Feasibility of preirradiation temozolomide in cases of high-grade gliomas: Our experience and review of literature.

Aim: The purpose of this study was to evaluate the efficacy and safety of preradiation temozolomide (TMZ) in high-grade gliomas. Study and Design: It is a single-center, single arm, prospective study. The study included postoperative, histopatholgically proven cases of high-grade gliomas. Materials and Methods: Nine patients of anaplastic astrocytoma (AA) and twenty patients of glioblastoma multiforme (GBM) were enrolled in the study. All patients had undergone partial or complete resection. Three weeks after surgery, patients were started on chemotherapy, consisting of two cycles of TMZ, 150 mg/m2/day for 5 days, repeated at an interval of 4 weeks. Patients were subsequently treated with concomitant chemoradiotherapy. A dose of 60 Gy was given over thirty fractions along with TMZ, 75 mg/m2/day. Four cycles of TMZ were given after completion of radiotherapy, in a dose and manner similar to preradiotherapy. Statistical Analysis and Result: Treatment-related toxicity was assessed using common terminology for toxicity criteria (CTCAE v4). Progression-free survival and overall survival (OS) analysis was done. Nearly 79% of patients completed the two cycles of preradiation chemotherapy. Chemotherapy was tolerated well. Median time to progression was 11 months and 8.2 months in AA and GBM patients, respectively. Median OS was 17.4 months in AA patients and 11.4 months in GBM patients. Conclusions: Most patients of postoperative high-grade gliomas tolerated two cycles of TMZ. A good safety profile of TMZ allows it to be used in frontline settings, especially in high volume centers where a delay in starting radiotherapy frequently occurs. The use of TMZ before radiotherapy is a safe and feasible approach, and further studies are required to validate this approach.

Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice.

BACKGROUND: The randomised double-blinded placebo-controlled EXIST-1-3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC. RESULTS: The study included 64 patients with TSC (median age: 19, range 0.9-54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients < 18 years (46%) than among patients ≥ 18 years (14%, p = 0.03). In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months. SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months. Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0-106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common. The most common laboratory abnormalities were increased cholesterol (41%), anaemia (30%), and leucopoenia (25%). Grade 3-4 adverse effects were reported in 36% of cases, and life-threatening conditions were reported in two patients. Nine patients discontinued everolimus treatment. CONCLUSIONS: Seizure reduction in this study sample was consistent with results from EXIST, but might be lower than expected, given that changes in concomitant ASMs are part of clinical practice. Seizure reduction was associated with younger age. As with EXIST, everolimus reduced or stabilised rAML size in most patients. SEGA volume was reduced in all three patients. Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects.

Effects of lipid association on lomustine (CCNU) administered intracerebrally to syngeneic 36B-10 rat brain tumors.

A syngeneic, intracerebral rat brain tumor model was developed and characterized and then used to evaluate the therapeutic enhancement of lipid-associated 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). The Fisher rat glioma cell 36B-10 (100,000-500,000 cells) was implanted intracranially to Fisher F-344 rats into the caudate nucleus. Animals treated with lipid-associated CCNU showed a 2- to 10-fold decrease in tumor size compared with animals treated with free CCNU, indicating that lipid association increases the therapeutic index of intracerebral CCNU treatment. Moreover, the syngeneic rat brain tumor model may be useful for evaluation of other therapeutic modalities.

N-ethyl-N-nitrosourea-induced spinal tumors in an inbred strain of W albino rats.

Exposure to N-ethyl-N-nitrosourea (ENU) either transplacentally via the maternal bloodstream or postnatally by direct injection into the cerebellum or the cisterna magna resulted in a high incidence of spinal tumors in an inbred strain of W albino rats. After prenatal exposure to 60 mg ENU/kg maternal body weight, as many as 92% of the offspring developed 1 or more tumors in the spinal cord, whereas after postnatal exposure to 0.2 mg ENU/animal, 50% of the animals eventually developed spinal tumors. These tumors included relatively pure oligodendrogllomas, astrocytomas, and the usual mixed gllomas. Obvious clinical symptoms of paralysis of the limbs and weight loss accompanying the high incidence of tumors in the spinal cord make this system pertinent to the study of carcinogenesis in the central nervous system as well as to the study of related problems to the incidence of these tumors are discussed.

Carcinogenicity of nitrosotrialkylureas in Fischer 344 rats.

Three nitrosotrialkylureas were administered to female F344 rats as approximately 1-mM solutions in drinking water. Nitrosotrimethylurea, given for 47 weeks, gave rise to astrocytomas of the brain and tumors of the forestomach; nitrosotriethylurea induced a high incidence of adenocarcinomas of the breast and uterus and tumors of the forestomach. Nitrosomethyldiethylurea induced almost exclusively a high incidence of both astrocytomas of the brain and tumors of the spinal cord.

