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Biomedical subjects

J C Buckner

Publications and source records attributed to J C Buckner.

At least 19 recordsLinked to original sources
PubMed2001

PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme.

BACKGROUND: Survival of patients with anaplastic astrocytoma is highly variable. Prognostic markers would thus be useful to identify clinical subsets of such patients. Because specific genetic alterations have been associated with glioblastoma, we investigated whether similar genetic alterations could be detected in patients with anaplastic astrocytoma and used to identify those with particularly aggressive disease. METHODS: Tissue specimens were collected from 174 patients enrolled in Mayo Clinic Cancer Center and North Central Cancer Treatment Group clinical trials for newly diagnosed gliomas, including 63 with anaplastic astrocytoma and 111 with glioblastoma multiforme. Alterations of the EGFR, PTEN, and p53 genes and of chromosomes 7 and 10 were examined by fluorescence in situ hybridization, semiquantitative polymerase chain reaction, and DNA sequencing. All statistical tests were two-sided. RESULTS: Mutation of PTEN, amplification of EGFR, and loss of the q arm of chromosome 10 were statistically significantly less common in anaplastic astrocytoma than in glioblastoma multiforme (P =.033, P =.001, and P<.001, respectively), and mutation of p53 was statistically significantly more common (P<.001). Univariate survival analyses of patients with anaplastic astrocytoma identified PTEN (P =.002) and p53 (P =.012) mutations as statistically significantly associated with reduced and prolonged survival, respectively. Multivariate Cox analysis of patients with anaplastic astrocytoma showed that PTEN mutation remained a powerful prognostic factor after adjusting for patient age, on-study performance score, and extent of tumor resection (hazard ratio = 4.34; 95% confidence interval = 1.82 to 10.34). Multivariate classification and regression-tree analysis of all 174 patients identified EGFR amplification as an independent predictor of prolonged survival in patients with glioblastoma multiforme who were older than 60 years of age. CONCLUSION: PTEN mutation and EGFR amplification are important prognostic factors in patients with anaplastic astrocytoma and in older patients with glioblastoma multiforme, respectively.

Adolescent↗
PubMed2001

A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in the treatment of patients with newly diagnosed high-grade glioma.

BACKGROUND: The current study was conducted to determine whether the addition of interferon-alpha (IFN-alpha) to treatment with radiation therapy and carmustine (BCNU) improves time to disease progression or overall survival in patients with high-grade glioma. METHODS: Patients with anaplastic astrocytoma, anaplastic oligoastrocytoma, glioblastoma multiforme, or gliosarcoma received radiation therapy plus BCNU as initial therapy. Subsequently, patients without tumor progression at the completion of radiation therapy were stratified by age, extent of surgery, tumor grade and histology, Eastern Cooperative Oncology Group performance status, and treating institution, and then were randomly assigned to receive either BCNU alone (200 mg/m(2) on Day 1) or BCNU (150 mg/m(2) on Day 3) plus IFN--alpha (12 million U/m(2) on Days 1-3, Weeks 1, 3, and 5) every 7 weeks for a maximum of 6 cycles. RESULTS: Of the 383 patients enrolled in the study, 275 eligible patients were randomized. There was no significant difference with regard to time to disease progression or overall survival between the two groups. Patients receiving IFN-alpha experienced more fever, chills, myalgias, and neurocortical symptoms including somnolence, confusion, and exacerbation of neurologic deficits. Cox multivariate regression models confirmed known favorable prognostic variables including younger age, Grade 3 tumor (according to World Health Organization criteria), and greater extent of surgery. Cox and classification and regression tree analysis models also demonstrated that a normal baseline Folstein mini-mental status examination (MMSE) score was associated with better prognosis. CONCLUSIONS: IFN-alpha does not appear to improve time to disease progression or overall survival in patients with high-grade glioma and appears to add significantly to toxicity. The baseline MMSE score may serve as an independent prognostic factor and warrants further investigation.

Adult↗
PubMed2001

Oligodendrogliomas: reproducibility and prognostic value of histologic diagnosis and grading.

