 and 3.2 ± 0.6 days, respectively (P=0.007). Conclusion: Frame-based and frameless stereotactic biopsy approaches were equally effective at providing a tissue diagnosis with minimum morbidity and mortality. The frame-based approach, however, required significantly less anesthesia resources, less operating room time and shorter hospital stays, and thus should still be considered a first-line approach for stereotactic brain biopsy.
137 citations
TL;DR: It is concluded that TMZ combined with CDDP is an active and well-tolerated combination in patients with brain metastases from solid tumors.
Abstract: Purpose: To evaluate the efficacy of temozolomide (TMZ) combined with cisplatin (CDDP) in terms of response rate, time to progression (TTP) and overall survival (OS), as well as the tolerability of the regimen in patients with brain metastases from solid tumors
114 citations
TL;DR: Posterior or lateral tumor position in the spinal canal, location below C4, age less than 60 years, and duration of preoperative symptoms seem to be correlated with a good outcome.
Abstract: Intraspinal meningiomas are slow growing benign tumors that produce indolent neurological deficits, which are often reversible following operation. It is unclear, if there is a correlation between postoperative neurological restoration and histopathological parameters. The aim of the present work was to seek for existence of such parameters. Retrospectively, we reviewed the charts of 33 patients with spinal meningiomas who were operated on from January 1980 through December 1995. Histological classification was performed according to WHO criteria. Laminoplasty or hemilaminoplasty was performed in 29 patients (88%) and suboccipital craniotomy with cervical laminoplasty in 4 patients (12%). Mean age of the 30 women (91%) and the 3 men (9%) was 63 ± 20 years (range 22–88). Spinal meningiomas were of high-cervical location in 9 (27%) and of low-cervico–thoracic location in 24 (73%) patients. Tumor position was laterally in 19 (58%), posteriorly in 8 (24%) and anteriorly in 6 (18%) patients. Histological classification was psammomatous in 22 (66%), fibroblastic in 7 (22%) and meningothelial in 4 (11%) patients. Following tumor resection, neurological deficits resolved in 26 of 33 patients (79%) and worsened in 7 of 33 patients (21%) all of the latter had meningiomas of the psammomatous type. Resection of psammomatous meningiomas of the spine is associated with a less favorable neurological outcome postoperatively than resection of spinal meningiomas of other pathological subtypes. Posterior or lateral tumor position in the spinal canal, location below C4, age less than 60 years, and duration of preoperative symptoms seem to be correlated with a good outcome.
TL;DR: Spinal cord epidural metastasis is a common complication of systemic cancer with an increasing incidence and the prognosis is usually poor and preferred modality of treatment is radiotherapy.
Abstract: Spinal cord epidural metastasis (SEM) is a common complication of systemic cancer with an increasing incidence. Prostate, breast and lung cancer are the most common offenders. Metastasis usually arises in the posterior aspect of vertebral body with later invasion of epidural space. Pathophysiologically, vascular insufficiency is more important than direct spinal cord compression. The most common complaint is pain, and two thirds of patients with SEM have motor signs at initial diagnosis. Currently magnetic resonance imaging is the most sensitive diagnostic tool. The optimal management of SEM is still arguable, but recent advances in surgical management of SEM and higher complication rate of surgery following radiotherapy should persuade clinicians to consider de novo surgery where possible. Radiotherapy has an important role, particularly in treatment of radiosensitive tumors and in patients who are not candidates for surgery. Novel approaches such as stereotactic radiosurgery are promising; however, response to chemotherapy depends on inherent properties of primary tumor. Recurrent SEM is a substantial problem for which surgery or repeat radiotherapy may be options. Intramedullary metastasis is rare but should be considered in patients with systemic malignancy and asymmetrical presentation of myelopathic symptoms. The prognosis is usually poor and preferred modality of treatment is radiotherapy.
TL;DR: Attention has been refocused on disease control instead of radiotherapy avoidance and risk factors for tumor control and late effects, and testing novel agents in the treatment of ependymoma.
Abstract: Recent advances in neuroimaging, neurosurgery and radiation therapy have improved disease control and functional outcomes for children with ependymoma, including children under the age of 3 years. The rate of gross-total resection has been increased to 85% in some series and 3 year progression-free survival after radiation therapy as high as 75% has been reported along with significant reductions in neurologic, endocrine and cognitive deficits. Based on these advances and renewed interest in radiation therapy as a frontline treatment modality, attention has been refocused on disease control instead of radiotherapy avoidance. Future research in the treatment of this tumor, that afflicts fewer than 200 children in the US each year, will focus on molecular biology, clarifying risk factors for tumor control and late effects, and testing novel agents.
