Circulating PD-L1 levels change during bevacizumab-based treatment in recurrent glioma.

PURPOSE: In primary brain tumors, the efficacy of immune-modulating therapies is still under investigation as inflammatory responses are restricted by tight immunoregulatory mechanisms in the central nervous system. Here, we measured soluble PD-L1 (sPD-L1) in the plasma of patients with recurrent glioblastoma (GBM) and recurrent WHO grade II-III glioma treated with bevacizumab-based salvage therapy. METHODS: Thirty patients with recurrent GBM and 10 patients with recurrent WHO grade II-III glioma were treated with bevacizumab-based salvage therapy at the Medical University of Vienna. Prior to each treatment cycle, EDTA plasma was drawn and sPD-L1 was measured applying a sandwich ELISA with a lower detection limit of 0.050 ng/ml. Leukocyte counts and C-reactive protein (CRP) levels were measured according to institutional practice. RESULTS: Median number of sPD-L1 measurements was 6 per patient (range: 2-24). At baseline, no significant difference in sPD-L1 concentrations was observed between WHO grade II-III glioma and GBM. Intra-patient variability of sPD-L1 concentrations was significantly higher in WHO grade II-III glioma than in GBM (p = 0.014) and tendentially higher in IDH-mutant than in IDH-wildtype glioma (p = 0.149) In WHO grade II-III glioma, sPD-L1 levels were significantly lower after one administration of bevacizumab than at baseline (median: 0.039 ng/ml vs. 0.4855 ng/ml, p = 0.036). In contrast, no significant change could be observed in patients with GBM. CONCLUSIONS: Changes in systemic inflammation markers including sPD-L1 are observable in patients with recurrent glioma under bevacizumab-based treatment and differ between WHO grade II-III glioma and GBM.

Antibodies Against Hypothalamus and Pituitary Gland in Childhood-Onset Brain Tumors and Pituitary Dysfunction.

Purpose: To detect the presence of antipituitary (APA) and antihypothalamus antibodies (AHA) in subjects treated for brain cancers, and to evaluate their potential association with pituitary dysfunction. Methods: We evaluated 63 patients with craniopharyngioma, glioma, and germinoma treated with surgery and/or radiotherapy and/or chemotherapy at a median age of 13 years. Forty-one had multiple pituitary hormone deficiencies (MPHD), six had a single pituitary defect. GH was the most common defect (65.1%), followed by AVP (61.9%), TSH (57.1%), ACTH (49.2%), and gonadotropin (38.1%). APA and AHA were evaluated by simple indirect immunofluorescence method indirect immunofluorescence in patients and in 50 healthy controls. Results: Circulating APA and/or AHA were found in 31 subjects (49.2%) and in none of the healthy controls. In particular, 25 subjects out of 31 were APA (80.6%), 26 were AHA (83.90%), and 20 were both APA and AHA (64.5%). Nine patients APA and/or AHA have craniopharyngioma (29%), seven (22.6%) have glioma, and 15 (48.4%) have germinoma. Patients with craniopharyngioma were positive for at least one antibody in 39.1% compared to 33.3% of patients with glioma and to 78.9% of those with germinoma with an analogous distribution for APA and AHA between the three tumors. The presence of APA or AHA and of both APA and AHA was significantly increased in patients with germinoma. The presence of APA (P = 0.001) and their titers (P = 0.001) was significantly associated with the type of tumor in the following order: germinomas, craniopharyngiomas, and gliomas; an analogous distribution was observed for the presence of AHA (P = 0.002) and their titers (P = 0.012). In addition, we found a significant association between radiotherapy and APA (P = 0.03). Conclusions: Brain tumors especially germinoma are associated with the development of hypothalamic-pituitary antibodies and pituitary defects. The correct interpretation of APA/AHA antibodies is essential to avoid a misdiagnosis of an autoimmune infundibulo-neurohypophysitis or pituitary hypophysitis in patients with germinoma.

The role of neutrophil-to-lymphocyte ratio in predicting overall survival in patients undergoing laser interstitial thermal therapy for glioblastoma.