Prognostic value of histological grading of oligodendroglial tumors is controversial and interobserver reproducibility in grading of these tumors is unknown. Seven neuropathologists and 6 surgical pathologists experienced in brain tumor-diagnosis assessed 124 oligodendroglial tumors operated at the Mayo Clinic (1960-1990). Among histologic parameters upon which current oligodendroglioma grading systems are based, only high cellularity, presence of mitoses, microcalcifications, endothelial hypertrophy, endothelial proliferation, and necrosis appeared to be reproducible. Reproducible histologic features, based on consensus ratings among neuropathologists (defined as > 60%), were evaluated for the association with cause-specific survival by fitting Cox regression models. By univariate analysis, a significant association with survival was found for age, high cellularity, presence of mitoses, endothelial hypertrophy and proliferation and necrosis. On multivariable analysis with a stepwise variable selection method, only age and presence of endothelial proliferation were found to be independently associated with survival with a discriminatory index of the model of 0.68. Mitotic index was significantly associated with survival based on the grading from each separate neuropathologist, but it was not based on consensus, most likely because this was classified as indeterminate in 54% of cases. Alternatively, "models fit" considering the assessment of single neuropathologists, identified a model based on age and on mitotic index with similar discriminatory indices of 0.69-0.7. Our study found few factors independently associated with cause specific-survival among morphological parameters. These findings are consistent with the present WHO stratification of oligodendrogliomas into low- and high-grade variants.

Adult↗
PubMed2001

Management of malignant pineal germ cell tumors with residual mature teratoma.

OBJECTIVE: The treatment of intracranial mixed germ cell tumors presents a unique challenge, since eradication of malignant tumor by radiation and/or chemotherapy may spare the benign tumor component. We reviewed our surgical experience with residual malignant pineal germ cell tumors after neoadjuvant therapy. METHODS: Between 1987 and 1997, 16 patients with malignant intracranial germ cell tumors were treated at the Mayo Clinic with a protocol of neoadjuvant chemotherapy and radiation therapy. After the diagnosis was confirmed by histopathological examination, all patients were treated with four cycles of etoposide and cisplatin as well as external beam radiation therapy (range, 3030-5940 cGy). Six patients had an incomplete response to therapy, as demonstrated by observation of residual tumor on magnetic resonance imaging scans. Initial pathology in these six patients was germinoma in four and combinations of yolk sac tumor, embryonal carcinoma, malignant teratoma, and germinoma in two. Two patients had synchronous pineal and suprasellar tumors, with leptomeningeal dissemination. Tumor markers were elevated in four of the six patients at presentation. RESULTS: All patients with residual pineal tumors underwent surgical resection via an infratentorial, supracerebellar approach. Pathological examination revealed mature teratoma in five patients and amorphous debris in one patient. No patient had recurrent malignancy. Significant neurological morbidity occurred in one patient, with no mortality. At a mean follow-up of 23 months, no recurrence on magnetic resonance imaging has been documented. CONCLUSION: Residual pineal tumor occurring after treatment of malignant intracranial germ cell tumor with neoadjuvant therapy is likely to be mature teratoma. Operative resection of these benign recurrences is safe and effective.

Adolescent↗
PubMed2000

A North Central Cancer Treatment Group phase II trial of topotecan in relapsed gliomas.

Current systemic treatment options for patients with relapsed gliomas are limited. The topoisomerase I inhibitor topotecan has demonstrated broad antitumor activity in both preclinical studies as well as a number of phase I and II trials in humans. Studies in primates have shown good cerebrospinal fluid levels of topotecan following systemic administration. We therefore performed this phase II trial in patients who developed evidence of progressive glioma after definitive radiation therapy. Patients were treated with 1.5 mg/m2 intravenously daily for 5 consecutive days repeated every three weeks. For patients who had received prior nitrosourea-containing chemotherapy, the starting dose was 1.25 mg/m2. Thirty-three patients were entered on this study. All patients were eligible and evaluable for both response and toxicity. Seven patients experienced grade 4 leukopenia with 2 of these patients dying of infection-related complications. Six of these seven patients were not taking anticonvulsants during treatment. Nine patients developed grade 3-4 thrombocytopenia, seven of whom were not taking anticonvulsants. Nonhematologic side effects were infrequent and manageable. One patient experienced a partial response to this treatment for an overall response rate of 3% (95% binomial confidence interval 0.3%-20.4%). The median time to progression was 14.9 weeks and median survival 19.9 weeks. Topotecan at this dose and schedule showed no substantial activity in relapsed gliomas.

