Drop metastases to the spinal cord from infratentorial glioblastoma multiforme in post-temozolomide era.

Drop metastases from glioblastoma multiforme (GBM) to the spinal cord are extremely rare in clinical practice. We report herewith multiple drop metastases to the cervical and thoracic spinal cord presenting as paraplegia in a patient treated initially with tumor resection followed by chemoradiation and later with temozolomide-.based adjuvant chemotherapy.

Triple-negative breast cancer possibly transforming into malignant melanoma due to targeted therapy? A case report and review of literature.

BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by lacking expression of estrogen receptor and progesterone receptor as well as absence of human epidermal growth factor receptor 2 overexpression and is an aggressive clinical phenotype. PATIENTS AND METHODS: We report the case of a 33-year-old woman who has been treated using a targeted approach for TNBC and developed a malignant melanoma metastasis without any primary. RESULTS AND CONCLUSION: Using targeted therapies, tumors can be treated much more effectively, but up to now, we do not know much about potential adverse reactions. Due to the targeted therapy, tumors may be pressurized for transformation. We call for further investigations to rule out the potential risks of targeted therapy in TNBC. This is the first report of a potential transforming of one tumor entity to another by a targeted therapy.

Hormone replacement therapy increases the risk of cranial meningioma.

AIM: We investigated the influence of hormone replacement therapy (HRT) use on the risk of meningioma in a population-based setting. METHODS: We conducted a nationwide case-control study in Denmark based on population-based administrative and health registries. The study included all female patients aged 55-84 years with a first time diagnosis of meningioma during 2000-2009. The cases were matched on birth year with female population controls. Ever use of HRT since 1995 was defined as ≥2 HRT prescriptions and categorised according to HRT type (oestrogen only, combined oestrogen-progestagen, and progestagen only) and cumulated duration of use (<1, ≥1 to <5, ≥5 to <10, ≥10 years). We used conditional logistic regression to compute odds ratios (ORs), with 95% confidence intervals (CIs), for meningioma associated with HRT use, and adjusting for potential confounders. RESULTS: We identified 924 cases and 6122 controls. Ever use of HRT was associated with an increased risk of meningioma (OR, 1.3; 95%CI, 1.1-1.5) compared with non-use (0-1 prescriptions). The risk increased with increasing duration of HRT use, reaching an OR of 1.7 (95% CI, 1.2-2.3) after more than 10 years of use. The risk of meningioma associated with long-term (≥10 years) HRT use was most pronounced for combined oestrogen-progestagen therapy (OR, 2.2; 95% CI, 1.4-3.3), especially when this regimen constituted the sole HRT therapy (OR, 2.7; 95% CI, 0.9-7.5), although the latter estimate was based on small numbers. CONCLUSIONS: Long-term HRT use, particularly of combined oestrogen-progestagen therapy, may increase the risk of meningioma.

Subacute steroid-induced paraparesis: surgical treatment of a devastating "invisible" side effect.

PURPOSE: To emphasize an underestimated side effect following long-term use of steroids. METHODS: We report on surgical treatment of two patients with serious neurologic deficits caused by epidural spinal lipoma following long-term intake of cortisone. RESULTS: Early decompression of the spinal cord by removal of epidural lipoma was the most effective treatment in these patients with progressive symptoms. CONCLUSION: Diagnostic work-up of such patients should include early spinal MRI resulting in surgical intervention, if indicated. Decompression of the spinal cord eventually combined with fusion is necessary.

Retroviral delivery of platelet-derived growth factor to spinal cord progenitor cells drives the formation of intramedullary gliomas.