Laser interstitial thermal therapy (LITT) offers a minimally-invasive treatment option for glioblastomas (GBM) which are relatively small or in eloquent areas. While laser ablation for malignant gliomas has been shown to be safe and effective, the role of the subsequent immune response in not well established. In this study we aim to analyze the prognostic potential of edema volume and acute inflammation, quantified as neutrophil-to-lymphocyte ratio (NLR), in predicting overall survival. Twenty-one patients were identified with new or recurrent GBMs that were candidates for LITT. Laser ablation was performed using standard solid tumor protocol for treatment volume, intensity and duration. Edema volume was quantified using MRI imaging, while retrospective chart review was performed to calculate NLR and survival. In patients treated with LITT for GBM, peri-tumoral vasogenic edema volumes did not significantly change post-operatively, p > 0.200, while NLR significantly increased, p = 0.0002. The degree of NLR increase correlated with longer overall survivals, and ROC analysis demonstrated an area under the curve of 0.827, p = 0.0112. A delta-NLR cutoff of 7.0 results in positive and negative predictive values of 78% and 75%, respectively, in predicting overall survival >1 year. Patients with with delta-NLR > 7.0 lived significantly longer that those with delta-NLR < 7.0, median survival 440 days compared to 239 days, p = 0.0297. We demonstrate preliminary data that monitoring the inflammatory response after LITT in GBM patients offers a potential prognostic measurement to assist in predicting treatment efficacy and overall survival.

Preoperative low tri-iodothyronine concentration is associated with worse health status and shorter five year survival of primary brain tumor patients.

BACKGROUND: Low tri-iodothyronine syndrome is associated with worse prognosis of severely ill patients. We investigated the association of thyroid hormone levels with discharge outcomes and 5-year mortality in primary brain tumor patients. METHODS: From January, 2010 until September, 2011, 230 patients (70% women) before brain tumor surgery were evaluated for cognitive (Mini mental State Examination; MMSE) and functional (Barthel index; BI) status, and thyroid function profile. The Low triiodothyronine syndrome was defined as triiodothyronine concentration below the reference range. Unfavorable discharge outcomes were Glasgow outcome scale score of ≤3. Follow-up continued until November, 2015. RESULTS: Seventy-four percent of patients had Low triiodothyronine syndrome. Lower total tri-iodothyronine concentrations were associated with lower MMSE (p=.013) and BI (p=.023) scores independent of age, gender and histological diagnosis. Preoperative Low tri-iodothyronine syndrome increased risk for unfavorable discharge outcomes adjusting for age, gender and histological diagnosis (OR=2.944, 95%CI [1.314-6.597], p=.009). In all patients, lower tri-iodothyronine concentrations were associated with greater mortality risk (p≤.038) adjusting for age, gender, extent of resection, adjuvant treatment and histological diagnosis. The Low tri-iodothyronine syndrome was associated with greater 5-year mortality for glioma patients (HR=2.197; 95%CI [1.160-4.163], p=.016) and with shorter survival (249 [260] vs. 352 [399] days; p=.029) of high grade glioma patients independent of age, gender, extent of resection and adjuvant treatment. CONCLUSIONS: The Low tri-iodothyronine syndrome is common in brain tumor patients and is associated with poor functional and cognitive status, and with worse discharge outcomes. The Low tri-iodothyronine syndrome is associated with shorter survival of glioma patients.

Characterization of the serum metabolome following radiation treatment in patients with high-grade gliomas.

