Multimodality imaging and clinical features in Castleman disease: single institute experience in 30 patients.

OBJECTIVE: To analyse imaging features of subtypes of Castleman disease (CD), emphasizing differentiating features from lymphoma. METHODS: Institutional review board-approved, Health Insurance Portability and Accountability Act compliant, retrospective study examined 30 patients with CD. 30 patients (females, 20; mean age, 46 years; range, 22-87 years) with histopathologically confirmed CD and pre-treatment imaging formed the analytic cohort. Imaging at presentation in all patients [CT, 30; positron emission tomography (PET)/CT, 5; MR, 4; ultrasound, 3] and subsequent imaging in three cases that developed lymphoma was reviewed by two radiologists in consensus. RESULTS: Subtypes: hyaline-vascular (n = 18); multicentric not otherwise specified (NOS) (n = 6); human herpesvirus 8 associated (n = 2); mixed unicentric (n = 2); pure plasma-cell variant (n = 1); and unicentric NOS (n = 1). Distribution: unicentric (n = 17); and multicentric (n = 13). Nodal sites-unicentric: 13 thoracic, 3 abdominal and 1 cervical; multicentric: 9 abdominal, 8 thoracic, 6 cervical, 5 inguinal, 4 axillary and 4 supraclavicular. On CT, differentiating features from lymphoma were calcification (n = 8; 26.7%) and heterogeneous enhancement (n = 5; 19.2%). No association between CD subtype, degree or enhancement pattern, or calcification was noted. On PET/CT (n = 5), nodes were typically fluorine-18 fludeoxyglucose avid (n = 4). On ultrasound (n = 3), nodes were hypoechoic, homogeneous with posterior acoustic enhancement. On MR (n = 4), nodes were hypointense (n = 2) to isointense (n = 2) on T1 weighted images and isointense (n = 1) to hyperintense (n = 3) on T2 weighted images. All (n = 4) demonstrated homogeneous enhancement. Three cases developed non-Hodgkin's lymphoma, two of the three had larger spleens, and these cases had effusions/ascites. CONCLUSION: CD can be unicentric or multicentric and involve nodes above and below the diaphragm. Patients with CD can develop lymphoma. ADVANCES IN KNOWLEDGE: Assessing individual risk of developing lymphoma in patients with CD is difficult, although the findings of splenomegaly, pleural effusion and ascites may be suggestive.

Metastatic patterns of breast cancer subtypes: what radiologists should know in the era of personalized cancer medicine.

There is accumulating evidence that molecular phenotyping of breast cancer determines the timing, pattern, and outcome of metastatic disease. The most clinically relevant subtypes are hormonal-positive [oestrogen and progesterone receptor (ER/PR) positive], HER2 expressing, and triple-negative breast cancers (TNBCs). ER/PR-positive breast cancers demonstrate the best prognosis; however, metastases, in particular osseous disease, may develop much later. HER2-expressing breast cancers, although aggressive, have improved outcomes due to the advent of HER2-targeted therapies, with increased risk of central nervous system (CNS) relapses later. Finally, TNBCs present in younger women, BRCA1 mutations carriers, and carry the worst overall prognosis, with high incidence of CNS metastases, especially during the first 5 years of diagnosis. It is important for radiologists to understand the nuances of these breast cancer subtypes to predict metastatic behaviours and guide possible imaging surveillance.

Malignant peripheral nerve sheath tumors: prognostic impact of rhabdomyoblastic differentiation (malignant triton tumors), neurofibromatosis 1 status and location.