Adult↗
PubMed2000

A randomized phase II and pharmacokinetic study of dacarbazine in patients with recurrent glioma.

We conducted a randomized phase II study to determine the efficacy of dacarbazine (DTIC) in recurrent gliomas. Patients were randomly assigned to receive either DTIC 750 mg/m2 IV day 1 every 28 days (Arm A) or DTIC 200 mg/m2 IV days 1-5 every 28 days (Arm B). Pharmacokinetics were studied in 6 patients on each arm using HPLC analysis. Thirty-nine patients (30 male, 9 female), ages 27-67 years (median 53) were entered on the study (20 on Arm A, 19 on Arm B). No objective responses were seen. Median time to progression was 3 months. Median survival was 8 months. Treatment was generally well tolerated. Major toxicities were grade 1-2 nausea (33%). lethargy (28%), diarrhea (15%), alopecia (15%), and grade 3 neutropenia (8%). Four patients on Arm A had mild self-limited episodes of intravascular hemolysis occurring immediately after drug infusion, the mechanism of which is unknown. Mean AUC for DTIC, HMMTIC (5-[3-hydroxymethyl-3-methyl-1-triazeno] imidazole-4-carboxamide), and MTIC (5-[3-methyl-1-triazenol imidazole-4-carboxamide), in Arm A were 14.8, 0.17, and 1.15 mM min, respectively. Corresponding values for Arm B (on day 1 of 5) were 1.7, 0.06, and 0.29 mM min, respectively. The predicted HMMTIC and MTIC exposure over 5 days for Arm B, based on the day 1 data, is higher than with Arm A. We conclude that DTIC is well tolerated but does not have activity in patients with recurrent gliomas. The 5-day schedule appears less toxic, and pharmacokinetic studies show that it provides greater exposure to MTIC and HMMTIC compared to the one-day schedule.

Adult↗
PubMed2000

Chemotherapy of brain tumors.

This is a review of chemotherapy options for patients with brain tumors, both at the time of initial diagnosis and at recurrence. Gliomas, the most common malignant brain tumors, represent the main focus of the review; chemotherapeutic options for supratentorial, brain stem, and optic track gliomas are discussed.

Animals↗
PubMed2000

Efficacy of neuroradiological imaging, neurological examination, and symptom status in follow-up assessment of patients with high-grade gliomas.

OBJECT: It is standard practice for the oncological follow-up of patients with brain tumors (especially in the setting of clinical trials) to include neurological examination and neuroradiological studies such as computerized tomography (CT) or magnetic resonance (MR) imaging in addition to evaluation of the patients' symptomatology and performance score. The validity of this practice and its impact on the welfare of patients with high-grade gliomas has not been adequately assessed. The purpose of this study is to provide such an assessment. METHODS: The authors studied 231 similarly treated patients who were participating in three prospective North Central Cancer Treatment Group or Mayo Clinic trials who developed progressive disease during follow up. According to the protocol, the symptom status, performance score, results of neurological examination, and CT or MR status were recorded prospectively in each patient at each evaluation (every 6-8 weeks). At progression, 177 (77%) of 231 patients experienced worsening of their baseline symptoms or they developed new ones. In the remaining 54 asymptomatic patients (23%), neuroradiological imaging revealed the progression. Asymptomatic progression was more likely to be detected on MR imaging compared with CT studies (p < 0.01). In no asymptomatic patient was progression detected on neurological examination alone. The median survival time after tumor recurrence was 13.3 weeks in symptomatic patients compared with 41.7 weeks in the asymptomatic group (p < 0.0001). Asymptomatic patients were more aggressively treated, with surgery (p < 0.0001) and second-line chemotherapy (p < 0.0002). Multivariate analysis of survival time following first progression by using both classification and regression trees and Cox models showed that treatment at recurrence was the most important prognostic variable. CONCLUSIONS: Symptoms are the most frequent indicators of progression in patients with high-grade gliomas (77%). All asymptomatic progressions were detected on neuroradiological studies; MR imaging was more likely than CT scanning to reveal asymptomatic recurrences. Survival after disease progression was significantly longer in asymptomatic patients and could be related both to treatment following progression and to other favorable prognostic factors such as performance score.

