Effect of natalizumab on brain atrophy and disability progression in multiple sclerosis patients over 5 years.

BACKGROUND AND PURPOSE: The long-term benefit of natalizumab on brain atrophy progression in multiple sclerosis (MS) patients is unknown. Our aim was to investigate its effect over 5 years. METHODS: This prospective study included 60 relapsing MS patients who started natalizumab treatment in years 2006-2007. RESULTS: At the 5-year follow-up, 20 patients discontinued natalizumab after an average of 29.5 cycles, 27 continued natalizumab treatment with some periods of honeymoon (average of 38.4 infusions) and 13 never stopped natalizumab (average of 60.6 infusions). In multiple linear regression analysis, adjusted for age, sex and baseline magnetic resonance imaging (MRI) status, the number of natalizumab infusions was associated with decrease of relapse rate (adjusted P = 0.037), but no association was found with the progression of disability, accumulation of lesion burden or brain volume loss. However, only one (8%) patient in the continuous monthly group experienced disability progression compared to 10 (37%) in the non-continuous and seven (35%) in the discontinuation natalizumab groups. At the follow-up, two patients had died [one from a fatal case of progressive multifocal leukoencephalopathy (PML) and one from a car accident] and 15 patients were lost to follow-up. There was another case of non-fatal PML over the follow-up. CONCLUSIONS: In line with previous reports, MS patients with longer and continuous use of natalizumab had fewer relapses and remained stable in their disability status. No difference in lesion burden accumulation or brain atrophy development was found in relation to the duration of natalizumab use. PML occurred in 2.5% of patients in this small sample cohort. Given the increased risk of PML and uncertain benefit of prolonged natalizumab use on clinical and MRI outcomes of disease progression found in this study, a careful risk-benefit therapeutic assessment is mandatory.

Disclosing large scale adverse events in the US Veterans Health Administration: lessons from media responses.

OBJECTIVES: We examined print, broadcast and social media reports about health care systems' disclosures of large scale adverse events to develop future effective messaging. STUDY DESIGN: Directed content analysis. METHODS: We systematically searched four communication databases, YouTube and Really Simple Syndication (RSS) feeds relating to six disclosures of lapses in infection control practices in the Department of Veterans Affairs occurring between 2009 and 2012. We assessed these with a coding frame derived from effective crisis and risk communication models. RESULTS: We identified 148 unique media reports. Some components of effective communication (discussion of cause, reassurance, self-efficacy) were more present than others (apology, lessons learned). Media about 'promoting secrecy' and 'slow response' appeared in reports when time from event discovery to patient notification was over 75 days. Elected officials' quotes (n = 115) were often negative (83%). Hospital officials' comments (n = 165) were predominantly neutral (92%), and focused on information sharing. CONCLUSIONS: Health care systems should work to ensure that they develop clear messages focused on what is not well covered by the media, including authentic apologies, remedial actions taken, and shorten the timeframe between event identification and disclosure to patients.

Autoimmune Comorbidities Are Associated with Brain Injury in Multiple Sclerosis.

BACKGROUND AND PURPOSE: The effect of comorbidities on disease severity in MS has not been extensively characterized. We determined the association of comorbidities with MR imaging disease severity outcomes in MS. MATERIALS AND METHODS: Demographic and clinical history of 9 autoimmune comorbidities confirmed by retrospective chart review and quantitative MR imaging data were obtained in 815 patients with MS. The patients were categorized on the basis of the presence/absence of total and specific comorbidities. We analyzed the MR imaging findings, adjusting for key covariates and correcting for multiple comparisons. RESULTS: Two hundred forty-one (29.6%) study subjects presented with comorbidities. Thyroid disease had the highest frequency (n = 97, 11.9%), followed by asthma (n = 41, 5%), type 2 diabetes mellitus (n = 40, 4.9%), psoriasis (n = 33, 4%), and rheumatoid arthritis (n = 22, 2.7%). Patients with MS with comorbidities showed decreased whole-brain and cortical volumes (P < .001), gray matter volume and magnetization transfer ratio of normal-appearing brain tissue (P < .01), and magnetization transfer ratio of gray matter (P < .05). Psoriasis, thyroid disease, and type 2 diabetes mellitus comorbidities were associated with decreased whole-brain, cortical, and gray matter volumes (P < .05). Psoriasis was associated with a decreased magnetization transfer ratio of normal-appearing brain tissue (P < .05), while type 2 diabetes mellitus was associated with increased mean diffusivity (P < .01). CONCLUSIONS: The presence of comorbidities in patients with MS is associated with brain injury on MR imaging. Psoriasis, thyroid disease, and type 2 diabetes mellitus comorbidities were associated with more severe nonconventional MR imaging outcomes.