Inhibitory effect of sodium ascorbate on ethylurea and sodium nitrite carcinogensis and negative findings in progeny after intestinal inoculation of precursors into pregnant hamsters.

To assess their carcinogenic effects, the ethylnitrosourea (ENU) precursors, ethylurea and sodium nitrite, [were administered to pregnant hamsters as a single intragastic] dose on day 15 of gestation, or introduced into the cecum on day 14. Since sodium ascorbate (NaASC) inhibits the biosynthesis of nitrosamides, identical doses of the precursors were given concomitantly with NaASC. Progeny of mothers treater intragastrically developed significant incidences of neurogenic tumors of the peripheral nervous system, with a predominance in females. The concurrent administration of NaASC with ENU precursors prevented carcinogenic effects in the progency, whereas the simultaneous inoculation of the precursors into the cecum produced no carcinogenic effects in the offspring.

[Tumour induction by ethylnitrosourea in the central nervous system]. / Inducción de tumores en el sistema nervioso central mediante etilnitrosourea.

INTRODUCTION: Experimental central nervous system (CNS) tumours have been proposed as a useful model for the study of oncogenesis, epiphenomena related to cancer and for the design of new therapeutic strategies. DEVELOPMENT: The administration of chemical substances is one of the most commonly-used methods to induce CNS neoplasms. N-ethyl-N-nitrosourea (ENU) belongs to the nitrosourea family, a wide group of alkylating agents that are able to induce brain tumours in litters after transplacentary administration at the 15th day of pregnancy. This nitrogenous urea compound has a high mutation inducibility affecting the expression of oncogenes such as p53, neu/erbB-2 and Ras. Prenatal exposition of Sprague Dawley rats to ENU induces intra-axial tumours of glial lineage and extra-axial malignant schwannomas. Although the precise mechanism of tumour induction is unclear, it is known to affect cell differentiation of primitive neuroepithelium from the subventricular plate generating oligodendrogliomas, astrocytomas, mixed gliomas or ependimomas. CONCLUSION: The transplacentary administration of ENU induces the development of gliomas and schwannomas that are similar to those found in humans. Animal models are necessary and useful for further studies to get an early diagnosis and to establish correct therapeutic indications.

CNS tumors and exposure to acrylonitrile: inconsistency between experimental and epidemiology studies.

Acrylonitrile is a potent CNS tumorigen in rats leading to concern that it may be a tumorigen in humans. There have been 12 epidemiology studies of 37,352 workers exposed to acrylonitrile which evaluate CNS cancers. We summarize and evaluate these epidemiology studies for CNS cancers using the methods of meta-analysis. Our analyses indicate that workers with acrylonitrile exposure have null findings for CNS cancer (relative risk = 1.1, 95% confidence interval 0.8-1.5), which are in stark contrast to the projected risk to humans using the rat findings (relative risk = 3.5, 95% confidence interval 3.0-4.0). We discuss several explanations for the inconsistency between animal and human findings, including the possibility that the acrylonitrile-induced rat CNS tumors may not be relevant to humans. Given the rarity of CNS tumors in humans and a lack of understanding of the causal mechanisms of these tumors in rats, however, a more definitive conclusion will have to await additional experimental and observational data. Nevertheless, the epidemiology evidence indicates that acrylonitrile is not a potent CNS tumorigen.

Increased telomerase activity and absence of p53 mutation in oligoastrocytomas induced by N-ethyl-N-nitrosourea in rats.

The question of whether the changes in telomerase activity and/or the alteration of the p53 gene are involved in the development of oligo-astrocytomas induced by N-ethyl-N-nitrosourea (ENU) in rats was addressed. Telomerase activity levels of oligo-astrocytomas, including early neoplastic lesions, were significantly increased as compared to the normal controls, correlating with the degree of malignancy. In contrast, no mutations of p53 exons 5-7 were found in early neoplastic lesions or oligo-astrocytomas. These results indicate that the activation of telomerase occurs during astrocytoma carcinogenesis and contributes to the development of brain tumors, but the alterations of p53, at least on exons 5-7, may not be involved in this process.

Household water source and the risk of childhood brain tumours: results of the SEARCH International Brain Tumor Study.