BACKGROUND: High-grade gliomas of the spinal cord are poorly understood tumors that are very commonly associated with bad outcomes. The transforming effects of platelet-derived growth factor (PDGF) on spinal cord glial progenitor cells may play an important role in the development of these tumors. OBJECTIVE: To investigate the possible tumor-initiating effects of PDGF overexpression in the spinal cord, we delivered a PDGF retrovirus directly into the substance of the spinal cord. METHODS: The spinal cords of wild-type adult rats were surgically exposed and injected with 106 colony-forming units of a green fluorescent protein-tagged, PDGF-expressing retrovirus. A control virus was injected to assess the cell types that become infected during retroviral delivery to the spinal cord. RESULTS: It was observed that PDGF overexpression in the spinal cord causes morbidity from high-grade intramedullary glioma formation between 27 and 49 days after PDGF retrovirus injection. Retroviral transduction was highly efficient with 100% of injected animals displaying the tumor phenotype. The tumors produced were highly proliferative, were locally invasive, and displayed the immunophenotype of virus-targeted glial progenitor cells (Olig2+PDGFR+NG2+GFAP-). CONCLUSION: PDGF is capable of driving glial progenitor cells within the adult spinal cord to form high-grade gliomas. Further investigation of PDGF signaling in the spinal cord is needed to better understand and treat these devastating tumors.

A case of cervical spine meningioma following etanercept use in a patient with RA.

BACKGROUND: A 70-year-old female with active rheumatoid arthritis (RA) was administered etanercept to treat active disease that persisted despite therapy with conventional DMARDs. After 18 months of etanercept therapy, her RA symptoms had improved; however, she developed quadriparesis. She presented to a specialist rheumatology clinic with weakness and numbness in her arms and legs; she also had difficulty in standing up and walking. INVESTIGATIONS: Physical examination, neurological examination, nerve conduction studies, measurement of serum inflammatory markers and autoantibodies, MRI of the cranium and cervical spine, and X-rays of the chest and hands. DIAGNOSIS: The patient underwent neurosurgery to resect a 1 x 2 cm mass in the cervical spine at C6-C7. Histopathologic examination of the excised mass revealed it to be a meningioma. MANAGEMENT: Etanercept was discontinued because of a possible association between the drug and development of meningioma; however, shortly afterwards the patient experienced a flare of RA symptoms. High-dose NSAIDs and prednisolone were administered, but the patient died because of gastric perforation. To our knowledge, this is the first report in the literature of meningioma developing following use of tumor necrosis factor inhibitor therapy, and the first to suggest a cause-effect relationship.

A rare case of lumbosacral meningioma: nondural attachment and possible enlargement by orally administered sex steroid.

STUDY DESIGN: A case report is presented. OBJECTIVES: To present a very rare case of orally ingested sex hormone pills inducing nondurally attached meningioma in the lumbosacral region. SUMMARY OF BACKGROUND DATA: Meningiomas are known to enlarge in response to female sex hormones. At this writing, few cases of nondurally based intradural meningioma have been reported. Moreover, meningiomas in the lumbosacral region are very rare. Spinal meningiomas predominantly arise in the fourth to sixth decades of life and are more common in women. METHODS: The patient was a 20-year-old woman. She had undergone oral sex steroid therapy for long-term oligomenorrhea. The patient complained of intolerable lumbago and numbness in her buttocks. Nonopioid analgesics did not relieve her pain, and she was unable to walk without the aid of a walker. Radiography disclosed a lumbosacral intradural tumor. RESULTS: Complete removal of the tumor was performed. The tumor was not adherent to the dura, and its appearance was that of a typical neurilemmoma. However, the pathologic diagnosis was meningioma. CONCLUSIONS: The tumor in the reported case may have enlarged in response to orally ingested sex steroid pills. Nondural attachment intradural meningiomas are quite uncommon. The gross appearance of the tumor during surgery was typical of neurilemmoma. All the cases reported so far, including the current case, have involved tumor located in the lumbosacral region. Care must be taken in the management of lumbosacral intradural tumors because tumors resembling neurilemmoma may in fact represent meningioma, some subtypes of which possess a high rate of recurrence.

The effects of 860 MHz radiofrequency radiation on the induction or promotion of brain tumors and other neoplasms in rats.