BACKGROUND: Glioblastomas progress rapidly making response evaluation using MRI insufficient since treatment effects are not detectable until months after initiation of treatment. Thus, there is a strong need for supplementary biomarkers that could provide reliable and early assessment of treatment efficacy. Analysis of alterations in the metabolome may be a source for identification of new biomarker patterns harboring predictive information. Ideally, the biomarkers should be found within an easily accessible compartment such as the blood. METHOD: Using gas-chromatographic- time-of-flight-mass spectroscopy we have analyzed serum samples from 11 patients with glioblastoma during the initial phase of radiotherapy. Fasting serum samples were collected at admittance, on the same day as, but before first treatment and in the morning after the second and fifth dose of radiation. The acquired data was analyzed and evaluated by chemometrics based bioinformatics methods. Our findings were compared and discussed in relation to previous data from microdialysis in tumor tissue, i.e. the extracellular compartment, from the same patients. RESULTS: We found a significant change in metabolite pattern in serum comparing samples taken before radiotherapy to samples taken during early radiotherapy. In all, 68 metabolites were lowered in concentration following treatment while 16 metabolites were elevated in concentration. All detected and identified amino acids and fatty acids together with myo-inositol, creatinine, and urea were among the metabolites that decreased in concentration during treatment, while citric acid was among the metabolites that increased in concentration. Furthermore, when comparing results from the serum analysis with findings in tumor extracellular fluid we found a common change in metabolite patterns in both compartments on an individual patient level. On an individual metabolite level similar changes in ornithine, tyrosine and urea were detected. However, in serum, glutamine and glutamate were lowered after treatment while being elevated in the tumor extracellular fluid. CONCLUSION: Cross-validated multivariate statistical models verified that the serum metabolome was significantly changed in relation to radiation in a similar pattern to earlier findings in tumor tissue. However, all individual changes in tissue did not translate into changes in serum. Our study indicates that serum metabolomics could be of value to investigate as a potential marker for assessing early response to radiotherapy in malignant glioma.

A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma.

PURPOSE: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. METHODS AND MATERIALS: Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). RESULTS: A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. CONCLUSIONS: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study.

Leptin concentration and nutritional status in the course of treatment in children with brain tumours--preliminary report.

PURPOSE: To assess the nutritional status in children with central nervous system (CNS) tumours, including concentration of leptin, the neuropeptide responsible for regulation of energetic homeostasis in an organism. METHOD: The studied group comprised 44 children with brain tumours, aged (4.02-18.7). In all children during the whole therapy (from the start to the period of 1 year and more after the end of therapy), a number of standard deviations (SDs) for the body mass index (SDS BMI) was derived from anthropometric measurements. Concentrations of leptin were assayed simultaneously. RESULT: The lowest values of the anthropometric indices were found in children during the maintenance therapy. Concentrations of leptin in patients with malignant CNS tumours and significant undernutrition were slightly greater as compared to patients presenting normal nutritional status; however, without statistical significance. CONCLUSION: In children with tumours of the central nervous system, there are quantitative disorders of the nutritional status which correlate with the period of the treatment. The most significant disorders in the nutritional status are observed during maintenance chemotherapy. There was no statistically significant correlation between the concentration of leptin and nutritional status in children with malignant brain tumours during the course of treatment and after its completion.

Do anti-angiogenic therapies prevent brain metastases in advanced renal cell carcinoma?

BACKGROUND: We analyzed renal cell carcinoma (RCC) brain metastasis (BM) risk factors and compared BM occurrence in metastatic RCC (mRCC) treated with or without anti-angiogenic agents (AA). METHODS: Data from all consecutive metastatic RCC patients (patients) treated in a french cancer center between 1995 and 2008 were reviewed. Patients had histologically confirmed advanced RCC without synchronous BM at the time of metastasis diagnosis. AA were sorafenib, sunitinib and bevacizumab. We also included patients treated with mTor inhibitors, temsirolimus and everolimus, as they also demonstrated anti-angiogenic activities. Characteristics of the two groups treated with or without AA were compared with a Fisher exact test. Impact of AA on overall survival (OS) and cumulative rate of brain metastasis (CRBM) was explored by Kaplan-Meier method. RESULTS: One hundred and ninety-nine patients with advanced RCC were identified, 51 treated with AA and 148 without AA. The median follow-up duration was 40 months. BM occurred in 35 patients. Characteristics between AA treated and non-AA treated groups were unbalanced and favoring better prognostic factors in AA treated group. Median OS was 24 months. AA treatment was not associated with a lower CRBM (HR = 0.58 [0.26-1.30], P = 0.187). Median survival free of BM was 11.8 months, CI95% (4.95-18.65) in the group without AA treatment and 28.9 months in the AA group, CI95% (18.64-39.16). Alkaline phosphatase (AP) was an independent prognostic factor for BM (P = 0.05). In multivariate Cox model, after adjustment to AP, AA did not improve the CRBM (aHR = 0.53 [0.22-1.32]). CONCLUSION: In this retrospective study, AA did not decrease significantly the CRBM. Elevated AP was a predictive factor for BM in mRCC.