Multimodal imaging in systemic lupus erythematosus patients with diffuse neuropsychiatric involvement.

OBJECTIVES: The objective of this paper is to investigate conventional and nonconventional brain magnetic resonance imaging (MRI) findings in systemic lupus erythematosus (SLE) patients with diffuse neuropsychiatric involvement (dNPSLE) compared to healthy controls (HCs). METHODS: Twenty-six (26) SLE patients with one or more diffuse NP syndromes related to the central nervous system (CNS) (dNPSLE) and 36 age- and sex-matched HCs were scanned on a 3T MRI using a multimodal imaging approach. Univariate and multivariate analyses were used to determine MRI-specific measure differences between dNPSLE and HCs for lesion burden, tissue-specific atrophy, magnetization transfer ratio (MTR) and diffusion-tensor imaging (DTI) outcomes. RESULTS: In univariate analyses, dNPSLE patients showed significantly increased T1 lesion number (p = .001) and T1-lesion volume (LV, p = .008) compared to HCs. dNPSLE patients showed decreased whole brain volume (p < .0001), gray matter volume (p < .0001), cortical volume (p < .0001) and increased lateral ventricle volume (p = .004) compared to HCs. dNPSLE patients had increased axial diffusivity (AD) of NAWM (p = .008) and NA brain tissue (p = .017) compared to HCs. In the multivariate regression analysis, decreased cortical volume was associated with SLE (R (2) = 0.59, p < .0001). CONCLUSIONS: This study shows that cortical and central atrophy are associated with SLE patients with diffuse CNS syndromes. Microscopic tissue injury in the NAWM on AD DTI measures in SLE patients indicates a predominant reduction of axonal density.

Smoking is associated with increased lesion volumes and brain atrophy in multiple sclerosis.

BACKGROUND: Cigarette smoking has been linked to higher susceptibility and increased risk of progressive multiple sclerosis (MS). The effects of smoking on MRI characteristics of patients with MS have not been evaluated. OBJECTIVES: To compare the MRI characteristics in cigarette smoker and nonsmoker patients with MS. METHODS: We studied 368 consecutive patients with MS (age 44.0 +/-SD 10.2 years, disease duration 12.1 +/- 9.1 years) comprising 240 never-smokers and 128 (34.8%) ever-smokers (currently active and former smokers). The average number of packs per day smoked (+/-SD) was 0.95 +/- 0.65, and the mean duration of smoking was 18.0 +/- 9.5 years. All patients obtained full clinical and quantitative MRI evaluation. MRI measures included T1, T2, and gadolinium contrast-enhancing (CE) lesion volumes (LVs) and measures of central, global, and tissue-specific brain atrophy. The associations between smoking status and MRI measurements were assessed in regression analysis. RESULTS: Smoking was associated with increased Expanded Disability Status Scale (EDSS) scores (p = 0.004). The median EDSS scores (interquartile range) in the ever-smoker group and the active-smoker group were both 3.0 (2.0), compared with 2.5 (2.5) in never-smokers. There were adverse associations between smoking and the lesion measures including increased number of CE lesions (p < 0.001), T2 LV (p = 0.009), and T1 LV (p = 0.003). Smoking was associated with decreased brain parenchymal fraction (p = 0.047) and with increases in the lateral ventricle volume (p = 0.001) and third ventricle width (p = 0.023). CONCLUSIONS: Smoking is associated with increased blood-brain barrier disruption, higher lesion volumes, and greater atrophy in multiple sclerosis.

Gender-related differences in MS: a study of conventional and nonconventional MRI measures.

