Impact of radiation therapy and extent of resection for ependymoma in young children: A population-based study.

BACKGROUND: Young children with posterior fossa ependymoma (PF-EPN) have a worse prognosis than older children, and they have a unique molecular profile (PF-EPN-A subtype). Alternative treatment strategies are often used in these young patients, and their prognostic factors are less clear. METHODS: We characterized the prognostic factors and treatment outcomes of 482 patients between ages 0 and 3 years with the diagnosis of ependymoma identified from the Surveillance, Epidemiology, and End Results registry (1973-2013). RESULTS: Radiation therapy (RT) was delivered to 52.3% of patients, and gross total resection (GTR) was performed in 51.0% of patients. Overall survival (OS) at 10 years was 48.4% with median follow-up of 3.3 years. WHO grade was not predictive of OS. Extent of resection was significant for survival; the 10-year OS with GTR was 61.0%, and with subtotal resection (STR) and biopsy was 38.2% and 35.0%, respectively (P < 0.001). RT significantly benefitted OS for both grades II and III. The 10-year OS for grade II was 50.5% with RT and 43.4% without (P = 0.030); 10-year OS for grade III was 66.0% with RT and 40.0% without (P = 0.002). Multivariate analysis showed significantly improved OS with RT (hazard ratio [HR] 0.601, 95% CI: 0.439-0.820, P = 0.001) and GTR (HR 0.471, 95% CI: 0.328-0.677, P < 0.0001). CONCLUSIONS: Ependymoma outcomes in patients within 0-3 years of age significantly improved with RT and GTR. Histopathologic grading of ependymoma demonstrated no prognostic significance. Given the poor OS for this population and unique genetic profile, future prospective studies with molecular-based stratification should be performed to evaluate additional prognostic factors.

Clinical outcome of stereotactic radiosurgery for central nervous system metastases from renal cell carcinoma.

BACKGROUND: Current treatment modalities for central nervous system (CNS) metastases from renal cell cancer (RCC) include surgical resection, stereotactic radiosurgery (SRS), and whole-brain radiotherapy. Existing studies describing treatment outcomes for CNS metastases include multiple tumor types and thus provide little insight into how RCC CNS metastases respond to these modalities. MATERIALS AND METHODS: RCC patients with brain metastases treated with SRS at the Cleveland Clinic between 1996 and 2010 were retrospectively identified. Radiosurgery and systemic therapy characteristics were recorded. Patients were followed up radiographically at 1 to 2 months after radiosurgery and every 3 to 6 months thereafter with magnetic resonance imaging scans. RESULTS: Of the 166 patients identified, local control was obtained in 90% of patients. In 38% of patients there were additional distant CNS metastases at a median of 12.8 months (95% CI, 8.5-21.1) after SRS. The median time to progression (either local or distant) was estimated to be 9.9 months (95% CI, 5.9-12.9). Higher (> 2.5) RCC-specific graded prognostic assessment (GPA) score was the only factor examined that was found to be a significant prognostic factor for improved outcome (P = .02); however, there was some suggestion that a single target lesion (P = .07) and age ≥ 60 years (P = .07) may also be associated with better CNS control. CONCLUSION: Stereotactic radiosurgery for a limited number of CNS metastases from RCC is associated with excellent local control and is an effective if not preferred treatment modality.

Principles of radiobiology of stereotactic radiosurgery and clinical applications in the central nervous system.

Stereotactic radiosurgery (SRS) has become an important treatment option for intracranial lesions and has recently been adapted to treat lesions outside the brain. Many studies have shown the effectiveness of SRS for the treatment of benign and metastatic tumors. Although DNA damage has been thought to be the principal form of radiation-induced damage, recent studies have shown that vascular endothelial damage is perhaps more important in the setting of high radiation doses per fraction such as those used in SRS. Furthermore, it has been shown that molecular responses to radiation differ based on dose per fraction. The principles of classical radiobiology are reviewed with explanation on why fractionation of radiotherapy allows optimization of the therapeutic ratio. The current understanding of the molecular responses that occur soon after the delivery of high radiation doses per fraction is also reviewed. A summary of current clinical evidence of radiation tolerance to SRS of brain, brainstem, optic chiasm and spinal cord is also provided. Recent advances in understanding the molecular basis of SRS response have uncovered a different biological response than previously thought. Further understanding of these molecular mechanisms will allow for the development of targeted radiosensitizers and radioprotectors to optimize the therapeutic ratio.