BACKGROUND: The period in utero is a time of increased vulnerability. Offspring of pregnant women exposed to carcinogenic substances in drinking water may be more likely to develop cancer. We examined whether household water source and the presence of nitrates or nitrites in residential water were associated with increased risks of childhood brain tumours (CBT). METHODS: We used data from a multicentre, case-control study with maternal information on residential water source, and nitrate/nitrite levels of tap water measured by dipstick. Subjects included 836 CBT cases and 1485 controls from five countries. RESULTS: The risks of CBT associated with reliance on well water (versus public water) during pregnancy varied widely, with significantly increased risks noted in two (of seven) regions and a decreased risk observed in one region. CBT risk did not increase with increasing nitrate levels. However, our results based on tap water tested in the pregnancy residences suggest the risk of astrocytoma may be associated with increasing levels of nitrite (odds ratio [OR] = 4.3, 95% CI: 1.4, 12.6 for nitrite levels of 1-<5 mg/l nitrite ion; OR = 5.7, 95% CI: 1.2, 27.2 of nitrite > or =5 mg/l). CONCLUSIONS: These results should be interpreted with caution because women's recollection of water sources may have contained inaccuracies, and nitrate and nitrite measurements, available for only a portion of subjects, were often obtained years after the pregnancies occurred. However, our results suggest a need for closer evaluation of well water content in some regions and the possibility that a nitrite-related water exposure may be associated with CBT.

Maternal exposure to N-nitrosatable drugs as a risk factor for childhood brain tumours.

BACKGROUND: Animal models suggest that compounds containing a nitrosyl group (N-nitroso compounds (NNO)) can act as potent transplacental carcinogens. Many common drug formulations have the potential to undergo nitrosation in vivo. The association between maternal use of nitrosatable drugs during pregnancy and development of brain tumours in the offspring was examined in a SEER-based case-control study. METHODS: Maternal exposure to nitrosatable drugs during pregnancy was compared among 361 childhood brain tumour cases and 1083 matched controls recruited through random-digit dialing. RESULTS: There was no increase in risk observed for childhood brain tumours overall (OR = 1.15; 95% CI: 0.69-1.94) or for astrocytomas individually (OR = 1.16; 95% CI: 0.50-2.69). A slight elevation in risk was noted for medulloblastomas (OR = 1.47; 95% CI: 0.28-7.62) and 'other' tumours (OR = 1.27; 95% CI: 0.56-2.86), however, both estimates were based on small numbers. CONCLUSIONS: Our findings suggest that no increased risk of childhood brain tumours was associated with maternal exposure to nitrosatable drugs. The study results should be viewed with caution given the imprecision of the point estimates as well as the lack of data on specific timing and dosage of exposure and degree of nitrosatability of drugs taken.

Changes in VEGF expression and in the vasculature during the growth of early-stage ethylnitrosourea-induced malignant astrocytomas in rats.

Vascular endothelial growth factor (VEGF), a potent angiogenic and vascular permeability factor, may be important as a mediator of brain tumour progression. However, it is still not clear whether VEGF plays a causative role in the early stage of glioma development. We investigated the relationship between VEGF protein expression (as assayed by immunohistochemistry) and different morphological parameters reflecting tumour progression (tumour diameter, vascular density and vascular diameter) in tumours at various stages. As a tumour model, ethylnitrosourea (ENU)-induced rat malignant astrocytoma was used. Tumours were classified by size and level of vascularity estimated by the von Willebrand factor (vWF) staining. Tumours less than 10 mm in diameter were designated early stage neoplastic lesions. All 34 early astroglial tumours were found to be VEGF positive. Increase in the VEGF immunopositive rate of tumour cells correlated significantly with increase in vascular density and vascular diameter. We suggest that VEGF induces angiogenesis and growth of microvessels, promoting growth of the early stage malignant astrocytoma.

Dyke Award Paper. Kinetics of pathologic blood-brain-barrier permeability in an astrocytic glioma using contrast-enhanced MR.