BACKGROUND: Studies showed gender-associated differences in multiple sclerosis (MS) disease evolution and in the evolution of conventional magnetic resonance imaging (MRI) findings. OBJECTIVE: The aim of this study was to investigate gender differences according to a number of conventional and nonconventional MRI measures in patients with MS. METHODS: We examined 763 consecutive patients with MS [499 (19.2% men) relapsing-remitting (RR), 230 (24.8% men) secondary-progressive, and 34 (44.1% men) primary-progressive], 32 (21.9% men) patients with clinically isolated syndrome (CIS), and 101 (30.7% men) normal controls (NC). Patients were assessed using conventional and nonconventional MRI measures. Gender-related MRI differences were investigated using general linear model analysis, corrected for MS disease type. RESULTS: In the total MS group, male patients showed lower normalized peripheral gray matter (GM) (P<0.001) and normalized GM (P=0.011) volumes than female patients. Female patients presented lower normalized white matter (WM) volumes (P=0.011). These gender effects were not observed in NC. Male patients also showed more advanced central atrophy (P=0.022). In RRMS male patients, there was also a higher lateral ventricle volume (P=0.001). The GM-WM normalized ratio was lower for male patients with MS compared with male NC (0.97 vs. 1.09, P<0.001) but not in patients with CIS compared with NC. CONCLUSIONS: There were no significant gender-related differences regarding nonconventional MRI measures. GM and central atrophy are more advanced in male patients, whereas WM atrophy is more advanced in female patients. These gender-related MRI differences may be explained by the effect of sex hormones on brain damage and repair mechanisms.

Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate.

INTRODUCTION: Phenylbutyrate (PB) and its metabolite phenylacetate (PA) demonstrate anticancer activity in vitro through promotion of cell differentiation, induction of apoptosis through the p21 pathway, inhibition of histone deacetylase, and in the case of PB, direct cytotoxicity. We studied the pharmacokinetics, metabolism, and cerebrospinal fluid (CSF) penetration of PA and PB after intravenous (i.v.) administration in the nonhuman primate. METHODS: Three animals received 85 mg/kg PA and 130 mg/kg PB as a 30-min infusion. Blood and CSF samples were obtained at 15, 30, 35, 45, 60 or 75 min, and at 1.5, 2.5, 3.5, 5.5, 6.5, 8.5, 10.5 and 24.5 h after the start of the infusion. Plasma was separated immediately, and plasma and CSF were frozen until HPLC analysis was performed. RESULTS: After i.v. PA administration, the plasma area under the concentration-time curve (AUC) of PA (median +/- SD) was 82 +/- 16 mg/ml.min, the CSF AUC was 24 +/- 7 mg/ml.min, clearance (Cl) was 1 +/- 0.3 ml/min per kg, and the AUCCSF:AUCplasma ratio was 28 +/- 19%. After i.v. PB administration, the plasma PB AUC was 19 +/- 3 mg/ml.min, the CSF PB AUC was 8 +/- 11 mg/ml.min, the PB Cl was 7 +/- 1 ml/min per kg, and the AUCCSF:AUCplasma ratio was 41 +/- 47%. The PA plasma AUC after i.v. PB administration was 50 +/- 9 mg/ml.min, the CSF AUC was 31 +/- 24 mg/ml.min, and the AUCCSF:AUCplasma ratio was 53 +/- 46%. CONCLUSIONS: These data indicate that PA and PB penetrate well into the CSF after i.v. administration. There may be an advantage to administration of PB over PA, since the administration of PB results in significant exposure to both active compounds. Clinical trials to evaluate the activity of PA and PB in pediatric central nervous system tumors are in progress.

Modified procedure for implantation of subcutaneous central venous access devices in macaques (Macaca mulatta).

A nonhuman primate model comprising adult male rhesus monkeys (Macaca mulatta) with chronically indwelling subcutaneous central venous access devices provides a unique opportunity to determine plasma pharmacokinetics of new drugs such as anticancer and anti- retroviral agents. The central venous access we use is a low-profile, single-septum, titanium port that is attached to a radiopaque, indwelling catheter; the catheter is implanted in an internal jugular vein. A common complication following placement of the venous access device was migration of the catheter tip. We therefore modified the standard procedure by cutting the silicone catheter and introducing the rigid connector to secure the catheter to the vessel at the insertion site (approximately 9 to 13 cm from the distal end of the catheter). Prior to the use of the connector, three of five catheters migrated within 4 weeks after placement. In contrast, all 13 internal jugular catheters with connectors have remained patent without migration of the catheter tip. Therefore, incorporation of the catheter connector appears to have eliminated the problem of catheter migration.