Sprague-Dawley rats were irradiated with a continuous- wave (CW) or a pulsed-wave (P) radiofrequency (RF) for 6 h/day, 5 days/week from 2 up to 24 months of age. The RFs emanated from dipole antennas (1 W average output) 2.0 +/- 0.5 cm from the tip of each rat's nose. The RFs had an 860 MHz frequency, and the specific absorption rate was 1.0 W/ kg averaged over the brain. Fifteen groups of 60 rats (900 total) were formed from offspring of females injected i.v. with 0 (groups 1, 2, 9, 10, 13), 2.5 (groups 5, 6, 7, 8, 11, 12, 14) or 10 mg/kg (groups 3, 4, 15) ethylnitrosourea (ENU) to induce brain tumors. Groups 1, 3, 5 and 7 received the PRF, and groups 9 and 11 the CWRF; groups 2, 4, 6, 8, 10 and 12 were sham-irradiated, and groups 13-15 were cage controls. All rats but 2, totaling 898, were necropsied, and major tissues were studied histopathologically. There was no statistically significant evidence that the PRF or CWRF induced neoplasia in any tissues. Additionally, there was no significant evidence of promotion of cranial or spinal nerve or spinal cord tumors. The PRF or CWRF had no statistically significant effect on the number, volume, location, multiplicity, histological type, malignancy or fatality of brain tumors. There was a trend for the group that received a high dose of ENU and was exposed to the PRF to develop fatal brain tumors at a higher rate than its sham group; however, the result was not significant using the log-rank test (P = 0.14, 2-tailed). No statistically significant differences were related to the PRF or CWRF compared to controls in the low- or zero-dose groups regarding tumors of any kind.

The antimalarials quinacrine and chloroquine potentiate the transplacental carcinogenic effect of ethylnitrosourea on ependymal cells.

Quinacrine and chloroquine, two widely used antimalarials, bind strongly to deoxyribonucleic acid, thus preventing mutagenesis. We studied a possible chemoprotective effect of these substances on carcinogenesis of the nervous system induced in Wistar rats by transplacental administration of ethylnitrosourea. One experimental group consisted of rats born from mothers treated with quinacrine prior to prenatal exposure to ethylnitrosourea; a second group consisted of rats chronically treated with chloroquine after prenatal exposure to ethylnitrosourea. When compared with controls, no significant differences were observed in tumor incidence. However, early tumor growth was observed in both rats treated with quinacrine (P < 0.0004) and rats treated with chloroquine (P < 0.02). These differences were due mostly to rapid development of ependymomas of the spinal cord. Our results suggest that quinacrine and chloroquine do not prevent the structural alterations induced in DNA by ethylnitrosourea, which lead, in the long term, to a high incidence of neoplasms in the nervous system. Moreover, the antimalarials studied seem to promote the carcinogenic effects of ethylnitrosourea on ependymal cells.

Spontaneous and nitrosourea-induced primary tumors of the central nervous system in Fischer 344 rats exposed to frequency-modulated microwave fields.

In a 2-year bioassay, we exposed Fischer 344 rats to a frequency-modulated (FM) signal (836.55 MHz +/- 12.5 KHz deviation) simulating radiofrequency exposures in the head of users of hand-held mobile phones. We tested for effects on spontaneous tumorigenicity of central nervous system (CNS) tumors in the offspring of pregnant rats and also for modified incidence of primary CNS tumors in rats treated with a single dose of the neurocarcinogen ethylnitrosourea (ENU) in utero. ENU dosage (4 mg/kg) was selected to give an expected brain tumor incidence of 10-15% over the mean life span of 26 months. Pregnant dams (n = 102) were randomly assigned to six groups. Their offspring were treated as cohorts in each of the six groups (n = 90 per group; total, n = 540): Sham ENU/Sham Field, Sham ENU/Field Exposed, ENU/Sham Field, ENU/Field Exposed, ENU/Cage Control, and Sham ENU/Cage Control. Intermittent field exposures began on gestation day 19 and continued until weaning at 21 days, resuming thereafter at 31 days and continuing until experiment termination at 731-734 days. Energy absorption rates (SARs) in the rats' brains were similar to localized peak brain exposures of a phone user (female, 236 g, 1.0 W/kg; male, 450 g, 1.2 W/kg). Of the original 540 rats, 168 died before the termination of the experiment. In these rats, ENU significantly reduced survival from a mean of 708 days in three groups without ENU treatment to 645 days in three groups treated with ENU (P < 0.0005). There were no effects on survival attributable to FM field exposure in either ENU-treated or in sham-treated groups. Spontaneous CNS tumor incidence in control groups was 1.1-4.4% but sharply higher in rats receiving ENU (14.4-22.2%; P < 0.0001). No FM field-mediated changes were observed in number, incidence, or histological type of either spontaneous or ENU-induced brain tumors, nor were gender differences detected in tumor numbers. These negative findings with FM fields contrast with our study using standard digital phone fields pulsed on and off at 50/se, where a trend was noted toward reduced incidence of both spontaneous and ENU-induced CNS tumors (W. R. Adey et al., Radiat. Res., 152: 293-302, 1999). Although consistent but not attaining significance in the experiment overall (spontaneous CNS tumors, P < 0.08 one-tailed; P < 0.16 two-tailed; ENU-induced CNS tumors, P < 0.08 one-tailed, P < 0.16 two-tailed), the trend was significant (P < 0.015 one-tailed, P < 0.03, two-tailed) in rats that received ENU and died prior to experiment termination, with a primary brain tumor as the cause of death. We discuss differences in the signaling structure of digital and FM fields. Certain bioeffects induced by either amplitude-modulated or pulsed radiofrequency fields at athermal levels have not been seen with fields of similar average power but unvarying in intensity (continuous wave or frequency-modulated fields).

