Management Approaches in WHO Grade III Meningioma: A National Oncology Trainees' Collaborative for Healthcare Research (NOTCH) UK Multi-Centre Retrospective Study.

AIMS: WHO Grade 3 (G3) meningiomas are rare tumours with limited data to guide management. This retrospective study documents UK management approaches across 14 centres over 11 years. MATERIALS AND METHODS: Patients with WHO G3 meningioma between 01/01/2008 and 31/12/2018 were identified. Data were collected on demographics, management strategy, adjuvant radiotherapy, approach in recurrence setting and survival. RESULTS: 84 patients were identified. 21.4% transformed from lower-grade disease. 96.4% underwent primary surgical resection, with 20.8% having evidence of residual disease on their post-op MRI. 59.3% of patients underwent adjuvant radiotherapy (RT) following surgical resection. Overall median PFS and OS were 12.6 months and 28.2 months, respectively. Median OS in the group who underwent complete surgical resection was 34.9 months, compared to 27.5 months for those who had incomplete resection (HR 0.58, 95% CI 0.27-1.23, p = 0.15). Median OS was 33.1 months for those who underwent adjuvant RT and 14.0 months for those who did not (HR 0.48, 95% CI 0.27-0.84, p = 0.004). Median adjuvant RT dose delivered was 60Gy (range 12Gy-60Gy), 45.8% of adjuvant RT was delivered using IMRT. At disease relapse, 31% underwent salvage surgery and 29.3% underwent salvage RT. Of those treated with salvage RT, 64.7% were re-treats and all were treated with hypofractionated RT. CONCLUSION: Surgery continues to be the preferred primary management strategy. Post-operative MRI within 48 hours is indicated to assess presence of residual disease and guide further surgical options. Adjuvant radiotherapy plays an important part of the management paradigm in these patients with the data supporting an attached survival advantage. Further surgery and re-irradiation is an option in the disease recurrence setting with radiosurgery frequently utilised in this context.

Enhanced potency of daunorubicin against multidrug resistant subline KB-ChR-8-5-11 by a pulsed magnetic field.

Tumor cell resistance to many unrelated anticancer drugs is a major obstacle during cancer chemotherapy. One mechanism of drug resistance is thought to be due to the efflux of anticancer drugs caused by P-glycoprotein. In recent years, magnetic fields have been found to enhance the potency of anticancer drugs, with favorable modulation of cancer therapy. In this study, KB-ChR-8-5-11, a multidrug resistant (MDR) human carcinoma subline, was used as a model to evaluate the ability of pulsed magnetic fields (PMF) to modulate the potency of daunorubicin (DNR) in vivo and to determine the appropriate order of exposure to drugs and PMF using an in vitro cytotoxicity assay. Solenoid coils with a ramped pulse current source were used at 250 pulses per second for both in vivo and in vitro experiments. For the in vivo study, KB-ChR-8-5-11 cells were inoculated into thymic Balbc-nu/nu female mice. Treatment was begun when the average tumor volume reached 250-450 mm3. Treatment consisted of whole body exposure to PMF for one hour, followed immediately by intravenous (i.v.) injection of 8 mg/kg DNR designated as day 0, and repeated on days 7 and 14. Among the various groups, significant differences in the tumor volume were found between PMF + saline and PMF + DNR groups (p = 0.0107) at 39 days and 42 days (p = 0.0101). No mice died in the PMF alone group, and no toxicity attributable to PMF was found during the experimental period. For the in vitro studies, the sulforhodamine blue (SRB) cytotoxicity assay was used to determine the effect of the sequence which cells are exposed to PMF and/or DNR. Cells were exposed to PMF either before (pre-PMF) or after (post-PMF) drug was added. Results showed that the IC50 was significantly different between controls and pre-PMF + DNR groups (P = 0.0096, P = 0.0088). The IC50 of the post-PMF + DNR group was not found to be significantly different from control groups. Thus, the data in this report demonstrates that PMF enhanced the potency of DNR against KB-ChR-8-5-11 xenograft in vivo, while the efficacy of DNR was potentiated in vitro by PMF exposure only when PMF exposure occurred in the presence of drug. The data in vitro suggest that the mechanism by which PMFs modulate DNR's potency may be by inhibition of the efflux pump, P-glycoprotein. Further work to determine conditions for maximum modulation of drug potency by PMFs is warranted.

In vitro cytotoxicity against human cancer cell lines during pulsed magnetic field exposure.