Stereotactic radiosurgery for spinal metastases: update on treatment strategies.

Metastatic tumors are the most common tumors that affect the spinal column and are the source of significant pain and disability in cancer patients. The management of symptomatic spinal metastases presents unique challenges to surgeons as a number of considerations specific to the underlying tumor histology, extent of disease, the functional status of the patient and response to systemic therapy often affect the role, timing and effectiveness of any surgical intervention. As surgical techniques have evolved, the focus of therapy has shifted towards minimizing the morbidity associated with treatments for patients in whom limited nutrition and functional reserve impact their overall survival. As such, stereotactic spinal radiosurgery (SRS) has emerged as a powerful adjunct to surgery as well as a stand-alone treatment option for patients with metastatic disease. Recent technological innovations such as intensity-modulated radiation therapy, image-guidance, and non-invasive spine immobilization have made significant improvements to the delivery of highly conformal radiation to spinal tumors. In this article, current treatment strategies utilizing SRS in the multidisciplinary management of spinal metastases are discussed.

Evidence-based adjuvant therapy for gliomas: current concepts and newer developments.

The incidence of gliomas is increasing worldwide, including India. Of the 18,820 new cases of primary central nervous system (CNS) tumors diagnosed annually in the United States, gliomas account for over 60% with 30-40% of them being glioblastoma multiforme (GBM), 10% being anaplastic astrocytoma (AA), and 10% being low grade gliomas (LGGs). This is in contrast to one study from West Bengal, India, in which only 7.9% of the brain tumors were GBMs, while 46.8% were astrocytomas. Of all adult primary CNS tumors, GBM is the most common and the most malignant with about 7,000 to 8,000 new cases annually in the United States. Given poor outcomes, a number of treatment approaches have been investigated. Common to these approaches is the use of adjuvant radiation therapy, even as surgery alone, with or without chemotherapy, may be the mainstay for some lower grade and low-risk gliomas. Today, treatment typically involves external beam radiation, with concurrent and adjuvant chemotherapy for more aggressive histologies. Although gliomas are relatively uncommon, active research is ongoing. Results of landmark trials along with some of the recently published trials are presented. These trials and management strategies as well as evolving concepts are found by reviewing over 200 articles in the National Library Medical (NLM) database, PubMed, more than 60 of which are refrenced. Specifically, the database is searched using the following keywords, with various combinations: glioma, low-grade, anaplastic, astrocytoma, oligodendroglioma, oligoastrocytoma, glioblastoma multiforme, chemotherapy, radiation, new concepts, phase III, MGMT, CDX-110 (Celldex), temozolomide, 1p/19q deletion, and bevacizumab.

The sensitivity and specificity of FDG PET in distinguishing recurrent brain tumor from radionecrosis in patients treated with stereotactic radiosurgery.

Radiation necrosis and recurrent brain tumor have similar symptoms and are indistinguishable on both magnetic resonance imaging (MRI) and computed tomograph scans. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has been proposed as a diagnostic alternative, particularly when co-registered with MRI. We studied 47 patients with brain tumors treated with stereotactic radiosurgery and followed with FDG PET. For all tumor types, the sensitivity of FDG PET for diagnosing tumor was 75% and the specificity was 81%. For brain metastasis without MRI co-registration, FDG PET had a sensitivity of 65% and a specificity of 80%. For brain metastasis with MRI co-registration, FDG PET had a sensitivity of 86% and specificity of 80%. MRI co-registration appears to improve the sensitivity of FDG PET, making it a useful modality to distinguish between radiation necrosis and recurrent brain metastasis.

Thio- and oxoflavopiridols, cyclin-dependent kinase 1-selective inhibitors: synthesis and biological effects.

Flavopiridol analogues, thio- and oxoflavopiridols which contain a sulfur (16) or oxygen (18) atom linker between a chromone ring and the hydrophobic side chain, are selective cyclin-dependent kinase 1 (CDK1) inhibitors with an IC(50) of 110 and 130 nM. These analogues were prepared from key intermediate 7 by substituting the ethyl sulfoxide. Enantio pure intermediate piperidone 10 was obtained from the racemic piperidone 8 via a very efficient "dynamic kinetic resolution" in 76% yield. Hydrophobic side chains such as chlorophenyl or tert-butyl produced potent CDK1 inhibitory activity, while hydrophilic side chains such as pyrimidine or aniline caused a severe reduction in CDK inhibitory activity. These analogues are competitive inhibitors with respect to ATP, and therefore activity was dependent upon the CDK subunit without being affected by the cyclin subunit or protein substrate. Thio- and oxoflavopiridols 16 and 18 are not only selective within the CDK family but also discriminated between unrelated serine/threonine and tyrosine protein kinases. CDK1 selective thio- and oxoflavopiridol analogues inhibit the colony-forming ability of multiple human tumor cell lines and possess a unique antiproliferative profile in comparison to flavopiridol.