Serum levels of selenium in patients with brain metastases from non-small cell lung cancer before and after radiotherapy.

PURPOSE: This study was to evaluate the influence of radiotherapy on the selenium serum levels of non-small cell cancer patients with brain metastases. PATIENTS AND METHODS: This prospective study included 95 non-small cell cancer patients with brain metastases treated by radiotherapy from December 2007 until November 2010. Plasma selenium levels were determined before and at the end of the radiotherapy. Age, body mass index (BMI), prior chemotherapy, pathological type and personal habits (smoking and alcoholism) were recorded for each patient. RESULTS: The mean age was 63 years; the mean BMI was 27.6. Seventy-six patients (80%) were non-smokers. Sixty-two patients (65.3%) showed no drinking habits and 8 (8.4%) have no prior chemotherapy. Thirty-nine patients (41.1%) were adenocarcinoma, 51 (53.7%) were squamous cell carcinoma and five (5.3%) were large cell carcinoma. At the beginning of radiotherapy, the mean selenium level for all patients was 90.4 µg/l and after radiation this value dropped to 56.3 µg/l. Multivariate analysis showed statistically significant difference in the plasma selenium concentration before and after radiotherapy for age (P<0.001), BMI (P<0.001), smoking (P<0.001), alcoholism (P<0.001), prior chemotherapy (P<0.001) and pathological type (P<0.001). CONCLUSION: Significant reduction in plasma levels of selenium was recorded in patients undergoing radiotherapy, suggesting attention to the nutritional status of this micronutrient and other antioxidant agents.

Effect of electroacupuncture preconditioning on serum S100beta and NSE in patients undergoing craniocerebral tumor resection.

OBJECTIVE: To investigate the effect of electroacupuncture preconditioning on the serum level of S100 calcium-binding protein beta (S100beta) and neuron-specific enolase (NSE) in patients undergoing craniocerebral tumor operation. METHODS: A total of 32 patients, who would go through craniocerebral tumor resection under general anesthesia, were randomly assigned to two groups, 16 in each group. Patients in the electroacupuncture (EA) group received electroacupuncture on Fengfu acupoint (Du16) and Fengchi acupoint (GB20) for 30 min, 2 h before operation. The stimulus is 1-4 mA with a density wave frequency of 2/15 Hz. Patients in the control group received no pretreatment. Anesthesia was maintained with remifentanil at the dose of 4-8 mg/kg per hour, pumped intravenous drip of vecuronium at 1.0-2.0 microg/kg each hour, and discontinuous intravenous dripped with vecuronium bromide at 0.5-1 mg. The serum levels of S100beta and NSE were measured with ELISA before operation, before skin incision, after tumor removal, at the end of operation, and at 24 h after operation. RESULTS: The serum level of S100beta and NSE did not change before skin incision. The serum level of NSE increased significantly and the level of S100beta increased insignificantly after the tumor resection. The serum levels of S100beta and NSE in the EA group and the control group were 1.16+/-0.28 microg/L vs 1.47+/- 0.33 microg/L, 24.7+/-13.3 microg/L vs 31.4+/-14.1 microg/L at the end of the operation, respectively. Twenty-four h after operation, the correspondence indices were 1.18+/-0.31 microg/L vs 1.55+/-0.26 microg/L, and 25.5+/-12.4 microg/L vs 32.4+/- 11.7 microg/L. The two indices at these two time points were significantly increased than those before operation, respectively (P<0.05). At the end of the operation and 24 h post-operation, the serum levels of S100beta and NSE in the EA group were significantly lower than those in the control group (P<0.05). CONCLUSION: Electroacupuncture Fengchi and Fengfu for 30 min before craniocerbral tumor operation could decrease the serum level of S100beta and NSE, thus may have potential protective effect on brain damage, which needs to be further studied.

Lycopene in treatment of high-grade gliomas: a pilot study.

