Treatment and outcomes for primary cutaneous extramedullary plasmacytoma: a case series.

BACKGROUND: Primary cutaneous plasmacytoma (pcp) is a rare disease, with few studies to guide therapy. Our primary study objective was to define treatments used for pcp; a secondary objective was to describe outcomes of patients, including disease recurrence and death. METHODS: An institutional cancer registry was used to identify cases for retrospective chart review. In a systematic review, treatments for, and outcomes of, all known cases of pcp were described. RESULTS: Three eligible cases identified at our institution; each patient had a solitary pcp. The systematic review identified 66 patients. Radiotherapy was the most commonly used primary treatment modality (31% of all patients; 42% for patients with solitary lesions), followed by surgery (28% of all patients; 36% for patients with solitary lesions). Median survival for all patients was 10.4 years [95% ci: 4.3 years to not reached], with a trend toward a decreased risk of death with solitary lesions compared with multiple lesions (hazard ratio: 0.37; 95% ci: 0.13 to 1.08; p = 0.059). For patients with solitary lesions, the median and recurrence-free survivals were, respectively, 17.0 years (95% ci: 1.7 years to not reached) and 11.0 years (95% ci: 2 years to not reached); for patients with multiple lesions, they were 4.3 years (95% ci: 1.3 to not reached) and 1.4 years (95% ci: 0.6 years to not reached). Disease recurrence, including progression to multiple myeloma, was the most common cause of death. CONCLUSIONS: Compared with patients having multiple pcp lesions, those presenting with a single pcp lesion might experience longer overall survival. Local therapy (radiation or surgery) is a reasonable curative treatment for a solitary pcp lesion.

Re-irradiation for Paediatric Tumours.

Despite best available therapy, many children with cancer develop recurrence after multimodal treatment, including initial radiation therapy. Re-irradiation is defined as the use of a second course of radiation therapy with a retreatment volume that overlaps substantially with that of a previously delivered course of radiation therapy. Re-irradiation is an important part of salvage treatment for patients with recurrent ependymoma, diffuse intrinsic pontine glioma, medulloblastoma and germinoma. In patients with ependymoma, conventionally fractionated re-irradiation (1.8 Gy/day) can provide long-term disease control with low rates of high-grade toxicity. For children with progressive diffuse intrinsic pontine glioma, re-irradiation provides effective palliation of symptoms and a survival gain as compared with those treated without re-irradiation. Repeat radiation therapy that includes craniospinal irradiation, if safe to deliver, may provide long-term tumour control in patients with medulloblastoma. Patients with recurrent intracranial germinoma can be effectively salvaged with re-irradiation that includes craniospinal irradiation. Finally, the emerging role of re-irradiation in non-brainstem high-grade glioma and extracranial solid tumours requires further study regarding its efficacy and safety. When given, re-irradiation should be delivered with care so that doses to organs at risk are minimised. In all cases, re-irradiation should be considered as an option alongside, or concurrently with, other salvage treatments, including surgery or systemic therapy, to maximise the likelihood of durable disease control.

Survival outcomes in elderly patients with glioblastoma.

AIMS: Many elderly glioblastoma patients are excluded from randomised trials due to age, comorbidity or poor functional status. The purpose of this study was to describe the survival outcomes in all elderly patients with glioblastoma managed at a tertiary cancer centre. MATERIALS AND METHODS: A retrospective chart review identified 235 elderly patients (age 65 years or over) with a histological diagnosis of glioblastoma between 1 December 2006 and 31 December 2013. The primary outcome of this study was overall survival by treatment type. Univariate and multivariate Cox proportional hazard models were used to explore significant prognostic variables associated with overall survival. RESULTS: The median survival for all patients was 6.5 months (95% confidence interval 5.3-7.7), with 1 year overall survival of 23.7% (95% confidence interval 18.8-30.0). The median survival for patients treated with radiation and chemotherapy was 11.1 months (95% confidence interval 8.1-13.7). Patients treated with radiation alone had a median survival of 6.8 months (95% confidence interval 5.6-7.9). For patients managed with comfort measures only, the median survival was 1.9 months (95% confidence interval 1.6-2.6). Univariate analysis revealed age, performance status, surgery type (biopsy, subtotal resection, gross total resection) and type of treatment received (comfort measures only, radiotherapy alone, radiotherapy and chemotherapy) to be statistically associated with overall survival. In the multivariate analysis, only two predictive factors (treatment received and surgery type) were significant. CONCLUSIONS: Elderly patients with glioblastoma selected for treatment (surgery followed by radiation alone or radiation and chemotherapy) survive longer than patients managed with comfort measures. Prospective randomised trials will help guide management for patients eligible for therapy. Elderly patients with glioblastoma who are deemed not eligible for active therapy have very short survival.