PURPOSE: The purpose of this study was to assess the impact of rhabdomyoblastic differentiation [malignant triton tumors (MTT)], neurofibromatosis 1 (NF1) status and location on the outcome of malignant peripheral nerve sheath tumors. METHODS: In this IRB-approved, HIPAA-compliant retrospective study medical records of 84 patients with pathologically confirmed MPNST from 1999 to 2011 were retrospectively reviewed. Patient and tumor characteristics including size, location, NF1 status, absence or presence of rhabdomyoblastic differentiation (MPNST versus MTT, respectively), recurrence and metastatic patterns and outcomes were evaluated. RESULTS: Of 84 patients, 62 were MPNST and 22 were MTT. MTT occurred in older patients than MPNST (50 years versus 40.7 years, p = 0.04) and were larger (12.3 cm versus 8.1 cm, p = 0.01). While there was no difference between the location, rate of recurrent or metastasis disease, and metastatic pattern between MTT and MPNST groups, MTT had shorter metastasis-free interval (median, 1 month versus 9 months, p = 0.02) and shorter survival (median, 10 months versus 43 months, p < 0.0001). NF1 status, while associated with earlier diagnosis (mean age, 35.1 years versus 46.5 years, p = 0.008), had no impact on rate of MTT or on prognosis. Patients with primary in the torso had shorter survival than those with extremity primary (median, 15 months versus 47 months, p = 0.0004). Multivariate analysis using the Cox proportional hazard regression model yielded age (p = 0.029), size (p = 0.0001), presence of rhabdomyoblastic differentiation (MTT) (p = 0.001), and location in the torso (p = 0.01) as independent predictors of survival. CONCLUSIONS: Among patients with malignant peripheral nerve sheath tumors, rhabdomyoblastic differentiation (MTT) and location in the torso are associated with poor prognosis. NF1 status has no impact on the prognosis.

A-Z of malignant peripheral nerve sheath tumors.

This article reviews the typical and atypical locations, imaging findings, local recurrence, and metastatic pattern of malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are rare soft tissue sarcomas, commonly occur in extremities, and are often associated with neurofibromatosis. Distinction between benign and malignant tumors can be challenging on imaging. MPNSTs have a poor prognosis; however, rhabdomyoblastic differentiation (malignant triton tumor), which has imaging features similar to MPNSTs, is associated with even more aggressive behavior.

Imaging features of bowel toxicities in the setting of molecular targeted therapies in cancer patients.

Molecular targeted therapies are becoming ubiquitous in cancer treatment. These drugs may cause gastrointestinal toxicities including perforation, pneumatosis, enteritis, colitis and fistula formation. Knowledge of these complications and their management enables early radiological identification and appropriate intervention, reducing patient morbidity and mortality.

Beta-lapachone inhibits proliferation and induces apoptosis in retinoblastoma cell lines.

AIMS: To investigate the cytotoxicity of beta-lapachone, a potent agent that may selectively target tumour cells, in retinoblastoma (RB) cell lines. METHODS: Growth inhibitory effects of beta-lapachone were evaluated in Y79, WERI-RB1, and RBM human retinoblastoma cell lines. Pro-apoptotic effects of beta-lapachone were evaluated in Y79 cells by detection of caspase 3/7 activity, by enzyme-linked immunosorbent assay for nucleosome fragments, and by cellular morphological analysis. RESULTS: Beta-lapachone induced significant dose-dependent growth inhibitory effects in all three retinoblastoma cell lines. The 50% growth inhibitory concentration (IC(50)) of this agent was 1.9 microM in Y79 cells, 1.3 microM in WERI-RB1 cells, and 0.9 microM in RBM cells. Beta-lapachone also induced proapoptotic effects in RB cells. Treatment of Y79 cells with 1.9 microM beta-lapachone (IC(50)) resulted in a peak, fourfold induction of caspase 3/7 activity at 72 h post-treatment; a peak, 5.6-fold increase in nucleosome fragments at 96 h post-treatment; and a peak, 1.7-fold increase in the frequency of apoptotic cells at 48 h post-treatment, relative to vehicle-treated controls. CONCLUSION: Beta-lapachone induced potent cytotoxic effects in RB cell lines at low micromolar concentrations, suggesting this agent could be useful in the clinical management of RB.

Effects of celecoxib in human retinoblastoma cell lines and in a transgenic murine model of retinoblastoma.

BACKGROUND/AIM: Celecoxib, a cyclooxygenase-2 inhibitor and antiangiogenic agent, has demonstrated potent anticancer effects in preclinical studies and in human clinical trials. To evaluate the potential utility of this agent in the treatment of retinoblastoma, the authors investigated the effects of celecoxib in retinoblastoma cell lines and in a murine model of this disease. METHODS: Growth inhibitory effects of celecoxib were evaluated in Y79 and Weri-RB1 human retinoblastoma cell lines by WST-1 cell proliferation assay. For animal study, two groups of 24, 8 week old LHbeta-TAg transgenic mice were treated with celecoxib (250 mg/kg, orally once a day) or vehicle control, 5 days/week for 6 weeks. Mice were sacrificed on day 43. Enucleated eyes were serially sectioned and ocular tumour burden was quantified by histopathological analysis. RESULTS: Celecoxib did not inhibit proliferation of Y79 or Weri-RB1 cells, even at concentrations far exceeding clinically achievable levels. No significant difference in ocular tumour burden between celecoxib treated and control mice (p=0.73) was found. CONCLUSION: Celecoxib was ineffective at inhibiting proliferation of retinoblastoma cells in vitro and was ineffective at controlling retinoblastoma tumour growth in a murine model of this disease. On the basis of these findings, oral celecoxib therapy is unlikely to have clinical utility in the treatment of retinoblastoma.