BACKGROUND: The therapeutic benefit of lycopene is well established for carcinoma prostate in various clinical trials and has been proposed for other malignancies including high-grade gliomas. SETTING AND DESIGN: Randomized placebo control study in the Department of Radiation Oncology of a teaching hospital. MATERIALS AND METHODS: Fifty patients with high-grade gliomas were treated with surgery followed by adjuvant radiotherapy and concomitant paclitaxel. Patients were randomized to receive either oral lycopene (Group A) 8 mg daily with radiotherapy or placebo (Group B). Pre-and post-radiotherapy plasma lycopene levels were measured using high-precision liquid chromatography. McDonald's criteria were used for response assessment. Magnetic resonance imaging (MRI) of brain and Single Photon Emission Computed Tomograph (SPECT) were done three-monthly for two visits and six-monthly thereafter. Primary endpoint was response at six months post radiotherapy. Statistical Analysis Used : The data was analyzed using SPSS Software v10.0 (SPSS corporation Chicago IL) by applying Student's t-test, ANOVA F test, Chi-square test and Karl Pearson Correlation Coefficient. RESULTS: Median age was 38 years. The commonest histology was glioblastoma multiforme (n = 32). Pre- and post-treatment plasma lycopene levels in the patients in Gropu A were 152 ng/ml and 316 ng/ml and in the patients in Group B were 93 ng/ml and 98 ng/ml (P = 0.009). There was non-significant differences in favor of lycopene between Group A and Group B with higher overall response at six months (P = 0.100), response at last follow-up (P = 0.171) and time to progression (40.83 vs. 26.74 weeks, P = 0.089)., The follow-up duration was significantly higher for Group A than Group B (66.29 vs. 38.71 weeks, P = 0.05). CONCLUSIONS: Addition of nutrition supplements such as lycopene may have potential therapeutic benefit in the adjuvant management of high-grade gliomas.

In vitro, high-resolution 1H and 31P NMR based analysis of the lipid components in the tissue, serum, and CSF of the patients with primary brain tumors: one possible diagnostic view.

In vitro, high-resolution (1)H and (31)P NMR based qualitative and quantitative analyses of the lipid components of the tissue, serum, and CSF of patients with primary brain tumors were performed. Proton NMR spectra of the lipid extract of serum (blood specimen collected before the surgical procedure) and surgically discarded tissue showed that the total cholesterol (T.CHOL) and choline containing phospholipids (PL) were significantly higher in quantity in medulloblastoma and glioblastoma multiforme as compared to normal subjects. Serum lipid extracts of grade II/ III gliomas showed a higher quantity of PL than normal subjects. Cholesterol esters (CHOLest) were detectable in the tissue lipid extract of the patients with tumors and absent in normal tissue. There was a reduction in the quantity of CHOLest in the serum lipid extract of the tumor patients as compared to normal subjects. Ratio of PL to T.CHOL in serum lipid extract showed a significant difference between different grades of tumors versus normal subjects, while, a significant difference was observed only in medulloblastoma versus normal subjects in tissue lipid extract. Ratio of CHOL to CHOLest distinguishes the different grades of tumors versus normal subjects as well as between different grades of tumors (except medulloblastoma versus glioblastoma). The ratio of the Ph (total phospholipids except phosphatidylcholine) to PC (phosphatidylcholine) in (31)P NMR based study showed a significant difference in all grades of tumors (except medulloblastoma) in normal subjects in tissue lipid extract as well as between different grades of tumors. Medulloblastoma could be differentiated from glioblastoma as well as from normal subjects in serum lipid extract by the ratio of the Ph to PC. Proton NMR spectra of the lipid extract of CSF showed that the CHOL, CHOLest, and PL were present in the patients with tumors, although these were absent in the patients with meningitis, motor neuron disease, and mitochondrial myopathies as well as in normal subjects. PL and T.CHOL provided discrimination between different grades of tumors (except glioblastoma versus medulloblastoma) in the lipid extract of the CSF. This study suggests the role of lipid estimation in CSF and serum as a complementary diagnostic tool for the evaluation of brain tumors preoperatively. NMR-based lipid estimation of post-surgical tumor tissue may also contribute to differentiating the tumor types.

Clinical implementation of 4-dihydroxyborylphenylalanine synthesised by an asymmetric pathway.