Axonal sprouting in the hemisected adult rat spinal cord.

The morphological and biochemical changes were studied in adult Sprague-Dawley rats after hemisection at the L3 spinal cord level. After survival periods of one, two and three months, fluorescent tracers, FluoroGold or rhodamine B, were implanted into the dorsal white columns of these rats at the positions of the corticospinal tract below the lesion. Following uptake of the tracer, the rats were killed and the motor cortices and spinal cords of both control and hemisected rats were analysed for positively labelled neurons. The highest number of labelled cells were found two months after hemisection. They were present in both sides of the cortices, particularly in the contralateral cortex, and also in the gray matter of the spinal cord above the hemisection. A few rats which were subjected to complete transection of the spinal cord also showed labelling of neurons in the motor cortex two months after lesion. The Protargol silver technique and the [3H]choline uptake study confirmed the presence of nerve fibres traversing the lesion site in the hemisected spinal cord. Furthermore, when the rats that had been hemisected two months earlier were subjected to a second cut at the same site, chromatolytic neurons were observed in the spinal cord as well as in the motor cortices of both sides. The hemisected rats demonstrated limited recovery in limb movement. The evidence of this study clearly shows that sprouting of nerve fibres has occurred in the lesioned adult rat spinal cord.

Effects of astrocyte implantation into the hemisected adult rat spinal cord.

Morphological and biochemical methods were applied to assess the effects of implanting cultured astrocytes into the hemisected adult rat spinal cord. Astrocytes were purified from neonatal rat cortex and introduced into the lesioned spinal cord either in suspension injection or cultured on gelfoam first. The control groups were rats which had hemisection with injection of culture media or with gelfoam grafted alone. At various time points after surgery (two weeks to two months), the spinal cord was removed and processed for routine light microscopy, immunofluorescence, gel electrophoresis and immunoblotting. As early as two weeks after surgery, a significantly smaller volume of scar tissue was consistently found in the experimental groups. This reduced scarring was also confirmed by immunofluorescence staining and immunoblotting for glial fibrillary acidic protein in the specimens two months after hemisection. Compared to the control groups, the experimental groups also had more intense staining for neurofilaments, which was confirmed by immunoblotting. However, labelling of the astrocytes with Phaseolus vulgaris leucoagglutinin conjugated with fluorescein showed that the astrocytes migrated at a rate of 0.6 mm/day from the original implanted site. The results therefore suggested that the cultured astrocytes probably exerted their effects over a short time period (less than two weeks) around the lesion site. They could have altered the microenvironment and as a result less scar tissue was formed. Hence, there was less barrier to the regrowth of nerve fibres.

Optic nerve transection and tectal removal affect phagocytic activity of the pigment epithelium in goldfish.

The phagocytic ability of the pigment epithelium after optic nerve sectioning and tectal removal was investigated in the goldfish by the method of ingestion of latex beads. 4 days after sectioning, an increase in latex beads was evident which decreased by the end of the first week. Tectal removal also triggered increase intake of latex beads which was presented after 7 days.

A multiple approach to the study of high dose laser lesions on the retina.

The retinae after high dose laser treatment were followed for a period of 60 d. Histochemical evaluation (cytochrome oxidase and succinic dehydrogenase reactions), neurochemical evaluation (labelled DOPAmine uptake) as well as ERG recordings of the lesioned eyes were performed in this period. It was found that the results of different evaluations agreed well with each other and with our previous E.M. studies.