TL;DR: Routine use of AED prophylaxis in patients with brain tumors undergoing neurosurgical procedures remains the prevailing practice pattern among members of the AANS.
Abstract: Introduction: The American Association of Neurology issued guidelines discouraging the prophylactic use of anti-epilepsy drugs (AEDs) in patients with brain tumors. We surveyed neurosurgeons to evaluate practice patterns with regard to using AEDs in neurosurgical patients with brain tumors. Methods: The survey consisted of 18 questions. Two group email blasts containing an internet link to the survey were sent to members of the American Association of Neurological Surgeons with email addresses. Uni- and multi-variate analysis of the responses was performed using t-test, Fisher’s exact test, or chi-squared test, where appropriate. Results: The response rate was 15.5% (386/2491). The majority of respondents (270/386; 70.0%) had more than 5 years of experience in neurosurgery. Most respondents described their practices as general (224/379; 59.1%); about one-third were members of the Joint Section on Tumors (136/381; 35.7%). More than 70% of respondents reported routine use of AED prophylaxis for patients with intra-axial gliomas or brain metastases. AED prophylaxis was also routinely used for extra-axial benign tumors or stereotactic biopsies by 53.8% and 21.4%, respectively. On multivariate analysis, the number of years in practice of ABNS certified neurosurgeons was the strongest predictor for the use of AED prophylaxis. Conclusions: Routine use of AED prophylaxis in patients with brain tumors undergoing neurosurgical procedures remains the prevailing practice pattern among members of the AANS. Additional larger prospective studies with appropriate patient stratification culminating in development of neurosurgical guidelines on AED prophylaxis in brain tumor patients is warranted.
TL;DR: Investigation of the correlation between MRS, DWI, histopathology and Ki-67 labeling index in a large number of brain tumors found that high Glx/Cr in vivo MRS index was a good predictor of tumor grading.
Abstract: With the advent of fast imaging hardware and specialized software, additional non-invasive magnetic resonance characterization of tumors has become available through proton magnetic resonance spectroscopy (MRS), hemodynamic imaging and diffusion-weighted imaging (DWI). Thus, patterns could be discerned to discriminate different types of tumors and even to infer their possible evolution in time. The purpose of this study was to investigate the correlation between MRS, DWI, histopathology and Ki-67 labeling index in a large number of brain tumors. Localized proton spectra were obtained in 47 patients with brain tumors who subsequently underwent surgery (biopsy or tumor removal). We performed MRS with short echo-time (30 ms) and metabolic values in spectra were measured using an external software with 25 peaks. In all patients who had DWI, we measured apparent diffusion coefficients (ADC) in the same region of interest (ROI) where the voxel in MRS was located. In most tumors the histological diagnosis and Ki-67 labeling index had been determined on our original surgical specimen. Cho/Cr, (Lip+Mm)/Cr, NAA/(Cho+Cr) and Glx/Cr indexes in MRS allowed discriminating between low- and high-grade gliomas and metastases (MTs). Likewise, absolute ADC values differentiated low- from high-grade gliomas expressed by Ki-67 labeling index. A novel finding was that high Glx/Cr in vivo MRS index (similar to other known indexes) was a good predictor of tumor grading.
TL;DR: Complete resection alone in spinal cord ependymoma can achieve excellent local control and survival, and postoperative local radiotherapy is recommended and it can also achieve excellentLocal Control and survival.
Abstract: Purpose: To evaluate the effectiveness of complete resection and postoperative radiotherapy in spinal cord ependymomas. Methods and materials: We conducted a retrospective study over 20 patients (13 males and 7 females) with histologically confirmed spinal cord ependymomas between July 1985 and April 2001. Among them, 13 patients had ependymomas, 6 had myxopapillary ependymomas, and 1 had anaplastic ependymoma. All patients received radical surgery for tumor removal with 13 patients achieving complete resection and 7 incomplete resection due to technical difficulty. Among those with incomplete resection, 6 patients received postoperative radiotherapy to tumor bed and only one patient with anaplastic ependymoma received surgery alone. The total tumor dose ranged from 50 to 60 Gy. Results: Among the 20 patients, 19 patients were alive and showed local control. The median survival time of all patients was 109 months, with 104 months in the complete resection alone group and 135 months in the incomplete resection with postoperative radiotherapy group. One patient with anaplastic ependymoma and no postoperative radiotherapy developed leptomeningeal seeding 9 months after surgery. Salvage therapy of radiotherapy and chemotherapy maintained normal neurological functions. The patient expired 34 months from the initial diagnosis due to progression of leptomeningeal seeding. Conclusion: Complete resection alone in spinal cord ependymoma can achieve excellent local control and survival. Patients should receive complete resection if technically possible. Postoperative radiotherapy is not recommended for complete resection. For incomplete resection, postoperative local radiotherapy is recommended and it can also achieve excellent local control and survival. Local radiotherapy with 50-60 Gy is effective and safe. Salvage radiotherapy improves quality of life for local recurrence or leptomeningeal seeding patients.