Evaluation of the potential promoting effect of 60 Hz magnetic fields on N-ethyl-N-nitrosourea induced neurogenic tumors in female F344 rats.

The present study investigated the possible effect of 60 Hz magnetic fields (MFs) as promoters of neurogenic tumors initiated transplacentally by a chemical carcinogen, N-ethyl-N-nitrosourea (ENU). In a preliminary study, 5 mg of ENU was shown to induce 30 to 40% neurogenic tumors in F344 rats offspring after 420 days of observation. In the present study, 400 female rats were divided into eight different groups (50 animals/group) and exposed in utero (on day 18 of gestation) to a single intravenous dose of either Saline (Group I), or ENU, 5 mg/kg (Group II to VIII). Dams in group II were given no further treatment while dams in Groups III to VII were exposed to 5 different intensities of MFs forty eight hours later. Animals in group III were sham exposed (<0.02 microT) while groups IV to VII were exposed to 2, 20, 200, and 2000 microT, respectively. Dams in Group VIII were injected intraperitoneally with 12-O-tetradecanoylphrobol-13-acetate (TPA; 10 micrograms/kg) from day 19 until delivery, and then their female offspring continued to be injected every 15 days, starting at day 14 after birth until sacrifice (positive controls). Accordingly, this study included three different types of controls: Internal controls (Groups II and III) and positive control (Group VIII). Body weight, mortality and clinical observations were evaluated in all groups of animals during in-life exposure. Necropsy was performed on all exposed and control animals that died, were found moribund or sacrificed at termination of the study. Histopathological evaluation was done for all brains, spinal cords, cranial nerves, major organs (lungs, liver, spleen, kidneys, pituitary, thyroid and adrenals) and all gross lesions observed during necropsy. All clinical observations and pathological evaluations were conducted under "blinded" conditions. The findings from this ENU/MFs promotion study clearly demonstrate that, under our defined experimental conditions, exposure to 60 Hz linear (single axis) sinusoidal, continuous wave MFs had no effect on the survival of female F344 rats or on the number of animals bearing neurogenic tumors. These results suggest that MFs have no promoting effect on neurogenic tumors in the female F344 rats exposed transplacentally to ENU.

Evaluation of ENU-induced gliomas in rats: nomenclature, immunochemistry, and malignancy.

Rats developed mixed gliomas, oligodendrogliomas, and a few astrocytomas in response to transplacental ethylnitrosourea. The neoplastic cell composition of mixed gliomas must be defined; this study required a 20-80% admixture of neoplastic astrocytes and oligodendroglia for the diagnosis of mixed glioma. A battery of immunoantibodies, including Leu-7, S-100, and vimentin, were helpful in classifying rat gliomas, and the histologic features of each tumor type are described. Other brain tumor characteristics that may decide the outcome of carcinogenicity studies include incidence, multiplicity, latency, fatality, size, and malignancy. The size of tumors was determined by measuring their 3-dimensional volumes. Brain tumor volume was found to be highly correlated with malignancy and fatality. Systematic evaluation of the malignancy of brain tumors is an important but often overlooked adjunct method of measuring the effectiveness of a carcinogen. A system to estimate malignancy, one that grades 9 tumor characteristics and weights, each according to clinical outcome, was developed. It was found that mixed gliomas grew larger, had a shorter latency, and were significantly more malignant than were other gliomas.