Disposition, elimination, and bioavailability of phenytoin and its major metabolite in horses.

OBJECTIVE: To determine pharmacokinetics and excretion of phenytoin in horses. ANIMALS: 6 adult horses. PROCEDURE: Using a crossover design, phenytoin was administered (8.8 mg/kg of body weight, IV and PO) to 6 horses to determine bioavailability (F). Phenytoin also was administered orally twice daily for 5 days to those same 6 horses to determine steady-state concentrations and excretion patterns. Blood and urine samples were collected for analysis. RESULTS: Mean (+/- SD) elimination half-life following a single IV or PO administration was 12.6+/-2.8 and 13.9+/-6.3 hours, respectively, and was 11.2+/-4.0 hours following twice-daily administration for 5 days. Values for F ranged from 14.5 to 84.7%. Mean peak plasma concentration (Cmax) following single oral administration was 1.8+/-0.68 microg/ml. Steady-state plasma concentrations following twice-daily administration for 5 days was 4.0+/-1.8 microg/ml. Of the 12.0+/-5.4% of the drug excreted during the 36-hour collection period, 0.78+/-0.39% was the parent drug phenytoin, and 11.2+/-5.3% was 5-(phydroxyphenyl)-5-phenylhydantoin (p-HPPH). Following twice-daily administration for 5 days, phenytoin was quantified in plasma and urine for up to 72 and 96 hours, respectively, and p-HPPH was quantified in urine for up to 144 hours after administration. This excretion pattern was not consistent in all horses. CONCLUSIONS AND CLINICAL RELEVANCE: Variability in F, terminal elimination-phase half-life, and Cmax following single or multiple oral administration of phenytoin was considerable. This variability makes it difficult to predict plasma concentrations in horses after phenytoin administration.

Simultaneous analysis of twenty-one glucocorticoids in equine plasma by liquid chromatography/tandem mass spectrometry.

A method for the simultaneous separation, identification, quantification and confirmation of the presence of 21 glucocorticoids (GCC) in equine plasma by liquid chromatography coupled with triple stage quadrupole tandem mass spectrometry (LC/TSQ-MS/MS) is described. Plasma sample augmented with the 21 GCC was extracted with methyl tert-butyl ether (MTBE) and analyzed by positive electrospray ionization. Desoxymetasone or dichlorisone acetate was used as the internal standard (IS). Quantification was performed by IS calibration. For each drug, one major product ion was chosen and used for screening for that drug. Analyte confirmation was performed by using the three most intense product ions formed from the precursor ion and the corresponding mass ratios. The recovery of the 21 GCC when spiked into blank plasma at 5 ng/mL was 45-200% with coefficient of variation (CV) from 0.3-18%. The limit of detection (LOD) and that of quantification (LOQ) for most of the analytes were 50-100 pg/mL and 1 ng/mL, respectively, whereas that of confirmation (LOC) was 100-300 pg/mL depending on the analyte. Intra- and inter-day precisions expressed as CV for quantification of 1 and 10 ng/mL was 1.0-17%, and 0.51-19%, respectively, and the accuracy was from 84-110%. The linear concentration range for quantification was 0.1-100 ng/mL (r(2) > 0.997). Estimated measurement uncertainty was from 11-37%. This study was undertaken to develop a method for simultaneous screening, identification, quantification and confirmation of these agents in post-race equine plasma samples. The method has been successfully applied to screening of a large number of plasma samples obtained from racehorses in competition and in pharmacokinetic studies of dexamethasone in the horse and concurrent changes in endogenous GCC, hydrocortisone and cortisone. The method is simple, sensitive, selective and reliably reproducible.

Photic responses of the retina at different ages: a comparative study using histochemical and biochemical methods.

The alkaline phosphatase and DNA-RNA activities in the retinas of young and old albino mice were determined histochemically after photic exposure. Different patterns between the two age groups were obtained for the alkaline phosphatase reaction before and after photic exposure. In the young animals, more retinal layers showed increased activity after exposure whereas in the old animals, the converse was true. DNA-RNA reaction also revealed decreased DNA activities in the old animals 30 h after exposure. The results were also correlated with biochemical studies on 2-deoxyglucose, dopamine and leucine uptakes.