Brain Neoplasms↗
PubMed2000

Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer.

We attempted to induce therapeutic immunity against prostate-derived tissues in patients suffering from progressive hormone-refractory metastatic prostate carcinoma. Thirteen patients were treated with two infusions, 1 month apart, of autologous dendritic cells (APC8015) preexposed ex vivo to PA2024, a fusion protein consisting of human granulocyte/macrophage-colony stimulating factor (GM-CSF) and human prostatic acid phosphatase (PAP). The infusions were followed by three s.c. monthly doses of PA2024 without cells. Three groups of patients each received PA2024 at 0.3, 0.6, or 1.0 mg/injection. All Ps were two-sided. Treatment was well tolerated. After infusions of APC8015, patients experienced only mild (grade 1-2) short-lived fever and/or chills, myalgia, pain, and fatigue. One patient developed grade 3 fatigue. Four patients developed mild local reactions to s.c. PA2024. Twelve patients were evaluable for response to treatment. Circulating prostate-specific antigen levels dropped in three patients. T cells, drawn from patients after infusions of APC8015, but not before, could be stimulated in vitro by GM-CSF (P = 0.0004) and PAP (P = 0.0001), demonstrating broken immune tolerance against these two normal proteins. Injections of PA2024 did not influence the reactivity of T cells against PAP and GM-CSF. However, antibodies to GM-CSF and, to a much lesser extent, to PAP reached maximum titers only after two or even three injections of PA2024, showing that directly injected PA2024 was involved in stimulation of humoral immunity. Dendritic cells exposed to antigen ex vivo can induce antigen-specific cellular immunity in prostate cancer patients, warranting further studies of this mode of immunotherapy.

Acid Phosphatase↗
PubMed1999

A phase 3 randomized study of radiotherapy plus procarbazine, CCNU, and vincristine (PCV) with or without BUdR for the treatment of anaplastic astrocytoma: a preliminary report of RTOG 9404.

PURPOSE: This study was an open label, randomized Phase 3 trial in newly diagnosed patients with anaplastic glioma comparing radiotherapy plus adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy with or without bromodeoxyuridine (BUdR) given as a 96-hour infusion each week of radiotherapy. METHODS AND MATERIALS: Only patients 18 years or older with newly diagnosed anaplastic glioma were eligible; central pathology review was accomplished, but was not mandated prior to registration. The study had initially opened as a Northern California Oncology Group (NCOG) trial in 1991, becoming an Intergroup RTOG, SWOG, and NCCTG study in July 1994. Total accrual of 293 patients was planned as the sample size, using survival and time to tumor progression as the primary endpoints. The experiment arm (RT/BUdR plus PCV) was to be compared to the control arm (RT plus PCV) using an alpha = 0.05, one-tailed, with a power of 85% for detecting an increase in median survival from 160 to 240 weeks, assuming a 3-year follow-up after completion of enrollment. RESULTS: As of July 1996, 281 patients had been randomized; 53 (20%) were ineligible, primarily based upon central pathology review, and another 39 cases were canceled. In total, 30% of cases were excluded from analysis. The treatment arms were well balanced despite this rate of exclusion. The RTOG Data Monitoring Committee recommended suspension of enrollment in July 1996 based upon a stochastic curtailment analysis which strongly suggested that the addition of BUdR would not be associated with increased survival. In February 1997, the study was closed prior to full enrollment. At that time, the 1-year survival estimates were 82% versus 68% for RT plus PCV and RT/BUdR plus PCV respectively (one-sided, p = 0.96). The conditional power analysis indicated that even with an additional 12 months of additional accrual and follow-up the probability of detecting the prespecified difference was less than 0.01%. The differences in the two arms seem to be due to early deaths in the BUdR arm, not related to toxicity of the treatment. CONCLUSIONS: Despite encouraging Phase 2 results with BUdR, it is unlikely that a survival benefit will be seen. A final study analysis will not be done for at least 3 more years.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Clinicopathologic study of 85 similarly treated patients with anaplastic astrocytic tumors. An analysis of DNA content (ploidy), cellular proliferation, and p53 expression.