TL;DR: It is demonstrated that among multiple known targets of LY 294002, PI3-kinase is the most likely molecule responsible for LY294002-induced radiosensitization and PKB/Akt is identified as the downstream molecule that mediates the synergistic cytotoxicity between LY284002 and radiation.
Abstract: The phosphoinositide 3-kinase (PI3-kinase) signaling pathway is frequently aberrantly activated in glioblastoma multiforme (GM) by mutation or loss of the 3' phospholipid phosphatase PTEN. PTEN abnormalities result in inappropriate signaling to downstream molecules including protein kinase B (PKB/Akt), and mammalian target of rapamycin (mTOR). PI3-kinase activation increases resistance to radiation-induced cell death; conversely, PI3-kinase inhibition enhances the sensitivity of tumors to radiation. The effects of LY294002, a biochemical inhibitor of PI3-kinase, on the response to radiation were examined in the PTEN mutant glioma cell line U251 MG. Low doses of LY294002 sensitized U251 MG to clinically relevant doses of radiation. In contrast to LY294002, rapamycin, an inhibitor of mTOR, did not result in radiosensitization. We demonstrate that among multiple known targets of LY294002, PI3-kinase is the most likely molecule responsible for LY294002-induced radiosensitization. Furthermore, using a myristoylated PKB/Akt construct, we identified PKB/Akt as the downstream molecule that mediates the synergistic cytotoxicity between LY294002 and radiation. Thus PI3-kinase dysregulation may contribute to the notable radioresistance of GM tumors and inhibition of PKB/Akt offers an excellent target to enhance radiosensitivity.
TL;DR: Although rare, malignant transformation of intracranial epithelial cysts has a poor prognosis and surgery followed by radiotherapy seems to be the best therapeutic modality.
Abstract: Introduction: Epidermoid and dermoid cysts are among the most benign intra cranial tumors. Their malignant transformation into squamous cell carcinoma is rare. The authors reviewed the literature. Materials and Methods: MEDLINE and SCIENCE DIRECT searches, and examination of the references in the selected articles yielded 74 patients, 52 of whom fulfilled Garcia’s criteria and were selected for the study. Survival analyses were performed to determine whether survival differences were of statistical significance, and P < 0.05 was considered as significant. Results: Malignant transformation is characterized by a rapid onset of symptoms, recurrence, leptomeningeal carcinomatosis (LC), and tumor enhancement at Computed Tomography Scan or Magnetic Resonance Imaging (87.8 showed this radiological feature). In this review, the SCCs were classified in five groups– (1) Initial malignant transformation of a benign cyst; (2) malignant transformation from a remnant cyst; (3) malignant transformation of a dermoid and epithelial cyst; (4) malignant transformation with leptomeningeal carcinomatosis; (5) other malignancies arising from benign cysts. The median survival was 9 months. Statistics show that LC was of poor prognosis and radiotherapy, although not statistically significant, seems effective against such lesions, with a median survival of 26 months as opposed to 3 months (P=0.077). Conclusion: Although rare, malignant transformation of intracranial epithelial cysts has a poor prognosis and surgery followed by radiotherapy seems to be the best therapeutic modality.
TL;DR: Evidence is provided that repeated subcutaneous and intracranial implantation experiments in nude mice using PAX6-stable transfectants provided solid evidence that PAX6 suppressed tumor growth in vivo and significantly extended mouse survival.
Abstract: Purpose: Glioblastomas (GBMs) are the most common primary malignant brain tumors. Majority of GBMs has loss of heterozygosity of chromosome 10. The PAX6 encodes a transcription factor that involves in development of the brain, where its expression persists. We have reported that the expression of PAX6 was significantly reduced in GBMs and that a low level of PAX6 expression is a harbinger of an unfavorable prognosis for patients with malignant astrocytic glioma. Interestingly, PAX6 expression was increased in suppressed somatic cell hybrids derived from introducing a normal human chromosome 10 into U251 GBM cells. Thus it is interesting to determine if repression of PAX6 expression is involved in anti-tumor suppression function in GBM.