Photic responses of the retina at different ages. A comparative study using histochemical and biochemical methods.

The alkaline phosphatase and DNA-RNA activities in the retinas of young and old albino mice were determined histochemically after photic exposure. Different patterns between the two age groups were obtained for the alkaline phosphatase reaction before and after photic exposure. In the young animals, more retinal layers showed increased activity after exposure whereas in the old animals, the converse was true. DNA-RNA reaction revealed decreased DNA activities in the old animals 30 h after exposure. The results were also correlated with biochemical studies on the uptake of 2-deoxyglucose, dopamine and leucine.

Studies of the maturation of the visual system of the albino mouse.

The maturation of the albino mouse visual system was studied using mainly the retinae and visual cortices. Increased proportion of ganglion cells was detected in the central region of the retinae of 4 month old animals. The relative thickness of layer 4 of the visual cortex also reached a high in the 4 month old mouse. These results were further strengthened by detection of an increase in the spicules on the dendrites of stellate cells in layer 4 of the cortex concomitant with an increase in GABA and Noradrenaline uptake in the visual cortex. All that appeared to point to that the visual system of the albino mouse reached maturation when they were 4 months old.

Effect of long-term bovine somatotropin (sometribove) treatment on nitrogen (protein) distribution in Jersey milk.

Twenty-six Jersey cows were assigned randomly to one of two treatments. Twelve cows received biweekly subcutaneous injection of 500 mg of sometribove, USAN (recombinant methionyl bovine somatotropin), beginning 60 +/- 3 d postpartum and continuing throughout one lactation. Fourteen control animals received injections of placebo carrier. Milk samples were taken biweekly on weeks alternate to injection when differences in milk components were expected to be greatest compared with controls. The milk samples were analyzed for total nitrogen, noncasein nitrogen, and non-protein nitrogen. The average SCC for control and treatment groups was 44,000 +/- 47,000 and 56,000 +/- 65,000. Milk from sometribove-treated cows was significantly lower in total protein (3.92, 4.12%), true protein (3.74, 3.95%), and casein (3.11, 3.34%) than that from control cows on d 8 of the 14 d injection cycle. Casein as a percentage of true protein was lower (83.38, 84.52%), and non-protein nitrogen as a percentage of total nitrogen was higher (4.61, 4.26%) in milk from treated cows. The theoretical yield of Cheddar cheese was ca. .07% less for milk from treated cows than from control cows due to ca. 1% less casein as a percentage of true protein in the former. The differences in nitrogen distribution represent the response during the middle of the injection cycle when milk output was the highest and milk protein the lowest rather than the average response for the injection cycle. The results of the study indicate minimal impact on the cheese manufacturer because in practice milk is commingled from many dairies.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelin-3 attenuates the cyclic GMP responses to C-type natriuretic peptide in cultured mouse astrocytes.

The effect of endothelin-3 (ET-3) on cyclic GMP (cGMP) responses to C-type natriuretic peptide (CNP) was studied in primary cultures of mouse astrocytes. Attenuation of CNP-stimulated cGMP formation by ET-3 was time-dependent, with maximum inhibition achieved at 30 min of preincubation. ET-3 suppressed cGMP production in response to 10 nM CNP in a dose-dependent fashion, with an IC50 of 0.04 nM and a maximal inhibitory concentration of 1 microM, which led to a 66% reduction of the cGMP increment from 45.0 +/- 4.2 pmol/mg protein to 15.4 +/- 2.6 pmol/mg protein. ET-1, ET-2, and ET-3 were equipotent in suppressing the CNP-induced cGMP response, suggesting that this effect was mediated by ETB receptors. Staurosporine, Ro 31-8220, calcium-free medium, nifedipine, verapamil, lanthanum, thapsigargin, BAPTA, W7, calmidazolium, U-73122, neomycin, quinacrine, wortmannin, herbimycin-A, okadaic acid, and sodium orthovanadate failed to block the effect of ET-3. Cycloheximide (100 microM), however, partially but significantly reversed the inhibitory effect of ET-3 on CNP-induced cGMP from 48.2 to 73.3% of the control value. The results support the premise that ET-3 and CNP interact within the central nervous system. The data also suggest that cGMP accumulation in mouse astrocytes is mediated by activation of certain kinases through as yet undefined mechanisms and not by protein kinase C, increased intracellular calcium, or other second messenger pathways such as phospholipases A2, C, D, tyrosine kinase, or protein phosphatases.