Mechanisms of estrogenic protection against gp120-induced neurotoxicity.

gp120, an HIV coat glycoprotein that may play a role in AIDS-related dementia complex (ADC), induces neuronal toxicity characterized by NMDA receptor activation, accumulation of intracellular calcium, and downstream degenerative events including generation of reactive oxygen species and lipid peroxidation. We have previously demonstrated estrogenic protection against gp120 neurotoxicity in primary hippocampal cultures. We here characterize the mechanism of protection by blocking the classical cytosolic estrogen receptors and by measuring oxidative end points including accumulation of extracellular superoxide and lipid peroxidation. Despite blocking ERalpha and ERbeta with 1 microM tamoxifen, we do not see a decrease in the protection afforded by 100 nM 17 beta-estradiol against 200 pM gp120. Additionally, 17alpha-estradiol, which does not activate estrogen receptors, protects to the same extent as 17beta-estradiol. 17beta-Estradiol does, however, decrease gp120-induced lipid peroxidation and accumulation of superoxide. Together the data suggest an antioxidant mechanism of estrogen protection that is independent of receptor binding.

Glucocorticoid modulation of gp120-induced effects on calcium-dependent degenerative events in primary hippocampal and cortical cultures.

The HIV coat protein gp120 has been implicated in damaging the nervous system and may play a role in AIDS-related dementia complex. The glycoprotein triggers the release of a glutamatergic agent from infected microglia and macrophages, causing NMDA receptor- and calcium-dependent excitotoxic damage to neurons. We have previously shown that glucocorticoids, the adrenal steroids secreted during stress, worsen gp120 neurotoxicity and calcium mobilization in various brain regions. This study explores events down-stream of gp120-induced calcium mobilization, specifically, generation of reactive oxygen species (ROS) and subsequent lipid peroxidation, destruction of the cytoskeleton through spectrin proteolysis, and the glucocorticoid modulation of these events in primary hippocampal cultures. We observe that 200 pM gp120 causes a significant accumulation of ROS, including superoxide, and of lipid peroxidation. Counter to our predictions, pretreatment with the glucocorticoid corticosterone (CORT) did not worsen the effects of gp120 on ROS accumulation, but did increase lipid peroxidation. We also observed that neither gp120 alone nor gp120 plus CORT caused detectable proteolysis of the cytoskeletal protein spectrin, whose breakdown has been shown to be a damaging consequence of calcium excess in other models of necrotic neuronal injury.

Energy dependency of glucocorticoid exacerbation of gp120 neurotoxicity.

The HIV envelope glycoprotein, gp120, a well documented neurotoxin, may be involved in AIDS-related dementia complex. gp120 works through an NMDA receptor- and calcium-dependent mechanism to damage neurons. We have previously demonstrated that both natural and synthetic glucocorticoids (GCs) exacerbate gp120-induced neurotoxicity and calcium mobilization in hippocampal mixed cultures. GCs, steroid hormones secreted during stress, are now shown to work in conjunction with gp120 to decrease ATP levels and to work synergistically with gp120 to decrease the mitochondrial potential in hippocampal cultures. Furthermore, energy supplementation blocked the ability of GCs to worsen gp120's effects on neuronal survival and calcium mobilization. A GC-induced reduction in glucose transport in hippocampal neurons, as previously documented, may contribute to this energetic dependency. These results may have clinical significance, considering the common treatment of severe cases of Pneumocystis carinii pneumonia, typical of HIV infection, with large doses of synthetic GCs.

The relative effectiveness of human plasma glutathione peroxidase as a catalyst for the reduction of hydroperoxides by glutathione.