BACKGROUND: The biologic behavior of anaplastic (World Health Organization Grade III) astrocytomas and oligoastrocytomas is highly variable, ranging from rapid progression to prolonged survival. It is difficult to predict the outcome of an individual patient based on morphology alone. METHODS: To determine the prognostic value of commonly used clinicopathologic markers, we reviewed our experience with 85 similarly treated patients enrolled in 3 North Central Cancer Treatment Group high grade glioma protocols. The pathology was comprised exclusively of primary anaplastic astrocytic tumors (66 astrocytomas and 19 oligoastrocytomas). Variables examined included patient age, morphologic type, preoperative performance score, extent of surgery, solitary versus multiple mitoses, DNA flow cytometric and image morphometric parameters, and expression of proliferating cell nuclear antigen, MIB-1, and p53 expression. RESULTS: The study was comprised of 48 men and 37 women ranging in age from 14-79 years (median age, 47 years). Overall survival ranged from <1 month to >12 years (median, 21.6 months). Statistical analyses revealed that age accounted for the majority of this extensive variability in survival. The median survival times were 65. 5 months, 22.1 months, and 4.4 months, respectively, for the groups <40 years, 40-59 years, and >/=60 years, respectively (P < 0.0001). On univariate analyses, aneuploidy by flow cytometry and a low performance score also predicted a better survival (P values of 0.04 and 0.009, respectively). Statistical trends predicting a better survival were observed for patients with a solitary mitosis and p53 immunopositivity. However, only patient age remained significant in multivariate models. CONCLUSIONS: In a small but relatively uniformly treated cohort of patients with anaplastic astrocytomas and oligoastrocytomas, patient age was associated strongly and inversely with overall survival. Once patient age was taken into account, the clinical and pathologic markers tested appeared to be of limited prognostic value.

Adolescent↗
PubMed1999

Chemotherapy for advanced CNS ependymoma.

BACKGROUND: The role of chemotherapy in recurrent ependymoma is poorly defined. This study was performed to help clarify the benefits of chemotherapy in this setting. PATIENTS AND METHODS: We retrospectively reviewed the charts of patients with advanced ependymoma of the CNS who received chemotherapy in our institution between 1974 and 1993, inclusive. Sixteen consecutive patients were treated with regimens containing either nitrosourea, platinum, or other combinations exclusive of nitrosourea or platinum. No patient received nitrosourea and platinum concurrently. Two methods were used to define response. The first was a direct comparison of radiographic images before and after chemotherapy more than one month apart. A second broader definition of response that employed four other criteria in addition to imaging studies (symptoms, signs, performance status, and neurologic functional status) was also used. RESULTS: Results were as follows (response rate by imaging studies followed by response rate by scoring in parenthesis): Platinum-based chemotherapy resulted in a 67% (83%) response rate with 33% (0%) remaining stable. Nitrosourea-based regimens resulted in a 25% (60%) response rate with 50% (10%) remaining stable. When combinations other than platinum or nitrosourea were used, 11% (22%) responded and 56% (44%) remained stable. Relative differences in response rates between chemotherapy regimens persisted when the data were analyzed by grade. Median time to progression was 6, 10, and 3 months, respectively. CONCLUSION: Platinum-based chemotherapy regimens appear to result in higher response rates with lower rates of progression than nitrosourea-based regimens. Other regimens that do not include cisplatinum or nitrosourea appear to be even less effective.

Adolescent↗
PubMed1999

Homelessness and its relation to the mental health and behavior of low-income school-age children.