Pharmacokinetics and cerebrospinal fluid penetration of CI-994 (N-acetyldinaline) in the nonhuman primate.

CI-994 is a substituted benzamide derivative that has demonstrated significant antitumor activity in vitro and in vivo against a broad spectrum of murine and human tumor models. Its mechanism of action is still unknown but seems to be novel compared with existing anticancer drugs. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of CI-994 in nonhuman primates. Three animals (total 4 doses) received an 80 mg/m2 dose of CI-994 administered over 20 min, and one animal received a dose of 100 mg/m2. Serial plasma and fourth ventricular CSF samples were obtained from 0 to 4320 min after administration of the 80-mg/m2 dose, and only plasma samples were obtained after the 100-mg/m2 dose. CI-994 was measured using a previously validated reverse-phase high-performance liquid chromatography assay. Elimination of CI-994 from plasma was triexponential (4 of 5 cases) or biexponential (1 of 5 cases), with a terminal half life (t1/2) of 7.4 +/- 2.5 h, volume of distribution of 15.5 +/- 1.8 L/m2, and clearance of 40 +/- 6 ml/min/m2. The area under the concentration-time curve (AUC) for the 80-mg/m2 dose was 125 +/- 17 microM x hr. CI-994 was first detected in CSF at the completion of the i.v. infusion. Peak concentrations of CI-994 in CSF were 3.4 +/- 0.3 microM. Elimination from CSF was monoexponential (2 of 4 cases) or biexponential (2 of 4 cases) with a terminal t1/2 in CSF of 12.9 +/- 2.5 h and AUC of 55 +/- 18 microM x hr. The AUC(CSF):AUCplasma ratio was 43 +/- 10%. This study demonstrates that there is excellent CSF penetration of CI-994 after i.v. administration. Additional studies are needed to evaluate the potential role of CI-994 in the treatment of central nervous system neoplasms.

Lymphatic mapping in gynecologic malignancies.

Gynecologic malignancies account for 15% of all cancer diagnosis in women. Primary lymphatic spread is well recognized in vulvar, cervical, uterine, and ovarian carcinomas. Vulvar carcinoma spreads locally to the inguinofemoral lymph nodes in a relatively predictable fashion similar to the local spread of breast carcinoma. Lymphatic mapping using radioactive colloid should provide adequate means to sample these nodal basins while attempting to reduce postoperative morbidity. Methods of vulvar lymphoscintigraphy are described.

A comparison of two computer input devices for uppercase letter matching.

OBJECTIVE: To determine whether the Touch Window or the mouse with an enlarged on-screen arrow was more effective or efficient for an on-screen letter-matching task completed by a boy 9 years of age with spastic quadriplegic cerebral palsy and visual and cognitive deficits. METHOD: A single-subject research design of 5 treatment phases, A1, B1, A2, B2, and A & B, was used. The total percentage of correct letter matches per treatment session, the total percentage correct per letter, and the amount of time needed to match 5 consecutive letters correctly were evaluated. RESULTS: The range and variability of letters correctly matched per session decreased and trends for correct letter matches accelerated when the participant used the mouse interface. Accuracy with matching 18 of 26 (69%) letters of the alphabet increased when selections were made with the mouse interface. The participant was faster when using the Touch Window to match 5 consecutive letters correctly; however, regardless of the interface device used, letter matching remained slow and tedious. CONCLUSION: The mouse with an enlarged on-screen arrow and cursor was the more effective interface device with this child. Making a minor adjustment such as increasing the size of the on-screen arrow can make a common piece of equipment accessible to a person with disabilities.

Plasma and CSF pharmacokinetics of ganciclovir in nonhuman primates.