To reveal clues to the function of human plasma glutathione peroxidase (GPx), we investigated its catalytic effectiveness with a variety of hydroperoxides. Comparisons of hydroperoxides as substrates for plasma GPx based on the ratio of Vmax/Km were blocked by the limited solubility of the organic hydroperoxides, which prevented kinetic saturation of the enzyme at the chosen glutathione concentration. Therefore, we compared the hydroperoxides by the fold increase in the apparent first-order rate constants of their reactions with glutathione owing to catalysis by plasma GPx. The reductions of aromatic and small hydrophobic hydroperoxides (cumene hydroperoxide, t-amyl hydroperoxide, t-butyl hydroperoxide, paramenthane hydroperoxide) were better catalyzed by plasma GPx than were reductions of the more "physiological" substrates (linoleic acid hydroperoxide, hydrogen peroxide, peroxidized plasma lipids, and oxidized cholesterol).

Endocrine modulators of necrotic neuron death.

In recent years, there has been extraordinary progress in understanding the cellular and molecular cascades that mediate neuron death following necrotic insults. With this knowledge has come the recognition of ways in which these cascades can be modulated by extrinsic factors, altering the likelihood of subsequent neuron death. In this review, we consider the ability of a variety of hormones to modulate necrotic death cascades. Specifically, we will examine the ability of the stress hormones glucocorticoids and corticotropin-releasing factor, of thyroid hormone, and of pre-ischemic exposure to catecholamines to augment necrotic neuron death. In contrast, estrogen, insulin and postischemic exposure to catecholamines appear to decrease necrotic neuron death. We review the heterogeneous mechanisms that are likely to mediate these hormone effects, some possible clinical implications and the therapeutic potentials of these findings.

Purification of a Trypanosoma cruzi trypomastigote 60-kilodalton surface glycoprotein that primes and activates murine lymphocytes.

We have purified a glycoprotein with a relative molecular mass of 60 kDa and present on the surface of Trypanosoma cruzi trypomastigotes and studied its ability to prime and stimulate the proliferation of murine spleen cells. T. cruzi trypomastigote membrane proteins were separated by preparative isoelectrofocusing. A trypomastigote 60-kDa surface protein with an isoelectric point of 4.2 was enriched by chromatofocusing and was readily purified in native form to homogeneity by gel filtration on a Superose column by use of a fast protein liquid chromatography system. Biotinylated wheat germ agglutinin, Ricinus communis agglutinin, and Datura stramonium agglutinin bound to blots containing the purified trypomastigote 60-kDa surface protein, indicating that this protein was glycosylated. The purified trypomastigote 60-kDa glycoprotein was recognized by antibodies produced during human infection, and immunoglobulin G against the purified glycoprotein immunoprecipitated a biotinylated 60-kDa molecule from the surface of trypomastigotes but not epimastigotes. Specific immunoglobulin G against the 60-kDa glycoprotein also increased the uptake of trypomastigotes and promoted parasite killing by macrophages. The purified 60-kDa glycoprotein was able to specifically activate primed lymphocytes, since there was a significant increase in [3H]thymidine incorporation by spleen cells obtained from CBA mice primed with this glycoprotein, with respect to control values. Furthermore, the 60-kDa glycoprotein did not stimulate unprimed spleen cells, indicating that the lymphoproliferation induced by this glycoprotein was specific and was not due to polyclonal activation. Our findings indicate that this T. cruzi trypomastigote 60-kDa surface glycoprotein primes and activates lymphocytes, which could lead to a beneficial immune response in the host.

A method for the preparation of polylactic acid microcapsules of controlled particle size and drug loading.

A solvent partition technique for the microencapsulation of hydrocortisone-polylactic acid has been developed for the preparation of microcapsules of controlled particle size distribution and drug loading. The method involves continuous injection of a drug-polymer solution with a syringe infusion pump into flowing mineral oil where microcapsules are formed as the solvent of the drug-polymer is partitioned into the mineral oil. Using preselected syringe needle size and mechanical control of the mineral oil flow rate at the needle tip, microcapsules of consistent particle sizes and desired drug loadings were prepared. Microcapsules of different internal structures were also prepared by varying the solvent system for the drug-polymer preparation. Dissolution studies showed that at the same drug loading, the rate of the percentage drug release increased with decreasing particle size, and that at similar particle size distributions, the rate increased with increasing drug loading. These results indicate that both the particle size distribution, and the drug loading must be controlled in a microencapsulation process to produce microcapsules of controlled drug release rate.