This study examined the relationship between housing status and depression, anxiety, and problem behaviors among children age 6 and older who were members of low-income, single-parent, female-headed families. Participants were 80 homeless and 148 never homeless children living in Worcester, Massachusetts. Children in both groups had recently been exposed to various severe stressors. Mother-reported problem behaviors were above normative levels for both homeless and poor housed youths but self-reported depression and anxiety were not. Controlling for other explanatory variables, housing status was associated with internalizing problem behaviors but not with externalizing behaviors. Among homeless youths, internalizing behavior problems showed a positive but curvilinear relationship with number of weeks having lived in a shelter. Housing status was not associated with self-reported depression and anxiety. Findings are discussed in terms of their implications for programmatic interventions and in light of recent welfare reform.

Adolescent↗
PubMed1999

Phase I evaluation of preirradiation chemotherapy with carmustine and cisplatin and accelerated radiation therapy in patients with high-grade gliomas.

OBJECTIVE: A Phase I study was conducted to determine the safety, toxicity, and maximum tolerated dose of preirradiation chemotherapy using carmustine (BCNU) and cisplatin in the treatment of high-grade gliomas. METHODS: Patients with newly diagnosed high-grade gliomas received BCNU and cisplatin after surgery, both before and during definitive radiation therapy. Preirradiation chemotherapy consisted of an administration of 40 mg/m2 BCNU on Days 1 through 3 and 30 mg/m2 cisplatin on Days 1 through 3 and 29 through 31 and repeated at 8 weeks to coincide with the start of radiation therapy. Postradiation chemotherapy consisted of an administration of 200 mg/m2 BCNU once every 8 weeks for four cycles. Radiation therapy consisted of 160-cGy fractions administered twice daily for 15 days, yielding a total dose of 4800 cGy. Dose escalation of BCNU was planned. If hematological toxicity was mild, the dose of cisplatin was to be held constant and BCNU dose escalated to 50 mg/m2 on Days 1 through 3. RESULTS: Eighteen patients were studied. The hematological toxicity was dose-limiting. Grade 3 or 4 leukopenia occurred in each of 10 patients (56%), and Grade 3 or 4 thrombocytopenia occurred in each of 9 patients (50%). Other toxicities included anorexia (94%), nausea (83%), emesis (33%), alopecia (94%), mild ototoxicity (50%), and, in one patient, death as a result of BCNU pulmonary toxicity. The median survival time was 14 months. Objective responses occurred in 45% of the patients evaluable for response. The maximum tolerated dose of this combination was 50 mg/m2 BCNU on Days 1 through 3 and 30 mg/m2 cisplatin on Days 1 through 3 and 29 through 31 before radiation and repeated in 8 weeks to coincide with the start of radiation. CONCLUSION: This schedule of the preirradiation administration of BCNU and cisplatin with accelerated hyper-fractionated radiation therapy for the treatment of high-grade gliomas provides a less toxic alternative to that of previous studies of preirradiation chemotherapy with these agents and merits further investigation.

Adult↗
PubMed1999

Phase II trial of primary chemotherapy followed by reduced-dose radiation for CNS germ cell tumors.

PURPOSE: A prospective phase II study was initiated to assess the response rate, survival, and late effects of treatment in patients with newly diagnosed CNS germ cell tumors (GCT), using etoposide plus cisplatin followed by radiation therapy prescribed by extent of disease, histology, and response to chemotherapy. PATIENTS AND METHODS: Seventeen patients aged 8 to 24 years with histologically proven CNS GCT received etoposide (100 mg/m2/d) plus cisplatin (20 mg/m2/d) daily for 5 days every 3 weeks for four cycles, followed by radiation therapy. Nine patients had germinomas; eight had mixed GCT. Four patients (three with germinomas and one with mixed GCT) presented with leptomeningeal dissemination. RESULTS: Radiographically, 14 of 17 patients were assessable for response; 11 patients experienced complete regression, and three had major partial regression before radiation. Six of seven assessable patients with elevated CSF levels of alpha-fetoprotein or betahuman chorionic gonadotropin had normalization with chemotherapy alone; all normalized with combined chemotherapy and radiation therapy. All 17 patients are alive without evidence of disease (median follow-up, 51 months). One patient developed a relapse in the spinal leptomeninges and was rendered free of disease with spinal radiation more than 5 years ago. One patient developed carotid stenosis requiring surgery. Thus far, only minimal long-term deterioration in neurocognitive function has been detected as a consequence of protocol treatment. CONCLUSION: Conventional-dose intravenous chemotherapy with etoposide and cisplatin can effect tumor regression in a high proportion of patients with CNS GCT, including those with leptomeningeal metastases. Acute and long-term toxicities are acceptable. Progression-free survival and overall survival are excellent.