Boron neutron capture therapy (BNCT) is an experimental therapeutic modality combining a boron pharmaceutical with neutron irradiation. 4-Dihydroxyborylphenylalanine (L-BPA) synthesised via the asymmetric pathway by Malan and Morin [Synlett. 167-168 (1996)] was developed to be the boron containing pharmaceutical in the first series of Finnish BNCT clinical trials. The final product was >98.5% chemically pure L-BPA with L-phenylalanine and L-tyrosine as the residual impurities. The solubility of L-BPA was enhanced by complex formation with fructose (BPA-F). The pH and osmolarity of the BPA-F preparation is in the physiological range. Careful attention was given to the pharmaceutical quality of the BPA-F preparations. Prior to starting clinical trials the acute toxicity of L-BPA was studied in male albino Sprague-Dawley rats. In accordance with earlier studies no adverse effects were observed. After completion of the development work L-BPA solution was administered to brain tumour patients in conjunction with clinical studies for development and testing of BPA-based BNCT. No clinically significant adverse events attributable to the L-BPA i.v. infusions were observed. We conclude that our synthesis development, complementary preclinical and clinical observations justify the safe use of L-BPA up to clinical phase III studies with L-BPA produced by the asymmetric pathway, originally presented by Malan and Morin in 1996.

Radiation dose-volume effects on growth hormone secretion.

PURPOSE: Growth hormone (GH) deficiency is a known consequence of central nervous system irradiation. The relationship between the dose to the hypothalamus and the time to onset of clinically significant GH deficiency is unknown. Conformal radiotherapy (CRT) techniques allow for a more accurate determination of hypothalamic dosimetry. We correlated the dosimetry of the hypothalamus and the peak GH value after CRT in children with localized primary brain tumors. METHODS AND MATERIALS: The arginine tolerance/L-dopa test was performed before (baseline) and repeated 6 and 12 months after CRT in 25 children (median age 4.8 years) with ependymoma (n = 15) or low-grade (n = 8) or high-grade (n = 2) astrocytoma. None had evidence of GH deficiency (arginine tolerance/L-dopa peak GH level >10 ng/mL [10 microg/L]) at baseline. Peak GH levels were modeled as a function of time after CRT and volume of the hypothalamus receiving a dose within the specified intervals of 0-20 Gy, 20-40 Gy, and 40-60 Gy. The model was used to predict the change in the peak GH levels over time (0-12 months) and fit under the assumption that the integral effect of irradiation was a linear sum of the products of the volume receiving a particular dose and the impact of that dose. RESULTS: The peak GH level declined during the 0-12 months after CRT (p < 0.0001). GH deficiency was observed in 11 children at 6 months and a total of 20 children at 12 months. As expected, the effect of the dose interval 0-20 Gy was smaller than the 20-40-Gy dose interval; the largest effect was noted with the dose interval 40-60 Gy. The peak GH level may be predicted using the following estimating equation within the time limit of 0-12 months: GH(t)=Exp[ln(bGH)-(0.00058V(0-20 Gy)+0.00106V(20-40 Gy)+0.00156V(40-60 Gy))x t], where bGH is the baseline peak GH level, V(0-20 Gy), V(20-40 Gy), and V(40-60 Gy) is the percent-volume of the hypothalamus irradiated from 0 to 20 Gy, 20 to 40 Gy, and 40 to 60 Gy, respectively, and t is time after irradiation. When included in the model, the rate of decline in the peak GH response also was influenced by hydrocephalus and tumor location. CONCLUSION: The peak GH response within 12 months after CRT depends on hypothalamic dose-volume effects and may be predicted on the basis of a linear model that sums the effects of the entire distribution of dose. The modeled effects may be used to optimize radiotherapy and minimize and treat GH deficiency.

The effect of anticonvulsant drugs on blood levels of methotrexate.

The reduced bioavailability of chemotherapeutic agents is one of the reasons that explains the limited efficacy of adjuvant chemotherapy in high grade glioma patients. We report how even the results of high dose sequential chemotherapy can be influenced by antiepileptic drugs.

Boron neutron capture therapy of brain tumors: biodistribution, pharmacokinetics, and radiation dosimetry sodium borocaptate in patients with gliomas.