Effect of surface active agents on drug release from polylactic acid-hydrocortisone microcapsules.

Polylactic acid microcapsules containing randomly distributed hydrocortisone particles were prepared. The rate of release of hydrocortisone from the microcapsules in pH 7.4 phosphate buffer was found to be largely increased by the presence of polysorbate 80, cetylpyridinium chloride, or aerosol OT in the dissolution medium. The surfactant effect was attributed to the ability of the surface active agent to improve solvent penetration into the microcapsules by lowering the surface tension at the solid-liquid interface. The effect of the cationic surfactant, cetylpyridinium chloride on the rate of drug release is similar in magnitude to that of the nonionic surfactant, polysorbate 80. In these systems, the rate of drug release from the microcapsules was found to be linearly related to the surface tension of the dissolution medium in the range of 40-60 dyn/cm (x 10(-3) N/m). In the same surface tension range, the effect of aerosol OT on rate increase was found to be much less than those of the cationic and nonionic surfactants. This suggests that the anionic surfactant is not well adsorbed at the interface due to the negative charge characteristics of the surface of the polylactic acid microcapsules. However, at nearly the critical micelle concentration of aerosol OT, where the corresponding surface tension is much lower than those of the cationic and nonionic surfactants, the microcapsules exhibited the highest rate of drug release.

Preparation and in vitro evaluation of polylactic acid-mitomycin C microcapsules.

An emulsion method was developed for the incorporation of water-soluble mitomycin C into polylactic acid biodegradable microcapsules. With an average particle size of about 95 microns, microcapsules with a desired loading of from 3.65 to 13.80 per cent were prepared. These microcapsules, which contained both crystalline and finely dispersed drug particles, showed a dose-dependent drug release pattern with microcapsules of higher drug loading having a faster release rate than those of lower drug loading. Effective sterilization of the microcapsules for parenteral use was achieved by 60Co gamma-ray irradiation, which did not affect the microcapsule structure, release rate or drug stability. Mitomycin C showed dose-dependent antiproliferative activity against the growth of the K562 human erythroleukaemia cells. The microencapsulated dosage form of mitomycin C was found to enhance the drug's activity through sustained drug release. In experiments where drug concentrations in the cell medium were reduced according to the drug's biological half-life, the microcapsule systems showed a distinct advantage over the non-capsulated dose for the kinetic inhibition of K562 cell growth.

Kinetics of drug release from polylactic acid-hydrocortisone microcapsules.

Polylactic acid microcapsules of similar particle size distribution containing various drug loadings of hydrocortisone were prepared. The microcapsules, which contained randomly dispensed drug particles, showed a dissolution pattern which consists of a fast first-stage and a slow second-stage drug release. Our studies showed that the kinetics of drug release from the microcapsules can be adequately described by a spherical matrix model based on a flux mechanism involving the diffusion of dissolved drug at the penetrating front of the dissolution medium. Drug loading played an important role in the control of drug release rate. An empirical relationship between drug loading and drug diffusibility through the polymeric matrix was developed and showed that the rate of drug release increased exponentially with the increase in drug loading. The microcapsules were further shown to exhibit increased rate of drug release in dissolution medium containing either cetylpyridium chloride or aerosol OT. The effect of the surfactants was attributed to surface tension lowering and improved wetting of the microcapsule particles.

Dissolution profiles for finely divided drug suspensions.

A suspension of micronized prednisolone acetate was separated into four fractions by the technique of centrifugal elutriation. Data showed that each fraction had a narrow particle size. The dissolution experiments were carried out under sink conditions (less than 10% of saturation concentration) in a dissolution apparatus with a rotating filter assembly and a continuous circulation of filtered fluid samples through a recording spectrophotometer. The dissolution profile was highly reproducible and substantially different for each fraction. As expected, fractions with the smallest and largest particles showed the fastest and slowest dissolution, respectively. Almost the entire dissolution profiles for four small particle size fractions can be satisfactorily described by the Higuchi-Hiestand model with the dissolution rate constant, K, in the range of 1.5-2.0 X 10(-9)cm2/sec. This is approximately 3.5 times greater than the value for K calculated on the basis of reported reasonable values for diffusion coefficient, density, and solubility.