Adolescent↗
PubMed1999

Tumor suppressor gene alterations in malignant gliomas: histopathological associations and prognostic evaluation.

We have examined a series of 135 gliomas for alterations of the p53, CDKN2A (p16) and PTEN tumor suppressor genes (TSGs) in order to evaluate the incidence of their inactivation as a function of tumor malignancy and cellular differentiation, and to examine potential associations with patient outcome. The composition of this series, classified using WHO criteria, is as follows: 27 grade 2 tumors (11 astrocytomas, 12 oligoastrocytomas, 4 oligodendrogliomas), 42 grade 3 tumors (22 astrocytomas, 16 oligoastrocytomas, 4 oligodendrogliomas), and 66 grade 4 tumors (63 astrocytomas and 3 oligoastrocytomas). Similar frequencies of p53 mutation were observed among grade 2 (37.0%), and grade 3 tumors (38.1%), as well as between astrocytomas and mixed tumors. CDKN2A and PTEN mutations were clearly associated with increasing tumor malignancy (occurring in 0% of grade 2 tumors, 14.3% and 4.8% respectively of grade 3 tumors, and 27.3% and 30.3% respectively of grade 4 tumors) and were observed at substantially higher rates among astrocytomas. For the tumor suppressor genes examined, there was no relationship between the occurrence of any two TSG inactivation events. With regard to outcome, the p53 genetic status showed no significant relationship with patient survival. The CDKN2 and PTEN alterations were negative prognostic indicators of survival when evaluated in all 135 gliomas, but failed to predict outcome when evaluated in either of the high grade (3 or 4) tumor groups.

Adolescent↗
PubMed1999

Phase II study of antineoplastons A10 (NSC 648539) and AS2-1 (NSC 620261) in patients with recurrent glioma.

OBJECTIVE: To assess the pharmacokinetics, toxicity, and efficacy of antineoplastons A10 (NSC 648539) and AS2-1 (NSC 620261). DESIGN: We initiated a phase II trial in order to determine whether evidence of antitumor activity of A10 and AS2-1 could be documented. MATERIAL AND METHODS: Patients with anaplastic astrocytoma or glioblastoma multiforme recurring after radiation therapy were eligible for enrollment in the trial. Patients received escalating doses of A10 and AS2-1 by multiple intermittent intravenous injections with use of a portable programmable pump to the target daily dose of 1.0 g/kg for A10 and of 0.4 g/kg for AS2-1. RESULTS: Nine patients were treated, in six of whom the treatment response was assessable in accordance with protocol stipulations. No patient demonstrated tumor regression. Reversible grade 2 or 3 neurocortical toxicity, consisting of transient somnolence, confusion, and exacerbation of an underlying seizure disorder, was noted in five patients. Mean steady-state plasma concentrations of phenylacetate and phenylacetylglutamine after escalation to the target doses of A10 and AS2-1 were 177+/-101 microg/mL and 302+/-102 microg/mL, respectively. Patients who exhibited confusion tended to have higher phenylacetate levels. CONCLUSION: Although we could not confirm any tumor regression in patients in this study, the small sample size precludes definitive conclusions about treatment efficacy. Antineoplaston-related toxicity was acceptable in most patients with appropriate dose modification, although severe neurocortical toxicity may occur. Steady-state plasma concentrations of phenylacetate with use of A10 and AS2-1 were similar to those reported with use of similar doses of phenylacetate alone.

Adult↗