PURPOSE: The feasibility of measuring blood-brain barrier permeability was studied in a 36B-10 brain glioma model in rats. MATERIALS AND METHODS: In stage I of our study, sequential MR images of glioma-implanted rats were obtained following intravenous administration of three contrast agents of different molecular sizes--Gd-DTPA, polylysine-(Gd-DTPA), and albumin-(Gd-DTPA). In a second set of experiments, sequential MR imaging with Gd-DTPA, quantitative measurements of plasma Gd-DTPA concentration, and postmortem tumor Gd-DTPA measurements were used to estimate the blood-to-tissue transport coefficient (Ki) in the rat glioma model at 11 and 15 days postimplantation. RESULTS: In stage I, Gd-DTPA caused rapid and greatest tumor enhancement with a significant washout from the tumor during the 120-min experiment. Tumor enhancement using polylysine-(Gd-DTPA) occurred later and was significantly less compared to Gd-DTPA. Tumor signal intensity increased only slowly over time and the peak level of enhancement was least using albumin-(Gd-DTPA). In stage II, the mean (+/- 1 SD) Ki values were 1.1 +/- .24 at 11 days, and 9.3 +/- .8 at 15 days postimplantation. These results correspond well with published data obtained by autoradiography. CONCLUSION: We believe that the differential enhancement pattern using contrast agents of different molecular sizes reflects a differential permeability of the pathologic blood-brain barrier, and that our studies demonstrate the feasibility of using frequent sequential images and a graphical approach to Ki calculation to determine the blood-to-tissue transport coefficient using contrast-enhanced MR.

[Deoxyribonucleases in spontaneous and experimental tumors of the nervous system]. / Desoxyribonucleasen in spontanen und experimentellen Tumoren des Nervensystems

DNA- and RNA-concentrations, as well as in vitro activities of DNase I (EC 3.1.4.5), DNase II (EC 3.1.4.6), and DNase I inhibitor, have been determined in 63 spontaneous (man) and 22 experimentally induced (rat) nervous system blastomas of various types and of different degrees of malignancy. Generally, a distinct elevation of DNA concentrations and of the ratio (Q) of DNase II- to DNase I-activities has been observed when compared with control values. A statistically significant relationship could be demonstrated between increase of DNA concentrations and Q in experimentally induced neurinomas of rats as well as in human astrocytomas and glioblastomas. Whereas the increase of Q may be a biochemical expression of elevated DNA synthesis of tumour cells, no conclusions can be drawn as to the role of DNases in the process of malignant transformation.

An improved rat brain-tumor model.

The widely used intracerebral tumor implantation method by freehand injection into parietal or hippocampal areas of the rat brain has proven inadequate for reliable experimental therapeutic studies. Problems include poor intracerebral growth yields and significant rates of spread to extracranial tissues, lungs, and spinal cord. Major variables have been examined experimentally on a model using nitrosourea-induced nervous system tumor cell lines in sygeneic rats. A rapid stereotaxic method greatly improved the consistency of tumor placement. The optimal site was found to be the caudate nucleus. The production of a spheroid intracerebral growth was further facilitated by the use of 1% agar in the cell suspension medium and by an injection volume of 10 mu1 containing at least 10(4) cells. Further improvements involved injection technique and flushing of the operative field. These modifications have resulted in a 99% to 100% yield of intracerebral growth, with a marked reduction in the number and size of extracranial extensions and with distant metastasis rates of 0% to 5%. These results have continually improved with further experience. The method is satisfactory for radiation and chemotherapeutic trials in which survival time as an index of tumor size may be used an an end point.

Three-generation reproduction study of rats receiving acrylonitrile in drinking water.

Acrylonitrile, a high volume organic chemical, was tested for reproductive effects in a three generation drinking water study with two matings per generation. Sprague-Dawley rats were exposed to acrylonitrile in drinking water at 0, 100, or 500 ppm. This corresponds to 0, 11+/-5 and 37+/-10 mg/kg, respectively, for males and 0, 20+/-3 and 40+/-8 mg/kg per day for the females, respectively. Water consumption was reduced in F0 rats in the 100 and 500 ppm groups. At 500 ppm, acrylonitrile reduced body weight gain and food intake of the first generation parental rats (F0). These parameters were not investigated at subsequent generations. The pup survival (both viability and lactation indices) was reduced at the 500 ppm treatment level in both matings of all three generations. Fostering the 500 ppm pups onto untreated mothers following the second mating lessened mortality, suggesting a maternal effect consistent with decreased water consumption. There was no remarkable change in the reproductive capacity in any of matings in rats at the 100 ppm concentration. In contrast, in all three generations, the body weights of the pups of the 500 ppm treatment level were reduced on Day 21 at both matings. No adverse findings were observed in the tissues of a limited number of third generation weanlings (F3b) upon gross and microscopic evaluation. No effect on the sciatic nerve was evident among the adult female rats held for 20 weeks after weaning of the second litter. There was a dose-related effect of acrylonitrile on gross masses in female rats at each parental generation held 20 weeks after the weaning of the second litter. Histopathological evaluation of these dams showed an increase in astrocytomas and zymbal gland tumors.

Risk of astrocytic brain tumors associated with occupational chemical exposures. A case-referent study.