Spontaneous and nitrosourea-induced primary tumors of the central nervous system in Fischer 344 rats chronically exposed to 836 MHz modulated microwaves.

We have tested an 836.55 MHz field with North American Digital Cellular (NADC) modulation in a 2-year animal bioassay that included fetal exposure. In offspring of pregnant Fischer 344 rats, we tested both spontaneous tumorigenicity and the incidence of induced central nervous system (CNS) tumors after a single dose of the carcinogen ethylnitrosourea (ENU) in utero, followed by intermittent digital-phone field exposure for 24 months. Far-field exposures began on gestational day 19 and continued until weaning at age 21 days. Near-field exposures began at 35 days and continued for the next 22 months, 4 consecutive days weekly, 2 h/day. SAR levels simulated localized peak brain exposures of a cell phone user. Of the 236 original rats, 182 (77%) survived to the termination of the whole experiment and were sacrificed at age 709-712 days. The 54 rats (23%) that died during the study ("preterm rats") formed a separate group for some statistical analyses. There was no evidence of tumorigenic effects in the CNS from exposure to the TDMA field. However, some evidence of tumor-inhibiting effects of TDMA exposure was apparent. Overall, the TDMA field-exposed animals exhibited trends toward a reduced incidence of spontaneous CNS tumors (P < 0. 16, two-tailed) and ENU-induced CNS tumors (P < 0.16, two-tailed). In preterm rats, where primary neural tumors were determined to be the cause of death, fields decreased the incidence of ENU-induced tumors (P < 0.03, two-tailed). We discuss a possible approach to evaluating with greater certainty the possible inhibitory effects of TDMA-field exposure on tumorigenesis in the CNS.

Measurement of amino acid metabolism derived from [1-13C]glucose in the rat brain using 13C magnetic resonance spectroscopy.

To clarify the unique characteristics of amino acid metabolism derived from glucose in the central nervous system (CNS), we injected [1-13C]glucose intraperitoneally to the rat, and extracted the free amino acids from several kinds of tissues and measured the amount of incorporation of 13C derived from [1-13C]glucose into each amino acid using 13C-magnetic resonance spectroscopy (NMR). In the adult rat brain, the intensities of resonances from 13C-amino acids were observed in the following order: glutamate, glutamine, aspartate, gamma-aminobutyrate (GABA) and alanine. There seemed no regional difference on this labeling pattern in the brain. However, only in the striatum and thalamus, the intensities of resonances from [2-13C]GABA were larger than that from [2,3-13C]aspartate. In the other tissues, such as heart, kidney, liver, spleen, muscle, lung and small intestine, the resonances from GABA were not detected and every intensity of resonances from 13C-amino acids, except 13C-alanine, was much smaller than those in the brain and spinal cord. In the serum, 13C-amino acid was not detected at all. When the rats were decapitated, in the brain, the resonances from [1-13C]glucose greatly reduced and the intensities of resonances from [3-13C]lactate, [3-13C]alanine, [2, 3, 4-13C]GABA and [2-13C]glutamine became larger as compared with those in the case that the rats were sacrificed with microwave. In other tissues, the resonances from [1-13C]glucose were clearly detected even after the decapitation. In the glioma induced by nitrosoethylurea in the spinal cord, the large resonances from glutamine and alanine were observed; however, the intensities of resonances from glutamate were considerably reduced and the resonances from GABA and aspartate were not detected. These results show that the pattern of 13C label incorporation into amino acids is unique in the central nervous tissues and also suggest that the metabolic compartmentalization could exist in the CNS through the metabolic trafficking between neurons and astroglia.

Pharmacodynamics of phenobarbital anesthesia and pentylenetetrazol-induced maximal seizures in a rat model of neoplastic spinal cord compression.