TL;DR: It is discovered that Δ9-THC decreases cell proliferation and increases cell death of human GBM cells more rapidly than WIN 55,212-2 and was also more potent at inhibiting the proliferation of G BM cells compared to WIN55,212,2.
Abstract: Normal tissue toxicity limits the efficacy of current treatment modalities for glioblastoma multiforme (GBM). We evaluated the influence of cannabinoids on cell proliferation, death, and morphology of human GBM cell lines and in primary human glial cultures, the normal cells from which GBM tumors arise. The influence of a plant derived cannabinoid agonist, Δ9-tetrahydrocannabinol Δ9-THC), and a potent synthetic cannabinoid agonist, WIN 55,212-2, were compared using time lapse microscopy. We discovered that Δ9-THC decreases cell proliferation and increases cell death of human GBM cells more rapidly than WIN 55,212-2. Δ9-THC was also more potent at inhibiting the proliferation of GBM cells compared to WIN 55,212-2. The effects of Δ9-THC and WIN 55,212-2 on the GBM cells were partially the result of cannabinoid receptor activation. The same concentration of Δ9-THC that significantly inhibits proliferation and increases death of human GBM cells has no significant impact on human primary glial cultures. Evidence of selective efficacy with WIN 55,212-2 was also observed but the selectivity was less profound, and the synthetic agonist produced a greater disruption of normal cell morphology compared to Δ9-THC.
TL;DR: Investigation of the incidence, treatment, prognosis, and reports of long term survival in a few cases with Wilms’ tumor, osteosarcoma and alveolar soft part sarcoma who had isolated brain metastasis suggest that a subset of patients may benefit from therapy.
Abstract: Objectives: Brain is a rare site of metastasis in most extracranial pediatric solid tumors. The aim of this study is to investigate the incidence, treatment, prognosis of brain metastasis in extracranial pediatric malignant tumors in a single institution and to review the literature.
TL;DR: The HFX regimen delayed but did not eliminate severe neurotoxicity from chemoradiation in PCNSL patients, and PFS and overall survival were not significantly affected.
Abstract: Purpose: To determine whether a lower dose of hyperfractionated whole brain radiation reduces central nervous system morbidity without compromising survival for primary CNS lymphoma (PCNSL) patients receiving combined modality treatment. Materials and Methods: One hundred and two patients received a course of pre-radiation chemotherapy, followed by whole brain radiation, followed by cytosine-arabinoside. Initial radiation dose was 45 Gy/25 fractions (RT) then the study was amended to reduce this dose for complete responders to induction chemotherapy to 36 Gy/30 fractions/3 weeks (HFX). Eighty-two patients received radiotherapy and were evaluable for toxicity analysis (66 RT patients and 16 HFX patients). MMSE scores and survival for the 40 patients who received radiotherapy after complete response to chemotherapy (27 RT and 13 HFX) were compared. There were no notable differences in pre-treatment patient characteristics between the RT and HFX groups. Results: Neurotoxicity: By 4 years, there were 8/82 (10%) grade 5 neurotoxicities which included 2/16 (13%) grade 5 encephalopathies and 0/27 in the RT group of complete responders to chemotherapy. Survival: There was no statistically significant difference in overall or progression-free survival (PFS) between the chemotherapy-complete responders who received RT and HFX. Cognitive function testing: MMSE scores improved at 8 months across both treatment groups. Analysis of the area under the MMSE curve at 8 months showed no statistically significant difference between RT and HFX groups (P=0.81). Leukoencephalopathy occurred later in the HFX group than in the RT patients. Conclusion: Although the HFX schedule represented a 25% reduction in biologically effective tumor dose in comparison, PFS and overall survival were not significantly affected. The HFX regimen delayed but did not eliminate severe neurotoxicity from chemoradiation in PCNSL patients.
TL;DR: Four children, two with newly diagnosed CNS AT/RT and two with progressive disease after multi-agent chemotherapy who are long term survivors are reported on using a combination of surgery, radiation therapy, and intensive chemotherapy.