Application of recursive partitioning analysis and evaluation of the use of whole brain radiation among patients treated with stereotactic radiosurgery for newly diagnosed brain metastases.

PURPOSE: To evaluate the usefulness of whole brain radiotherapy (WBRT) and of the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) for brain metastases among patients receiving stereotactic radiosurgery (SRS). METHODS AND MATERIALS: A retrospective analysis was performed on 135 patients who underwent linear accelerator (Linac) (n = 73) or Gamma Knife (n = 62) SRS for newly diagnosed brain metastases at the Cleveland Clinic Foundation between 8/89 and 12/98. Univariate and multivariate analyses were performed to evaluate the effects of age, primary site, control of the primary, interval to development of brain metastases (disease-free interval [DFI]), number of brain metastases, presence of extracranial metastases, Karnofsky performance status (KPS), treatment of brain metastases, and RPA class on overall survival. RESULTS: Application of the RPA classification revealed 29 patients fit the criteria for class I, 96 for class II, and 10 for class III. All of the patients underwent SRS. Fifty-seven patients also received WBRT at the time of initial presentation (SRS and immediate WBRT), and 78 patients received WBRT only if CNS relapse occurred (SRS alone). The median survival for all patients was 7.9 months (range: 1.1-90.1), and was 11.2 months for RPA class I compared to 6. 9 months for RPA classes II-III (p = 0.016). Median survival was 10. 5 months following SRS alone compared to 6.4 months following SRS and WBRT (p = 0.07). On univariate analysis, KPS >/= 80% (p = 0.002) and absence of systemic disease (p = 0.013) were also associated with longer survival, whereas control of the primary, DFI, and number of brain metastases did not have an impact. Multivariate analysis revealed only RPA class (p = 0.023) to be an independent predictor for overall survival, whereas treatment group (p = 0.079) was only marginally significant. At 2 years, immediate WBRT improved control at the original site of metastases (80% vs. 52%, p = 0.03) and prevention of new metastatic sites within the brain, 74% vs. 48% (p = 0.06). The 2-year intracranial disease-free survival was 60% following SRS and WBRT compared to only 34% following SRS alone (p = 0.03). CONCLUSIONS: Despite the inherent biases to select more favorable patients for SRS, the RPA class retains its prognostic value. Omission of WBRT from the initial management was not detrimental in terms of overall survival; however, progressive disease occurred in over 50% of patients treated in this manner. Further studies are required to determine which, if any, patients should be considered for SRS with WBRT held in reserve.

Transcriptional activation by the myb proteins requires a specific local promoter structure.

The biological effects of the cellular c-Myb and the viral v-Myb proteins are strikingly different. While c-Myb is indispensable for normal hematopoiesis, v-Myb induces acute leukemia. The v-Myb DNA-binding domain (DBD) differs from that of c-Myb mainly by deletion of the first of three repeats which correlates with efficient oncogenic transformation and a decrease in DNA-binding activity. To investigate the difference in DNA-binding and transcriptional activation, oligonucleotide selection and electrophoretic mobility shift assays were employed. The v-Myb DBD (R2R3) shows an intrinsic DNA-binding specificity for an AT-rich downstream extension of the Myb recognition element (MRE) PyAAC(T)/(G)G for efficient binding to this site, whereas R1 within the c-Myb DBD allows for more flexibility for this downstream extension. Therefore, due to the presence of repeat R1, c-Myb can bind to a greater number of target sites. The intrinsic DNA-binding specificity of R2R3 is further supported with the results from in vivo transcriptional activation experiments which demonstrated that both the v-Myb and c-Myb DBDs require an extension of the MRE (motif #1) by a downstream T-stretch (motif #2) for full activity. Surprisingly, the T-stretch improves binding when present on either strand, but is required on a specific strand for transcriptional activation.

Effect of transdermal iontophoresis codelivery of hydrocortisone on metoclopramide pharmacokinetics and skin-induced reactions in human subjects.