In an in vitro cell growth assay, carboplatin potency against A-431 cells increased after a 1 hour PMF (pulsed magnetic field) exposure (calculated peak field 5.2 mTesla, with an average field strength of 0.525 mTeslarms; pulses rose for 120 microseconds and then abruptly fell to neutral, and were repeated at a rate of 100 or 250 pulses per second). This potentiating effect was not observed with cisplatin or daunomycin. When cytotoxicity against HT-29 cells was measured, PMF exposure potentiated both carboplatin and daunomycin, but again, not cisplatin. Both cell types exhibited increased growth when exposed only to PMF. Exposure to PMF consistently increased the cell growth of these cancer cell lines, while only some in vitro antineoplastic agents were potentiated by PMFs.

Chemotherapy of human carcinoma xenografts during pulsed magnetic field exposure.

Immune deficient mice growing xenografts of HT-29 or A-431 cell lines were treated with cisplatin, carboplatin or doxorubicin in combination with one hour of wholebody pulsed magnetic field (PMF) exposure (calculated peak field 5.2 mTesla, with an average field strength of 0.525 mTeslarms; pulses rose for 120 microseconds and then abruptly fell to neutral, and were repeated at a rate of 250 pulses per second). At 24 days, the mice in each experiment were found to have significantly (p < 0.05, ANOVA) different tumor sizes among groups. The smallest mean tumor volume was consistently found in the drug+PMF group. With A-431 tumors, the cisplatin+PMF group (T) was significantly smaller, 52% [1-(100T/C)], than the cisplatin alone group (C). In HT-29 tumors, those treated with carboplatin+PMF had the smallest tumor volume at just 34% of the carboplatin-alone group. In HT-29 tumors, the doxorubicin+PMF group was 35% of the doxorubicin alone group.

Comparison of the effects of high dose testosterone and 19-nortestosterone to a replacement dose of testosterone on strength and body composition in normal men.

We examined the extent to which supraphysiological doses of androgen can modify body composition and strength in normally virilized men. In doubly blind tests, 30 healthy young men received testosterone enanthate (TE) or 19-nortestosterone decanoate (ND), at 100 mg/wk or 300 mg/wk for 6 weeks. The TE-100 mg/wk group served as replacement dose comparison, maintaining pretreatment serum testosterone levels, while keeping all subjects blinded to treatment, particularly through reduction in testicular volumes. Isokinetic strength measurements were made for the biceps brachii and quadriceps femoris muscle groups before treatment and 2-3 days after the 6th injection. Small improvements were noted in all groups but the changes were highly variable; a trend to greater and more consistent strength gain occurred in the TE-300 mg/wk group. There was no change in weight for TE-100 mg/wk but an average gain of 3 kg in each of the other groups. No changes in 4 skinfold thicknesses or in estimated percent body fat were observed. Of 15 circumferences, significant increases were observed only for men receiving TE-300 mg/wk (shoulders) and ND-300 mg/wk (shoulders and chest). The data suggest that high dose androgens increase body mass and may increase strength in normal men but, except for a consistent weight gain with greater than replacement doses, the detectable changes were highly variable and relatively small, especially in comparison to the significant alterations which were observed for other markers of androgen action.

Effects of high-intensity cycle exercise on sympathoadrenal-medullary response patterns.

Plasma proenkephalin peptide F immunoreactivity and catecholamines were examined on separate days in nine healthy males before and after maximal exercise to exhaustion at four intensities [36, 55, 73, and 100% of maximal leg power (MLP)] by use of a computerized cycle ergometer. The mean duration of 36, 55, 73, and 100% MLP was 3.31, 0.781, 0.270, and 0.1 min, respectively. All intensities were greater than those eliciting peak O2 uptake for the individual subjects. Blood samples were obtained before, immediately after exercise, and 5 and 15 min after exercise. Significant (P less than 0.05) increases in plasma peptide F immunoreactivity (i.e., from mean resting value of 0.18 to 0.43 pmol/ml) were observed immediately after exercise at 36% MLP. Significant increases in plasma epinephrine were observed immediately after exercise at 36% MLP (i.e., from mean resting value of 2.22 to 3.11 pmol/ml) and 55% MLP (i.e., from mean resting value of 1.67 to 2.98 pmol/ml) and 15 min after exercise at 100% MLP (i.e., from mean resting value of 1.92 to 3.88 pmol/ml). Significant increases for plasma norepinephrine were observed immediately after exercise (36, 55, 73, and 100% MLP), 5 min after exercise (36, 55, and 73% MLP), and 15 min after exercise (36% MLP). Increases in whole blood lactate were observed at all points after exercise for 36, 55, and 73% MLP and 5 min after exercise for 100% MLP. These data show that brief high-intensity exercise results in differential response patterns of catecholamines and proenkephalin peptide F immunoreactivity.