PURPOSE: The antiviral nucleoside analogue ganciclovir is a potent inhibitor of replication in herpes viruses and is effective against cytomegalovirus infections in immunocompromised patients. Ganciclovir is also used in cancer gene therapy studies that utilize the herpes simplex virus thymidine kinase gene (HSV-TK). The pharmacokinetics of ganciclovir in adults and children have been described previously but there are no detailed studies of the CNS pharmacology of ganciclovir. We studied the pharmacokinetics of ganciclovir in plasma and CSF in a nonhuman primate model that is highly predictive of the CSF penetration of drugs in humans. METHODS: Ganciclovir, 10 mg/kg i.v., was administered over 30 min to three animals. Ganciclovir concentrations in plasma and CSF were measured using reverse-phase HPLC. RESULTS: Peak plasma ganciclovir concentrations ranged from 18.3 to 20.0 microg/ml and the mean plasma AUC was 1075+/-202 microg/ml x min. Disappearance of ganciclovir from the plasma was biexponential with a distribution half-life (t(1/2)alpha) of 18+/-7 min and an elimination half-life (t(1/2)beta) of 109+/-7 min. Total body clearance (ClTB) was 9.4+/-1.6 ml/min/kg. The mean CSF ganciclovir AUC was 168+/-83 microg/ml x min and the mean peak CSF concentration was 0.7+/-0.3 microg/ml. The ratio of the AUCs in CSF and plasma was 15.5+/-7.1%. CONCLUSIONS: Ganciclovir penetrates into the CSF following i.v. administration. This finding will be useful in the design of gene therapy trials involving the HSV-TK gene followed by treatment with ganciclovir in CNS or leptomeningeal tumors.

Cytokine-based tumor cell vaccine is equally effective against parental and isogenic multidrug-resistant myeloma cells: the role of cytotoxic T lymphocytes.

Tumor cells that survive initial courses of chemotherapy may do so by acquiring a multidrug-resistant phenotype. This particular mechanism of drug resistance may also confer resistance to physiological effectors of apoptosis that could potentially reduce the efficacy of immune therapies that use these pathways of cell death. We have previously demonstrated high efficacy for a cytokine-based tumor cell vaccine in a murine MPC11 myeloma model. In the present study, the effects of this vaccination were compared in MPC11 cells and their isogenic sublines selected for mdr1/P-glycoprotein (Pgp)-mediated multidrug resistance (MDR). Immunization with MPC11 cells expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-12 (IL-12) led to long-lasting protection of mice against subcutaneous (sc) challenge with both parental cells or their MDR variants. Similarly, immunization with GM-CSF/IL-12-transfected MDR sublines caused rejection of transplantation of both parental cells and the MDR sublines. Whereas MPC11 cells and their MDR variants were resistant to APO-1/CD95/Fas ligand, the immunization generated potent granzyme B/perforin-secreting cytotoxic T lymphocytes (CTLs) that were similarly effective against both parental and isogenic MDR cells. We conclude that MDR mediated by mdr1/Pgp did not interfere with lysis by pore-forming CTLs. Immunotherapy based on pore-forming CTLs may be an attractive approach to the treatment of drug-resistant myeloma.

Adenocarcinoma of the Endometrium: An Institutional Review.

BACKGROUND: Many oncologists regard endometrial cancer as a relatively benign and easily treatable gynecologic tumor. Inadequate care can result in poor outcomes. METHODS: The authors review the epidemiology and pathology of the disease, and they compare disease characteristics and outcomes of FIGO staging with their own 11-year experience at a tertiary referral center. RESULTS: Patients referred to tertiary referral centers tend to present with more advanced stages of disease than those reported by FIGO, although the profile of histologic types is similar. CONCLUSIONS: Prevention and early detection of endometrial cancer can minimize the impact of this disease. Complete staging and tumor removal including extrafascial hysterectomy with bilateral salpingo-oophorectomy, pelvic lymphadenectomy, and selective paraaortic lymphadenectomy are the cornerstones of surgical therapy.

Prediction of preschool social behavior from social-emotional development at one year.

In an attempt to directly investigate later consequences of the early mother-infant relationship, several measures of social-emotional and cognitive-motivational development at 12 months of age were correlated with two measures of preschool adjustment for 26 children. Results indicated that both of our measures of early social functioning were related to more optimal adjustment in a peer-setting at three-and-a-half years of age. Taken together, the results of the study provide empirical support for the widely held, but seldom tested, hypothesis that the quality of the early mother-infant tie has important consequences for the child's subsequent development in most areas.