A case-referent study was conducted on the risk of brain tumors among workers exposed to organic chemicals in petroleum refining and chemical manufacturing. Brain tumor cases in northern New Jersey, Philadelphia, and the Gulf Coast of Louisiana were identified from death certificates of a recent three-year period. The cases (N = 300) were white men aged greater than or equal to 30 years with a confirmed diagnosis of glioblastoma multiforme, astrocytoma, or a mixed glioma with astrocytic cells. The referents (N = 386) were white men who died from causes other than brain tumor, epilepsy, cerebrovascular disease, suicide, or homicide and were frequency-matched with the cases on age at death, year of death, and study area. Next-of-kin were interviewed for complete occupational histories. No statistically significantly elevated odds ratios (OR) were associated with employment in the chemical industry. The risk of astrocytic tumors was elevated among the subjects with production or maintenance jobs in petroleum refining (OR 1.7, 95% confidence interval 0.7-4.2); however, it decreased with duration employed. There were nonsignificant excess risks of astrocytic tumors among the men exposed to cutting fluids (OR 1.6) or organic solvents (OR 1.3), and also among the subjects exposed to lubricating oils (OR 1.4), organic solvents (OR 1.5), or cutting fluids (OR 1.8) for greater than or equal to 20 years.

[Histochemical demonstration of a zinc activated tartrate resistant acid phosphatase in experimentally induced glial microtumors of the rat brain (author's transl)]. / Histochemische Darstellung einer durch Zink aktivierten tartrat-resistenten sauren Phosphatase in experimentell induzierten gliösen Mikrotumoren des Rattengrosshirns

The tartrat resistant zinc activated acid phosphatase (ZT-AP) was investigated in 17 glial microtumours of the rat brain. The tumours were induced by N-ethyl-N-nitrosourea injected to newborn rats subcutaneously (85 mg/kg body weight). The morphology of these microtumours corresponds to the statements in the literature. In regard to their behaviour of the investigated enzyme the microtumours may be divided in 2 groups: 1) Microtumours with an activity of acid phosphatases but without any histochemically demonstrable activity of ZT-AP. Histologically they correspond to oligodendric microgliomas. 2) Microtumours with a high activity of acid phosphatases and a remarkable activity of ZT-AP especially in the perivascular cell proliferations. This type corresponds histologically to the astrocytic and mixed glial proliferations including glioblastomas. According to our present findings the ZT-AP was found in astrocytes and especially in mesenchymal cells. In some cases a focal increased activity of ZT-AP could also be observed before histological alterations appeared. We regard it as an early stage of the development of tumours.

[Cytophotometric determination of DNA concentration in the cells of experimental brain tumors. II. Primary tumors of rat cerebellum induced by 9, 10-dimethyl-1, 2-benzanthracene]. / Tsitofotometricheskoe opredelenie soderzhaniia DNK v kletkakh éksperimental'nykh opukholei mozga. II. Pervichnye opukholi mozzhecka krys, indutsirovannye 9 10-dimetil-1, 2-benzantratsenom

The Feulgen-DNA cytophotometry was applied for studies of 31 rat cerebellum tumors induced by 9, 10-dimetyl-1,2-bensantracene. Most of these gliomas (22) were astrocytomas of different grades of malignancy. The histological diagnosis of other tumors was: glioblastoma -- 4, oligoastrocytoma -- 2, oligodendroglioma -- 1, gliosarcoma 1. The majority cells of 26 tumors had diploid or paradiploid DNA quantity, 4 tumors (1 astrocytoma, 3 dedifferentiated astroyctomas) had triploid modal classes. The tetraploid modal class and a large number of polyploid cells were found only once for glioblastoma multiforme. A supposition was made that drastic changes of ploidy could arise for the second time during the process of tumor evolution. The authors failed to show any exact differences in the ploidy of gliomas in rats with athyreosis or hyperthyreosis, and in the ploidy of somatic cells in control animals.

[A retrospective evaluation of exposure to dichloromethane by using a job-exposure matrix]. / Valutazione retrospecttiva della esposizione a diclorometano mediante una matrice mansione-esposizione.

The impact of three features of a job-exposure matrix has been tested in a case-control study that evaluated the association of occupational exposure to dichloromethane and astrocytic brain cancer. These features were probability of exposure, an exposure assessment by decades, and the use of a more specific coding system of industries and occupations. The introduction of each feature had a striking effect on the estimate of relative risk. The odds ratio increased from 1.47 with none of these features, to 2.47 with high probability of exposure, to 4.15 with high probability of exposure and the specific coding system, to 6.08 with all features combined. These results indicate that job-exposure matrices efficacy in reducing the degree of exposure misclassification may be greatly improved by the introduction of these features.