The purpose of this investigation was to determine whether paraplegia induced by neoplastic cord compression affects the pharmacodynamics of phenobarbital general anesthesia or of pentylenetetrazol (PTZ)-induced convulsions. Paraplegic rats harboring a thoracolumbar epidural tumor, or an identical hindlimb tumor mass, received an i.v. infusion of phenobarbital until the onset of anesthesia. At that point, the phenobarbital concentrations in the CSF and serum were measured. Similarly, PTZ was infused until the onset of maximal seizures. It was found that changes related to systemic tumor growth and newly developed paraplegia due to neoplastic spinal cord compression did not attenuate the pharmacodynamics of phenobarbital. However, sustained paraplegia of 4 days' duration reduced CNS sensitivity to the hypnotic action of the barbiturate as evidenced by the higher cerebrospinal fluid phenobarbital concentration required to induce anesthesia (170 +/- 31 vs 125 +/- 20 mg/L; P < 0.05). On the other hand, sustained paraplegia did not affect brain threshold concentration for PTZ-induced seizures.

Expression of neuronal markers in the so-called ENU-induced schwannomas.

The present data show that the so-called ENU-induced malignant schwannomas express neuronal markers. This finding supports the hypothesis that a population of tumor cells in these neoplasms are neuroblastic in nature, and suggests the classification of ENU-induced schwannomas as primitive neuroectodermal tumors.

High susceptibility of analbuminemic rats to neurogenic tumor induction by transplacental administration of N-ethyl-N-nitrosourea.

The susceptibilities of Nagase analbuminemic rats (NAR) and control Sprague-Dawley rats (SDR) to N-ethyl-N-nitrosourea (ENU) were compared. In Experiment I, the rats were given daily subcutaneous injections of 10 mg/kg of ENU for a week from 4 weeks of age. In Experiment II, mother rats were given a single subcutaneous injection of 60 mg/kg of ENU on day 17 of pregnancy and tumor development in their offspring was examined. In Experiment I, the incidence of neurogenic tumors was slightly, but not significantly, higher in NAR than in control rats. In Experiment II, the incidence of total tumors including neurogenic tumors was significantly higher in NAR (40/43, 93.0%) than in SDR (13/61, 21.3%). NAR showed particularly high susceptibility to induction of neurogenic tumors (34/43, 79.1%) and renal tumors (15/43, 34.9%). In an attempt to elucidate the underlying mechanisms of the increased susceptibility of NAR to ENU, O6-ethylguanine, a major premutagenic ethylated DNA adduct, was quantitated in fetal brain DNA of NAR and SDR after a pulse exposure to 60 mg/kg ENU. No significant difference in the initial formation or subsequent repair of O6-ethylguanine was observed in the two strains, indicating that abnormality at some later stage(s) of chemical carcinogenesis may lead to the increased susceptibility of NAR to induction of neurogenic tumors.

Spinal cord tumors: gadolinium-DTPA-enhanced MR imaging.

To assess the utility of gadolinium-DTPA (Gd) and of MR imaging in the evaluation of spinal cord tumors, ten consecutive patients were prospectively evaluated. T1-proton density-, and T2-weighted images were obtained in sagittal or axial planes. T1-weighted images were obtained before and after intravenous administration. Five tumors were within the cervical spinal cord; 3 neoplasms were within the thoracic cord; 1 neoplasm extended from the cervical to the thoracic cord and 1 neoplasm extended from the cervical cord to the conus medullaris. Four tumors were ependymomas; 3 were astrocytomas; 1 was an hemangioblastoma, and 1 was a metastatic malignant peripheral nerve sheath tumor. The remaining patient died prior to spinal surgery and no autopsy was obtained. Of the precontrast sequences, tumors were best evaluated using T1-weighted images. Abnormal findings included cord widening, presence of a tumor mass, intratumoral or other associated cyst(s), and hemorrhage. Nevertheless, T1-weighted images obtained following the administration of GD were superior relative to all other pre- and post-contrast sequences for defining tumor margins, characterizing cyst(s) and delineating tumor masses. Based primarily on their appearance on post-contrast T1-weighted images, tumor-associated cysts could be subcategorized into 3 types: intratumoral cysts (found within the contrast-enhancing soft tissue mass); nonenhancing extratumoral cysts (found eitherrostral or caudal to the enhancing tumor mass); and enhancing extratumoral cysts (having an enhancing wall or containing an enhancing nodule).(ABSTRACT TRUNCATED AT 250 WORDS)