OBJECTIVE: The purpose of this study was to obtain tumor and normal brain tissue biodistribution data and pharmacokinetic profiles for sodium borocaptate (Na2B12H11SH) (BSH), a drug that has been used clinically in Europe and Japan for boron neutron capture therapy of brain tumors. The study was performed with a group of 25 patients who had preoperative diagnoses of either glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) and were candidates for debulking surgery. Nineteen of these patients were subsequently shown to have histopathologically confirmed diagnoses of GBM or AA, and they constituted the study population. METHODS: BSH (non-10B-enriched) was infused intravenously, in a 1-hour period, at doses of 15, 25, and 50 mg boron/kg body weight (corresponding to 26.5, 44.1, and 88.2 mg BSH/kg body weight, respectively) to groups of 3, 3, and 13 patients, respectively. Multiple samples of tumor tissue, brain tissue around the tumors, and normal brain tissue were obtained at either 3 to 7 or 13 to 15 hours after infusion. Blood samples for pharmacokinetic studies were obtained at times up to 120 hours after termination of the infusion. Sixteen of the patients underwent surgery at the Beijing Neurosurgical Institute and three at The Ohio State University, where all tissue samples were subsequently analyzed for boron content by direct current plasma-atomic emission spectroscopy. RESULTS: Blood boron values peaked at the end of the infusion and then decreased triexponentially during the 120-hour sampling period. At 6 hours after termination of the infusion, these values had decreased to 20.8, 29.1, and 62.6 microg/ml for boron doses of 15, 25, and 50 mg/kg body weight, respectively. For a boron dose of 50 mg/kg body weight, the maximum (mean +/- standard deviation) solid tumor boron values at 3 to 7 hours after infusion were 17.1+/-5.8 and 17.3+/-10.1 microg/g for GBMs and AAs, respectively, and the mean tumor value averaged across all samples was 11.9 microg/g for both GBMs and AAs. In contrast, the mean normal brain tissue values, averaged across all samples, were 4.6+/-5.1 and 5.5+/-3.9 microg/g and the tumor/normal brain tissue ratios were3.8 and 3.2 for patients with GBMs and AAs, respectively. The large standard deviations indicated significant heterogeneity in uptake in both tumor and normal brain tissue. Regions histopathologically classified either as a mixture of tumor and normal brain tissue or as infiltrating tumor exhibited slightly lower boron concentrations than those designated as solid tumor. After a dose of 50 mg/kg body weight, boron concentrations in blood decreased from 104 microg/ml at 2 hours to 63 microg/ml at 6 hours and concentrations in skin and muscle were 43.1 and 39.2 microg/g, respectively, during the 3- to 7-hour sampling period. CONCLUSION: When tumor, blood, and normal tissue boron concentrations were taken into account, the most favorable tumor uptake data were obtained with a boron dose of 25 mg/kg body weight, 3 to 7 hours after termination of the infusion. Although blood boron levels were high, normal brain tissue boron levels were almost always lower than tumor levels. However, tumor boron concentrations were less than those necessary for boron neutron capture therapy, and there was significant intratumoral and interpatient variability in the uptake of BSH, which would make estimation of the radiation dose delivered to the tumor very difficult. It is unlikely that intravenous administration of a single dose of BSH would result in therapeutically useful levels of boron. However, combining BSH with boronophenylalanine, the other compound that has been used clinically, and optimizing their delivery could increase tumor boron uptake and potentially improve the efficacy of boron neutron capture therapy.

Dosimetry and growth hormone deficiency following cranial irradiation of childhood brain tumors.

BACKGROUND: Dosimetry of the hypothalamus-pituitary (HP) region could allow prediction of the risk of growth hormone deficiency (GHD) following cranial irradiation. PROCEDURE: Nineteen children (15 boys) with a median age of 6.3 years (range 1.7-16.5) at the time of irradiation of a brain tumor not involving the HP axis were followed for 1.2-6.3 years (median 3.4) from radiotherapy (RT). The dose to a standardized anatomical model including the HP region was calculated from dose-volume histograms of 10% to 100% in steps of 10% of the HP model based on data from a computer-based treatment planning system. If GHD was suspected from insulin-like growth factor-I, serum insulin-like growth factor binding protein-3, and/or height velocity measurements, an arginine stimulation test was performed. GHD was defined by a peak GH <15mU/liter. RESULTS: Ten patients developed GHD 10-26 months from irradiation. Cox regression analysis identified the 90% dose-volume of the HP box as the strongest predictor of development of GHD (P = 0.03). The median dose to the 90% dose-volume of the HP region was 37.5 Gy (range 2. 3-55.3). The cumulated risk of GHD 2.5 years after radiotherapy for children receiving more than and less than 37.5 Gy to the HP region was 87% and 33%, respectively (P = 0.036). CONCLUSIONS: Dosimetry of a defined HP volume provides the opportunity to 1) calculate the exact dose delivered to this region, 2) predict the risk of GHD and, 3) in the future revise the treatment planning and thus reduce the risk of endocrine adverse effects.