Psychological and serum homovanillic acid changes in men administered androgenic steroids.

We report a difference in the response of serum homovanillic acid (HVA) and in the performance of some psychological tasks before and after the administration of testosterone enanthate (TE, 100 or 300 mg/wk) or nandrolone decanoate (ND, 100 or 300 mg/wk) for 6 wk to healthy men. Serum HVA was significantly increased in both the low- and high-dose ND groups, from 8.4 +/- 1.0 and 8.7 +/- 0.5 pmol/ml (mean +/- SE) to 11.6 +/- 1.7 and 10.7 +/- 1.1 pmol/ml respectively. No significant changes in HVA were observed for the groups administered TE, nor in 5-HIAA for any of the groups. The influence of ND on the dopaminergic system, which is reflected in increased serum HVA, appears to be independent from the psychological effects which were produced by both androgens. The only change in psychomotor test performance was an improvement in the first trial of a pegboard task. All subjects except those receiving ND (100 mg/wk) were significantly more optimistic in the prediction of their own performance for all nondominant hand tasks (pegboard and finger tapping). The "hostility" and "resentment and aggression" subscales of the MMPI increased significantly in all groups, more so in the high-dose groups.

Serum lipids and lipoproteins in continuous or cyclic medroxyprogesterone acetate treatment in postmenopausal women treated with conjugated estrogens.

This study evaluates effects on serum lipids of continuous or sequential progestogens for hormonal replacement in women. Subjects received either a cyclic regimen of replacement (0.625 mg/d of conjugated equine estrogens (Es) for 25 days/month and 10 mg medroxyprogesterone acetate [MPA] for the last 13 days of E) or 0.625 mg/d E along with either 5 or 10 mg MPA (Provera, Upjohn Company, Kalamazoo, MI). Study parameters were measured over a 24-week period. No differences in total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoproteins I and II, sex hormone-binding globulin, or serum MPA levels were noted between the sequential and 5 mg continuous group. The 10 mg MPA group did not have an increase in HDL or decrease in low-density lipoprotein as did the other groups.

Physiological changes in the somatosensory forepaw cerebral cortex of adult raccoons following lesions of a single cortical digit representation.

The purpose of this study was to determine whether restricted lesions within primary somatosensory (SmI) cortex cause changes in the functional organization of cortical areas bordering on the site of injury. Focal ablations of cortical tissue were made in the representational area for digit 3 within the SmI forepaw cortex of adult raccoons. Electrophysiological mapping experiments done 15-17 weeks later showed that significant alterations had occurred in the response properties of clusters of neurons within those representational zones adjoining the lesion--the zones for digit 2, digit 4, and the palmar pads. These three cortical areas were modified by the appearance of new, usually weaker secondary inputs and changes in some properties of the normal primary inputs from the forepaw. (i) Many neurons responded to stimulation of previously ineffective skin regions; the new inputs often originated from digit 3 but frequently involved other digits or the pads as well. (ii) Neuronal receptive fields (RFs), mapped at a standard suprathreshold stimulus intensity, were larger than normal. (iii) Skin type and submodality sensitivity typically were less specific than normal; more neurons had RFs that included both glabrous and hairy skin or claws and displayed mixtures of responsiveness to skin touch, hair deflection, or claw touch. (iv) The representation of RF location, skin type, and submodality sensitivity was more variable as a function of horizontal and vertical distance through the cortex. In general, the physiological changes were found to degrade the somatotopic order and response specificity of the intact cortical areas adjoining the lesion.(ABSTRACT TRUNCATED AT 250 WORDS)

High-density lipoprotein cholesterol is not decreased if an aromatizable androgen is administered.