Detection of fluoroquinolones in urinary specimens from patients undergoing anti-tuberculous therapy.

A paper strip impregnated with ferric chloride has been developed for visual detection of fluoroquinolones in urine based on a change of colour due to the chelation of the transition metal ion to the beta-oxo acid array in the 4-oxo-1,4-dihydropyridine-3-carboxylic acid moiety of the fluoroquinolone molecule. In urine specimens, the detection limit of the strip was 100 mg/l for pefloxacin, 200 mg/l for ciprofloxacin, fleroxacin, levofloxacin, norfloxacin, ofloxacin and sparfloxacin, and 300 mg/l for trovafloxacin. In 193 urine specimens taken from 138 patients on ofloxacin therapy and 55 controls preliminary evaluation of the strip showed that all the 55 specimens from control patients were negative, while 112 out of the 138 ofloxacin-treated patients were positive. Quantitative analysis by high-performance liquid chromatography of the 26 strip-test-negative specimens taken from patients with ofloxacin treatment indicated that these urinary specimens contained less than 200 mg/l of the antimicrobial, mostly because of poor renal function and in some occasions, non-compliance. This strip method would provide a convenient way of monitoring drug compliance in patients who receive fluoroquinolone therapy for tuberculosis.

Quantification of phenytoin and its metabolites in equine plasma and urine using high-performance liquid chromatography.

A reliable and sensitive method for the extraction and quantification of phenytoin (5,5'-diphenylhydantoin), its major metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) and minor metabolite, 5-(m-hydroxyphenyl)-5-phenylhydantoin (m-HPPH) in horse urine and plasma is described. The method involves the use of solid-phase extraction (SPE), liquid-liquid extraction (LLE), enzyme hydrolysis (EH) and high-performance liquid chromatography (HPLC). The minor metabolite, 5-(m-hydroxyphenyl)-5-phenylhydantoin (m-HPPH) was not present in a reliably quantifiable concentration in all samples. The new method described was successfully applied in the pharmacokinetic studies and elimination profile of phenytoin and p-HPPH following oral or intravenous administration in the horse.

Pharmacokinetics and disposition of clenbuterol in the horse.

The pharmacokinetics of clenbuterol (CLB) following a single intravenous (i.v.) and oral (p.o.) administration twice daily for 7 days were investigated in thoroughbred horses. The plasma concentrations of CLB following i.v. administration declined mono-exponentially with a median elimination half-life (t(1/2k)) of 9.2 h, area under the time-concentration curve (AUC) of 12.4 ng.h/mL, and a zero-time concentration of 1.04 ng/mL. Volume of distribution (V(d)) was 1616.0 mL/kg and plasma clearance (Cl) was 120.0 mL/h/kg. The terminal portion of the plasma curve following multiple p.o. administrations also declined mono-exponentially with a median elimination half-life (t(1/2k)) of 12.9 h, a Cl of 94.0 mL/h/kg and V(d) of 1574.7 mL/kg. Following the last p.o. administration the baseline plasma concentration was 537.5 +/- 268.4 and increased to 1302.6 +/- 925.0 pg/mL at 0.25 h, and declined to 18.9 +/- 7.4 pg/mL at 96 h. CLB was still quantifiable in urine at 288 h following the last administration (210.0 +/- 110 pg/mL). The difference between plasma and urinary concentrations of CLB was 100-fold irrespective of the route of administration. This 100-fold urine/plasma difference should be considered when the presence of CLB in urine is reported by equine forensic laboratories.

Tissue distribution of clenbuterol in the horse.