The effects of transdermal iontophoresis (IP) codelivery of hydrocortisone (HC) on metoclopramide hydrochloride (MCP) pharmacokinetics and on skin-induced reactions were evaluated in a randomized, crossover clinical study. MCP, an antiemetic, low molecular weight, cationic drug intended for systemic delivery, was delivered from the anode of IP systems at a constant current of 100 microA/cm(2). HC, a neutral endogenous antiinflammatory agent, was codelivered from the same electrode, primarily by electroosmotic processes. Each subject (n = 7) wore two identical IP systems (MCP alone or MCP plus HC), each supplying 500 microA, one on each upper arm for 4 h. One week later, each subject repeated the procedure with the alternate type of MCP system. HC did not change the pharmacokinetics of MCP: There were no statistically significant differences in MCP plasma concentrations, half-life, area under the curve (AUC), or rate of absorption between the two treatment groups. However, HC significantly decreased erythema and edema scores produced by the IP of MCP. In both groups, a steady-state MCP flux of about 100 microg/(cm(2) x h) was achieved after only 1 h of transport, and input rate dropped dramatically immediately after removal of the system. In vitro, HC flux through human epidermis from an MCP plus HC formulation was 2.8 +/- 1.1 microg/(cm(2) x h) after 4 h transport at 100 microA/cm(2), suggesting negligible systemic exposure to hydrocortisone. These data indicate that MCP input rate and its clearance from the skin are unaltered by HC and that the codelivery of HC by IP is an effective strategy for inhibition of local reactions resulting from the transdermal delivery of drugs.

Effect of food on bioavailability of pseudoephedrine and brompheniramine administered from a gastrointestinal therapeutic system.

The purpose of this study was to determine how a high-fat meal affects the delivery and absorption of pseudoephedrine and brompheniramine maleate when delivered from a gastrointestinal therapeutic system (GITS). This study was a randomized, complete crossover trial with 12 healthy male volunteers who were given single doses of the 24-h GITS under fed and fasted conditions. Pharmacokinetic parameters for both drugs were comparable between fed and fasted treatments, except for a shorter time to maximum concentration of pseudoephedrine for fed subjects (p = 0.002). Bioavailability of pseudoephedrine was 91% for fed relative to fasted treatment; for brompheniramine it was 89%. These results indicate that codelivery of the two drugs from the GITS is reliable and prolonged, and that the resulting absorption of pseudoephedrine and brompheniramine is minimally affected by food.

Placental mono-oxygenation: characteristics and partial purification of a hematin-activated human placental mono-oxygenase.

Human placental mono-oxygenase activities were markedly increased after additions of micromolar quantities of hematin to reaction vessels. The magnitude of the increases diminished with increasing (induced) levels of hematin-independent activity. The activating effect of hematin could be observed in unbroken cell preparations, in whole homogenates, and in various subcellular fractions. Highest hematin-dependent activity was measured in microsomal fractions of placental homogenates. With benzo(a)pyrene as substrate, response to the stimulatory effect of hematin in human placental preparations was not as profound as that observed in monkey or rabbit placentas but was more marked than the responses observed in placental preparations from rats or mice. Hematin-activated mono-oxygenase activity present in washed microsomal fractions of human placental homogenates could be solubilized with detergents, the most effective of which was Triton N-101. The solubilized activity also could be partially purified by polyethylene glycol fractionation. Attempts to further purify, however, resulted in loss of activity. All results were consistent with the hypothesis that the effect of hematin is mediated via reconstitution of hematin-free apocytochrome(s) P-450.

Mono-oxygenase induction in the human placenta. Interrelationships among position-specific hydroxylations of 17 beta-estradiol and benzo[a]pyrene.

An investigation of the specific hydroxylations of aromatic ring carbon atoms 2 and 4 of 17 beta-estradiol (E2) in microsomal fractions of human placental tissues revealed that rates of 4-hydroxylation were elevated 3- to 5-fold in placentas of cigarette smokers. Minor increases in hydroxylation at carbon atom 2 were statistically insignificant. Correlation analyses and studies with inhibitors and activators also strongly indicated that 2-hydroxylase and 4-hydroxylase activities were under separate regulatory control. Attempts to determine possible correlations between placental E2 4-hydroxylase and aryl hydrocarbon (benzo[a]pyrene, BaP) hydroxylase (AHH) activities revealed an unusual threshold-type relationship. With AHH activities of 0-40 pmol/mg/15 min, no-statistically significant correlation existed. With AHH activities above 50 pmol/mg/15 min, E2 4-hydroxylase activities were markedly elevated but, in the range of 50- 180 pmol/mg/15 min, statistically significant correlations again were not observed. Analysis also were performed on the relationships of E2 2- and 4-hydroxylations to BaP metabolism as assessed with high-pressure liquid chromatography (HPLC). Strong positive correlations were observed between quantities of nearly all measured BaP metabolites and 4-hydroxy- but not 2-hydroxy-E2. The threshold effect again was evident. E2 exhibited only weak activity as an inhibitor of placental BaP hydroxylation as measured fluorimetrically or with HPLC. BaP effectively inhibited E2 4-hydroxylase activities at comparatively low inhibitor concentrations but inhibited E2 2-hydroxylase activities only weakly. Analyses of the effects of a series of modifiers on the three measured mono-oxygenase activities also suggested that each activity was under separate regulatory control.