We examined the influence of aromatization of testosterone on serum high-density lipoprotein cholesterol (HDL-C) and postheparin plasma hepatic triglyceride lipase activity (HTLA) in men. Eighteen healthy lean nonsmokers (ages, 20 to 33) were administered androgens in a weekly total dose of 280 mg for 12 weeks in one of three groups: testosterone enanthate (TE) (280 mg/wk intramuscularly [IM]); TE (280 mg/wk IM) + testolactone (TL) (250 mg orally [PO] four times daily); or methyltestosterone (MeT) (20 mg PO twice daily). Serum testosterone achieved steady state levels by 4 weeks with greater than 40 nmol/L (TE and TE + TL) and less than 15 nmol/L (MeT) while 17b-estradiol (E2) rose to greater than 250 pmol/L (TE) or remained below 70 pmol/L (TE + TL and MeT). LH fell to less than 5 U/L (TE and TE + TL) but remained unchanged with MeT. By 4 weeks, HDL-C had decreased significantly from 1.20 +/- 0.13 to 0.77 +/- 0.13 mmol/L (MeT), from 1.18 +/- 0.15 to 0.89 +/- 0.13 mmol/L (TE TL), and demonstrated no decrease in the TE group across the time course of the study. These changes were preceded by mean increases in HTLA of 102% (MeT) and 55% (TE + TL) over baseline, and no significant change with TE. The changes in HDL-C and HTLA returned to baseline within 2 weeks of steroid cessation. There were no changes in total cholesterol, triglycerides, or insulin in any group but, in the MeT group, apo AI levels decreased and low-density lipoprotein cholesterol (LDL-C) increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Atropine absorption after intramuscular administration with 2-pralidoxime chloride by two automatic injector devices.

Compared with manual intramuscular injection, automatic injector delivery substantially enhances drug absorption rate. We examined the effect of two types of automatic injector delivery of two drugs which are components of the standard antidote to anticholinesterase poisoning and which have been previously shown to have a reduced absorption rate when mixed together in a manual injection. In crossover experiments one week apart, 20 nonsmoking healthy young male humans (ages 20-30) were studied after citrated atropine (6.9 mumol/0.7 mL) and pralidoxime chloride (3.5 mmol/2.0 mL; PAMCL) were injected sequentially into a single intramuscular site by either a multichambered autoinjector or a device which delivers the drugs into two separate intramuscular sites (MARK I). Atropine absorption was assessed by the appearance of atropine in the serum and by changes in heart rate, salivary secretion, pupil diameters, and near vision accommodation. Atropine absorption was significantly greater in the first 30 min following injection with the MARK I. The results of this study suggest that: (1) the MARK I device produces a faster absorption of atropine, probably through some combination of its broader dispersal of atropine in the muscle site and its separation of atropine from the PAMCL; (2) salivary secretion may be the most convenient and sensitive marker of atropine action; and (3) the 6.9- mumol (2-mg) dose of atropine delivered by either autoinjector gives near maximal antisialogogue activity in normal male humans.

The administration of pharmacological doses of testosterone or 19-nortestosterone to normal men is not associated with increased insulin secretion or impaired glucose tolerance.

Excess androgen secretion and exogenous androgen administration may decrease insulin sensitivity and impair glucose tolerance. We examined the responses to an oral glucose tolerance test in 30 normal men before and after 6 weekly injections of androgen administered in a double-blinded study design. The men were randomly assigned to 1 of 4 treatment groups: testosterone enanthate (TE), 100 or 300 mg/week, or 19-nortestosterone decanoate (ND), 100 or 300 mg/week. Serum testosterone levels, measured 2-3 days after the last dose, did not change in the men given 100 mg TE/week, increased 3-fold in those given 300 mg TE/week, and decreased in both ND groups. All four groups had comparable reductions in serum LH levels. Weight increased significantly in all except the 100 mg TE/week group, but there was no change in waist to hip ratio in any group. In spite of the demonstrated biological effects of the doses of steroid administered, androgen administration for 6 weeks did not increase fasting serum glucose or insulin concentrations. There was also no increase in peak serum insulin levels and areas under the insulin and glucose response curves after a 100-g oral glucose load. However, the mean serum insulin area under the curve decreased significantly in the men given 300 mg ND/week. In contrast to the results of studies of 17-alkylated androgens, our results demonstrate that pharmacological doses of testosterone and the administration of 19-nortestosterone for 6 weeks do not impair glucose tolerance or alter insulin secretion in normal men.

Effect of eye color on heart rate response to intramuscular administration of atropine.