Effect of etoposide on the pharmacokinetics of methotrexate in vivo.

The effect of etoposide on the pharmakokinetics of methotrexate (MTX) was examined in vivo. High-dose (5g/m2/24 h) MTX therapy was combined with two etoposide (100mg/m2/ 1 h) infusions as a part of the medulloblastoma protocol developed in our department. Vepesid therapy was administered in two different schedules. The first group of patients received etoposide immediately before and at the end (24 h) of MTX treatment. The second group was treated with etoposide at 24 and at 48 h after starting MTX infusion. In this latter group both treatment-related grade III and grade IV toxicity developed more frequently than in the first group (58.6 versus 29.2%, for grade 3 toxicity p=0.019, for grade 4 toxic signs p=0.040, respectively). We observed that after the second dose of etoposide given at 48 h (second group) both total and unbound serum MTX levels (determined by high-performance liquid chromatography) were elevated by 53-109 and 26-65%, respectively, by the third hour after completion of Vepesid infusion. This effect was detectable for 6 h. All the liver and kidney functions of the patients were within the normal range. These results suggest the possibility of partial recirculation of extra/intracellular MTX into the blood after etoposide administration. Based on these results, the therapeutic protocol has been modified, and Vepesid is given prior to and at the end (24 h) of high-dose MTX treatment. Under these conditions only a slight decrease of MTX elimination has been detected between 25 and 28 h. These results emphasize the role of possible schedule-dependent interactions of cytostatic drugs.

Intraoperative autologous blood transfusion in intracranial surgery.

OBJECTIVE: The purpose of this study was to evaluate the benefits of intraoperative autotransfusion of autologous blood on the conservation of allogenic blood, including cost-effectiveness and the consequences for hemoglobin level and coagulation tests. METHODS: The Hoemonetics Cell Saver 4 autotransfusion system (Hoemonetics Corporation, MA) was used when the estimated blood loss was equal to or more than 500 ml. A total of 472 patients undergoing intracranial surgery were included in the study. RESULTS: Ninety patients (19%) received transfusions either with autologous blood or allogenic blood. Fifty-five patients (61%) received only autologous blood transfusions, 10 patients (11%) received both autologous and allogenic blood transfusions, and 25 patients (28%) received only allogenic blood transfusions. The amount of autologous blood transfused was 600 +/- 590 ml (range, 230-3000 ml). The amount of allogenic blood transfused was 3 +/- 3 units (range, 2-15 units). Autologous blood represented 68% of all blood products transfused. Mild abnormalities during coagulation tests occurred without clinical bleeding. CONCLUSION: Autologous blood transfusions were demonstrated to be safe in patients undergoing intracranial surgery and to be more cost-effective than allogenic blood transfusions. Intraoperative autologous blood transfusions may be used alone in more than half of the patients requiring transfusions during intracranial surgery and decrease the amount of allogenic blood used. Improvements in the monitoring for the need of performing this technique, as well as preoperative blood donations, would decrease the amount of allogenic blood transfused.

Effect of the type of serum in the medium on sodium ascorbate-induced cytotoxicity.

Sodium ascorbate induced cytotoxicity against human glioblastoma T98G cells in RPMI1640 medium supplemented with fetal bovine serum or human serum samples was studied. Several human serum samples significantly reduced the cytotoxic activity of sodium ascorbate, regardless of sex, age or the disease of the serum donor with or without heat-inactivation of the serum. ESR spectroscopy revealed that this serum effect was not simply due to the alteration of the ascorbyl radical intensity, produced from sodium ascorbate. The present study suggests that the apoptosis-inducing activity of sodium ascorbate might be significantly affected by human serum.