Catechol estrogen formation in placental and fetal tissues of humans, macaques, rats and rabbits.

Placental and fetal tissues obtained from humans, monkeys, rats and rabbits contained monooxygenases capable of catalyzing the formation of catechol estrogens. Treatments of pregnant rats with phenobarbital, Aroclor 1254, or 3-methylcholanthrene each increased measured rates of catechol estrogen formation in placentas, fetal brains and fetal livers, while other rat tissues exhibited either increased or decreased activity. Treatment of pregnant rabbits with Arocolor 1254 produced an increase in catechol estrogen formation in all fetal tissues studied and in the maternal liver and kidney. Catechol estrogen formation in placental microsomes of macaque monkeys (Macaca arctoides) was generally less than that observed in human placental microsomes. Human placentas obtained from smokers exhibited enhanced catechol estrogen formation and this activity appeared to be highly correlated with placental aryl hydrocarbon hydroxylase activity. The data suggested [a]pyrene in a similar fashion in placental tissues and that the enzyme systems involved may be under similar regulatory control.

Drug metabolism by the human fetus.

A review of the literature that pertains to drug biotransformation in human fetal tissues reveals that, in spite of several publications in this comparatively new area of research, only very limited definitive information is currently available. The large majority of the studies performed have dealt with the cytochrome P-450-dependent microsomal mono-oxygenase systems and for several of the common drug metabolising reactions, very little or no data are available at this time. Some of the more important data that have emerged include observations that important bioactivation reactions can be demonstrated in human fetal tissues obtained during the period of late embryogenesis (high susceptibility to chemical dysmorphogenesis) and that the human fetal adrenal gland possesses considerable capacity to catalyse several important oxidation-reduction reactions. From the data available to date, it would appear that, in most instances, the biotransformation of drugs in the human embryo and fetus would not affect maternal plasma concentrations significantly. From the viewpoint of parameters of the pharmacokinetics of parent drug (or other xenobiotic) substrates under steady-state conditions, human fetal drug metabolism probably is of little consequence in most cases, although exceptions may exist. Pharmacokinetic parameters observed after isolated exposure, however, are very likely to be affected, perhaps markedly, in some instances. The demonstrated capacity of human prenatal tissues and cells to generate reactive intermediary metabolites, including those that produce mutations, has attracted the greatest attention recently. This capacity may be associated with extremely important adverse reactions to drugs and other environmental chemicals. Such adverse responses include transplacental mutagenesis, carcinogenesis, dysmorphogenesis, and perhaps several other undesirable effects. Although far from conclusive, the data tend to suggest that humans and subhuman primates may be more vulnerable than the smaller common experimental animals to the toxic effects of foreign organic chemicals during prenatal life. These factors should be weighed whenever exposure of pregnant women to such agents (e.g. via drug administration) is contemplated.

Modulation of monooxygenase activities by hematin and 7,8-benzoflavone in fetal tissues of rats, rabbits, and humans.

The rates of benzo[a]pyrene metabolism were stimulated markedly by micromolar quantities of hematin when assayed with either fetal or maternal extrahepatic tissue parparations (9,000 g supernatant fractions) from rats, rabbits and humans. Enzymatic induction was accompanied by either decreases in the magnitude of hematin stimulation or hematin-mediated inhibition of monooxygenase activities. Additions of 7,8-benzoflavone (BF) resulted in the inhibition of reaction rates in most experiments. With either fetal or maternal hepatic preparations from untreated rabbits, however, BF stimulated enzymatic activities; the greatest simulation occurred in fetal rabbit liver (10-fold). Nevertheless, inducer pretreatment was associated with inhibitory of BF on activities in hepatic homogenates.