Plasma and tissue concentrations of clenbuterol (CLB) were determined following oral (p.o.) administration of 1.6 microg/kg twice daily (b.i.d.) for 2 weeks. Horses were administered the last dose on morning of day 15, killed at 0.25, 24, 48, and 72 h post-administration. At 0.25 h, the highest tissue concentrations of CLB were found in the liver (16.21 ng/g), lung (6.48 ng/g), left ventricle (4.99 ng/g), kidney (3.35 ng/g), bronchi (2.56 ng/g), right ventricle (2.08 ng/g), and eye fluids (1.09 ng/g) all of which were higher than that of plasma (1.10 ng/mL). The elimination half-lives (t(1/2k)) for CLB in tissues ranged from 21.2 to 56.3 h, the longest were in the eye fluids (56.9 h), spleen (21.2 h), cerebrum (27.1 h), cerebellum (21.5) and cecum (23.7 h). The t(1/2k) for plasma was 10.9 h. Tissue/plasma ratios of liver (14.7), lung (5.9), left ventricle (4.6), kidney (3.1), bronchi, (2.3) and right ventricle (1.9) were high at 0.25 h and remained elevated up to 72 h. Accumulation and sustained high concentration of CLB relative to plasma in these tissues contributed to the prolonged elimination and the ability to quantify CLB in plasma and urine for a prolonged period.

Effects of a prolonged-release formulation of sometribove (n-methionyl bovine somatotropin) on Jersey cows.

Milk production, feed efficiency, health, and reproduction were evaluated in 46 Jersey cows that received either 500 mg of sometribove (n-methionyl bST) in a prolonged-release formulation or an equivalent volume of excipient bi-weekly beginning at 60 +/- 3 DIM. Cows were fed a TMR for ad libitum intake and were milked twice daily. Treatment with sometribove increased 3.5% FCM production 5.3 kg/d (31.4%) over controls. Milk composition was not changed, except that milk P content averaged 51 ppm higher in bST-treated cows. Net energy intake was 4.8 Mcal/d (22.9%) higher in the bST-treated cows than in the controls. General health of all cows was good throughout the study, but the cows treated with bST had more cases of mastitis than did the control cows. The bST treatment produced localized reactions at the site of injection in some cows, but these reactions did not affect milk production. Sometribove treatment had no effect on reproductive performance; 85% of the treated and 100% of the control cows calved successfully. Treatment with bST for a full lactation did not affect performance during the initial 60 d of the subsequent lactation.

Effect of corn silage hybrid on dry matter yield, nutrient composition, in vitro digestion, intake by dairy heifers, and milk production by dairy cows.

Three corn hybrids, Mycogen TMF94, Cargill F337 (which contains a brown midrib trait), and Pioneer 3861 were compared in a plot trial, an intake trial, and a lactation trial. In the plot trial, the three corn hybrids were planted in replicated 15.2 x 385-m plots. Mycogen TMF94 and Cargill F337 had lower yields of dry matter (DM), higher concentrations of neutral detergent fiber, and higher in vitro true DM disappearance compared with Pioneer 3861. Mycogen TMF94 had a higher yield of DM than Cargill F337 despite having a lower plant population. However, Cargill F337 had a higher in vitro true DM disappearance than Mycogen TMF94. In the intake trial, six individually penned Holstein heifers were blocked and assigned randomly to one of three total mixed rations containing 79% (DM basis) Mycogen TMF94, Cargill F337, or Pioneer 3861 corn silages in replicated 3 x 3 Latin squares. Heifers fed the Pioneer 3861-based TMR had lower DMI than heifers fed Mycogen TMF94 and Cargill F337-based TMR. In the lactation trial, 75 midlactation Holstein cows were blocked and assigned randomly to one of three total mixed rations containing 31% (DM basis) Mycogen TMF94, Cargill F337, or Pioneer 3861 corn silages used in the intake trial. Milk production was highest for cows fed Cargill F337-based total mixed rations. It is concluded from this study that Mycogen TMF94 was higher yielding, but less digestible, and resulted in lower milk production by lactating cows than Cargill F337. In addition, Mycogen TMF94 had higher in vitro true DM disappearance, and similar DM yield and milk production by lactating cows when compared with Pioneer 3861.