Melanin has been previously shown to modify the mydriatic response to atropine instillation. Skin and iris pigmentation has also been shown to modify aspects of the heart rate response to injected atropine, although these observations have been generally overlooked. In this study, 20 healthy non-smoker male subjects, ages 20-30 years, were injected by two different automatic injector devices and the mydriatic and heart rate responses in the first 90 min were reported. The group included 8 brown-eyed, 4 hazel-eyed, and 8 blue-eyed subjects. Although there were differences in the rate of atropine delivery between the two injection devices, the heart rate responses were independently modified by eye color to a magnitude of difference as great as the differences between injectors. Subjects with more pigmented irides (brown-eyed) showed a more rapid rise in heart rate compared to less pigmented irides (hazel-eyed and blue-eyed subjects). Following injection by the device with a slower atropine absorption rate, these differences were particularly enhanced and an abbreviated bradycardic phase of the heart rate response was observed for the brown-eyed subjects. This observation confirms earlier reports and suggests the possibility of an interference by melanin (in the iris or elsewhere) in atropine accessibility to selected muscarinic target sites.

Plasma atropine concentrations via intravenous, endotracheal, and intraosseous administration.

To date, there have been limited studies on the pharmacokinetics of intravenous atropine and no pharmacokinetic studies on the endotracheal or intraosseous administration of atropine. This study examines the time to peak plasma concentration of atropine following intravenous, endotracheal, and intraosseous administration in anesthetized monkeys using a triple crossover design. Plasma atropine was assayed by a radioreceptor method. The time to peak plasma concentration of atropine was shortest with intravenous administration; and longest with endotracheal administration. The mean plasma concentration of atropine was significantly higher in intravenous administrations than in endotracheal administrations at 0.75 and 2 minutes; compared to that noted in intraosseous administrations, the concentration was significantly higher only at 0.75 minutes. The mean plasma concentration of atropine administered intraosseously was significantly higher than that of endotracheal administrations at 5 minutes and was greater than that of intravenous and endotracheal administrations for the samples collected from 5 to 30 minutes. The endotracheal and intraosseous routes provide alternatives to the intravenous administration of atropine when intravenous access is limited or not available.

Seasonal variation in antigens of the imported fire ant Solenopsis invicta.

Eight sequentially collected lots of aqueous extracts of imported fire ant (IFA) front end and abdominal end segments were assayed for phospholipase A (PLA), N-acetyl-beta-glucosaminidase (NAG), and hyaluronidase. Relative potency of each extract lot and pooled venom was measured by RAST inhibition against a venom standard. More than a hundredfold difference in PLA activity was observed. Early summer collections had the highest activity. The May to June collection had more than twice the PLA activity of the next most potent lot. Discordancy in enzyme patterns was noted only in AE extract. NAG levels peaked earlier in the spring and summer and fluctuated less widely. Front end extract had lower activity levels for both enzymes, with no seasonal fluctuation in NAG and a single elevation in PLA activity in the April to May collection. RAST inhibition varied directly with PLA activity (p less than .05) but not with NAG nor hyaluronidase activities. Fifty-one percent of systemic allergic reactions to IFA stings occurred in summer, and 19% occurred in spring. A reported demographic survey demonstrated a higher incidence of IFA stings in the spring (39.9%) with a lower attack rate in the summer (31.9%). These findings suggest that the rate of systemic reactions to stings of the IFA may be related to seasonal variations in allergenic potency, as measured by PLA and RAST inhibition, rather than the sting attack rate.

beta-phenylethylamine effect on brain and blood catechol-O-methyltransferase activity.

A significant decrease in catechol-o-methyltransferase (COMT) activity has been found in the striatum (77% of control) and hippocampus (63% of control) of gerbils treated with daily injections of beta-phenylethylamine (50 mg/kg) for 10 days. This treatment group also exhibited increased (204% above control) COMT activity in a lysed red blood cell preparation. There were no changes in COMT activity in groups receiving 10 mg/kg beta-phenylethylamine or haloperidol (0.5 mg/kg). In vitro beta-phenylethylamine has no demonstrable effect on COMT activity.

Thyrotropin-releasing hormone (TRH) increases morbidity and mortality in the gerbil stroke model.

The gerbil model for stroke, using permanent unilateral carotid artery occlusion and restriction of the contralateral artery, was used to assess exogenous thyrotropin-releasing hormone (TRH, 10 mg/kg, i.p.) effect on cerebral ischemia. TRH immediately post-occlusion, compared to saline controls, significantly increased mortality (P = 0.025). This was supported by worsening reflected in the stroke index and time to death. Thyrotropin (0.1 IU, i.p.) in the same model was without effect. These surprising results were unexpected due to the beneficial response to the pharmacologically related naloxone.