Abstract: Atypical teratoid/rhabdoid tumors (AT/RT) are highly malignant lesions of childhood that carry a very poor prognosis. AT/RT can occur in the central nervous system (CNS AT/RT) and disease in this location carries an even worse prognosis with a median survival of 7 months. In spite of multiple treatment regimens consisting of maximal surgical resection (including second look surgery), radiation therapy (focal and craniospinal), and multi-agent intravenous, oral and intrathecal chemotherapy, with or without high-dose therapy and stem cell rescue, only seven long-term survivors of CNS AT/RT have been reported, all in patients with newly diagnosed disease. For this reason, many centers now direct such patients, particularly those under 5 years of age, or those with recurrent disease, towards comfort care rather than attempt curative therapy. We now report on four children, two with newly diagnosed CNS AT/RT and two with progressive disease after multi-agent chemotherapy who are long term survivors (median follow-up of 37 months) using a combination of surgery, radiation therapy, and intensive chemotherapy. The chemotherapy component was modified from the Intergroup Rhabdomyosarcoma Study Group (IRS III) parameningeal protocol as three of the seven reported survivors in the literature were treated using this type of therapy. Our four patients, when added to the three reported survivors in the literature using this approach, suggest that patients provided this aggressive therapy can significantly alter the course of their disease. More importantly, we report on the first two survivors after relapse with multi-agent intravenous and intrathecal chemotherapy treated with this modified regimen.
TL;DR: Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system neoplasm that usually affects very young children and is typically deadly despite very aggressive treatment.
Abstract: Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system neoplasm that usually affects very young children and is typically deadly despite very aggressive treatment Considered rare, the tumor was not recognized as a distinct entity until the 80's, due to its similar features with other primitive tumors Although AT/RT has become increasingly recognized, published data has been based on small series and are retrospective Based on these data, there are occasional long-term survivors, most of whom received intensive multi-modal therapy AT/RT is the first pediatric brain tumor for which a candidate tumor suppressor gene has been identified A mutation or deletion in the INI1 gene occurs in the majority of AT/RT tumors The function of the gene is not yet understood Prospective clinical and biologic trials are greatly needed to understand the efficacy of therapeutic interventions, as well as the role of the gene
TL;DR: It is concluded that HDCT may improve survival rates in patients with high risk/recurrent medulloblastoma and stPNET despite treatment toxicity.
Abstract: Current treatment for high risk and recurrent medulloblastoma (MB) and supratentorial primitive neuroectodermal tumors (stPNET) has a very poor prognosis in children. High dose chemotherapy (HDCT) and autologous stem cell rescue have improved survival rates. We present 19 patients (thirteen classified in the high risk group and six patients with recurrent disease) that received HDCT and autologous stem cell rescue.
TL;DR: Stereotactically guided fractionated re-irradiation is a safe and effective treatment modality in selected cases of recurring glioblastoma multiforme and further evaluation in larger patient collectives is warranted.
Abstract: Purpose. To assess the feasibility, efficacy and toxicity of fractionated stereotactic radiotherapy in the treatment of recurrent glioblastoma multiforme.
TL;DR: Preliminary and published results from trials of gefitinib in recurrent GBM show no increased time to progression or overall survival (OS) compared with historical controls, and studies with erlotinib show greater antitumor activity in patients with GBM than with gefITinib, although the impact of both agents on OS remains unclear.
Abstract: Glioblastoma multiforme (GBM) is a highly malignant brain tumor with limited therapeutic options, a high recurrence rate and mortality. Standard therapy is maximal surgical resection and radiotherapy (RT). Recent data suggest combining temozolomide with RT is better than RT alone. Adjuvant chemotherapy has a modest impact on survival. For relapsed patients there is no standard therapy, but options include chemotherapeutic agents or new agents in development. One approach to improve outcome is using targeted agents that interfere with cell-surface receptors or intracellular signaling pathways. Between 40% and 50% of GBM tumors show HER1/EGFR dysregulation, and almost half co-express the constitutively active mutant receptor subtype EGFRvIII, which may contribute to the aggressive and refractory course of GBM. Numerous studies show a relationship between aberrant HER1/EGFR biology and tumorigenicity in GBM cells. Two available HER1/EGFR tyrosine kinase inhibitors (TKIs) are gefitinib (Iressa®) and erlotinib (Tarceva™); both show antitumor and radiosensitization effects in vitro and in animal models of GBM. Clinical trials in patients with GBM and other gliomas are ongoing. Preliminary and published results from trials of gefitinib in recurrent GBM show no increased time to progression or overall survival (OS) compared with historical controls. Studies with erlotinib show greater antitumor activity in patients with GBM than with gefitinib, although the impact of both agents on OS remains unclear. GBM treatment with HER1/EGFR TKIs alone or combined with other targeted therapies and conventional modalities deserve further investigation and refinement, as does our understanding of their mechanisms of action and the role of genetics.
TL;DR: Results suggest that β-catenin mutations may contribute to the initiation and subsequent growth of congenital craniopharyngiomas.
Abstract: Craniopharyngiomas and pituitary adenomas are both tumors of the hypothalamic and pituitary region, respectively that are frequently associated with endocrine defects either because of direct involvement of hormone producing cells (most pituitary tumors) or because of secondary defects due to disturbance of hypothalamic function (some pituitary tumors and craniopharyngiomas). Some studies suggest that mutant beta-catenin gene cells in craniopharyngiomas and pituitary adenomas contribute to their tumorigenesis. DNA was extracted from 73 cranial tumors and subjected to polymerase chain reaction (PCR) with previously described primers encompassing glycogen synthase kinase-3beta phosphorylation sites of the beta-catenin gene. Sequenced PCR products for possible beta-catenin gene mutations showed a total of 7/43 alterations in adamantinomatous craniopharyngioma-derived DNA samples. Two previously described beta-catenin mutations in codon 33 TCT(Ser) > TGT(Cys) and codon 37 TCT(Ser) > TTT(Phe), whereas three novel mutations in codon 41 ACC(Thr) > ATC(Ile), codon 33 TCT(Ser) > TAT(Tyr) and codon 32 GAC(Asp) > AAC(Asn) were observed. None of the 22 pituitary adenomas and the eight papillary craniopharyngiomas analyzed presented any sequence alterations. These findings demonstrate an association between beta-catenin gene alterations and craniopharyngiomas of the adamantinomatous type. Since this gene product is involved with development, these results suggest that beta-catenin mutations may contribute to the initiation and subsequent growth of congenital craniopharyngiomas.
TL;DR: Irradiation enhanced VEGF secretion in all three tested glioma cell lines (up to eight times basal levels) was found, tempting to associate the radiation-enhanced VEGf secretion with an increased angiogenic potential of the tumor, which may be a factor in radioresistance.
Abstract: Objective: Postoperative radiotherapy is standard treatment for patients with a glioblastoma multiforme (GBM). However, a GBM is radioresistant and almost always recurs, even after a high dose of radiation. A GBM is characterized by its extensive neo-angiogenesis, which can be attributed to the high levels of vascular endothelial growth factor (VEGF). The scope of this study is to investigate the VEGF secretion by GBM cells with different radiosensitivity after irradiation. Methods:Three human GBM cell lines (U251, U251-NG2 and U87) were irradiated with single doses of 0, 5, 10 and 20 Gy of γ-rays from a 137Cs source. VEGF levels in medium were measured by ELISA at 24, 48 and 72 h after radiation. Cell survival was measured by the XTT assay 7 days after irradiation. Results:Following single dose radiation, the VEGF levels showed a dose dependent increase in U251, U251-NG2 and U87 glioma cells. Both base-line and radiation-enhanced VEGF levels were about 10-fold higher in U87 compared to U251 and U251-NG2 cells. In addition, in the XTT assay, the U87 was more radioresistant than both U251 and U251-NG2 cell lines (dose modifying factor (DMF) = 1.6 and 1.7 resp). Conclusion:Irradiation enhanced VEGF secretion in all three tested glioma cell lines (up to eight times basal levels). It is tempting to associate the radiation-enhanced VEGF secretion with an increased angiogenic potential of the tumor, which may be a factor in radioresistance.
TL;DR: In 2003, a symposium was held to discuss the current state of progress and future challenges for the convection enhanced delivery (CED) technique as mentioned in this paper, and the focus of the CED Symposium was on the potential use of this novel drug delivery technology to enhance the delivery of chemotherapy to malignant brain tumors.
Abstract: In January 2003 a symposium was held to discuss the current state of progress and future challenges for the recently described technique of convection enhanced delivery (CED). The focus of the CED symposium was on the potential use of this novel drug delivery technology to enhance the delivery of chemotherapy to malignant brain tumors. The international panel of invited speakers included individuals who had a significant role in pioneering the concept of CED, were actively pursuing new areas of investigation into the uses of CED and/or who were directing the first clinical trials using CED in patients with malignant brain tumors. Topics covered included the physiology of the blood brain barrier, basic principles of CED, application of CED to the treatment of brain tumors, and research models that have been developed to further refine the technique of CED. Each speaker’s talk has been abstracted and a list of relevant references has been compiled.