Liver Transplantation Outcome in Patients With Angiographically Proven Coronary Artery Disease: A Multi‐Institutional Study

Over the last decade the age of liver transplant (LT) recipients and the likelihood of coronary artery disease (CAD) in this population have increased. There are no multicenter studies that have examined the impact of CAD on LT outcomes. In this historical cohort study, we identified adult LT recipients who underwent angiography prior to transplantation at seven institutions over a 12‐year period. For each patient we recorded demographic data, recipient and donor risk factors, duration of follow‐up, the presence of angiographically proven obstructive CAD (≥50% stenosis) and post‐LT survival. Obstructive CAD was present in 151 of 630 patients, the CAD(+) group. Nonobstructive CAD was found in 479 patients, the CAD(?) group. Patient survival was similar for the CAD(+) group (adjusted HR 1.13, CI = [0.79, 1.62], p = 0.493) compared to the CAD(?) group. The CAD(+) patients were further stratified into severe (CADsev, >70% stenosis, n = 96), and moderate CAD (CADmod, 50–70% stenosis, n = 55) groups. Survival for the CADsev (adjusted HR = 1.26, CI = [0.83, 1.91], p = 0.277) and CADmod (adjusted HR = 0.93, CI = [0.52, 1.66], p = 0.797) groups were similar to the CAD(?) group. We conclude that when current CAD treatment strategies are employed prior to transplant, post‐LT survival is not significantly different between patients with and without obstructive CAD.     

The lack of influence of IVS5-91 G>A polymorphism of the SCN1A gene on efficacy of lamotrigine in patients with focal epilepsy

ABSTRACT

Background: IVS5-91G>A (rs3812718) polymorphism of the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene has been associated with inadequate responsiveness to common antiepileptic drugs which act as sodium channel blockers. This study was performed to investigate the effect of IVS5-91G>A (rs3812718) polymorphism on lamotrigine (LTG) efficacy in a cohort of patients with non-lesional focal epilepsy taking LTG as monotherapy.

Methods: A total of 100 of patients with non-lesional focal epilepsy on LTG monotherapy was included in this prospective interventional study. After reaching a stable dose of LTG patients were followed-up for 12 consecutive months. LTG responsiveness was defined as a 75% or more reduction in seizure frequency on a stable dose of LTG. Genotyping was performed at the end of the study using standard procedures and data were correlated with clinical data.

Results: There were no significant differences in the prevalence of responsiveness to LTG between carriers of different genotypes. Average maintenance LTG doses in the responder group differed by genotype in the order AA>GA>GG, but these differences did not reach statistical significance.

Conclusion: Our data suggest lack of association between SCN1A IVS5-91G>A (rs3812718) polymorphism and response to LTG.     

Treatment of brain metastases from melanoma

Brain metastases from malignant melanoma have a poor prognosis, and treatment can be difficult because of rapid progression of the disease. To help define the treatment of this disease, we reviewed the published literature on brain metastases from melanoma. If a solitary metastasis is present, surgery might be beneficial, especially if systemic disease is absent. Stereotactic radiosurgery is a less invasive, attractive option for solitary or oligometastatic (up to 6) lesions. External beam whole-brain radiation therapy can produce responses and frequently palliates symptoms, but as the sole therapy, it is unlikely to eradicate brain metastases. Chemotherapy may be gaining a role with newer agents that penetrate the blood-brain barrier. Combined modality therapy appears to be the future direction of treatment of multiple metastases.     

Early diagnosis of asymptomatic neurocutaneous melanosis (60 month follow‐up)

Neurocutaneous melanosis (NCM) is a rare, sporadic, congenital neuroectodermal dysplasia. Large congenital melanocytic nevi (CMN) can evolve in a certain percentage of patients to NCM. Meningeal deposits are benign, but can be prone to malignant transformation in some cases. We describe the case of an infant with asymptomatic NCM, and typical magnetic resonance imaging (MRI) findings. The diagnosis was established shortly after delivery, and the patient was followed for 60 months. At that time, the girl did not have any neurologic symptoms; she reached normal developmental milestones and did not show mental retardation and did not develop malignant melanoma; further follow‐up will be needed, although there are no reliable guidelines as to the time range of follow up of asymptomatic NCM in the literature. We report the typical MRI signal abnormalities of the brain, and present a review of the literature regarding this rare and mysterious congenital disorder.     

Infused peripheral blood autograft absolute lymphocyte count correlates with day 15 absolute lymphocyte count and clinical outcome after autologous peripheral hematopoietic stem cell transplantation in non-Hodgkin's lymphoma

Absolute lymphocyte count at day 15 (ALC-15) after autologous peripheral blood hematopoietic stem cell transplantation (APHSCT) is an independent prognostic factor for survival in non-Hodgkin's lymphoma (NHL). Factors affecting ALC-15 remain unknown. We hypothesized that dose of infused autograft lymphocytes (A-ALC) directly impacts upon ALC-15. A total of 190 consecutive NHL patients received A-ALC between 1993 and 2001. The primary end point was correlation between A-ALC and ALC-15. A strong correlation was identified (r=0.71). A higher A-ALC was infused into patients achieving an ALC-15 > or =500/microl vs ALC-15 <500/microl (median of 0.68 x 10(9)/kg (0.04-2.21 x 10(9)/kg), vs 0.34 x 10(9)/kg (0.04-1.42 x 10(9)/kg), P<0.0001). The median follow-up for all patients was 36 months (maximum of 109 months). The A-ALC threshold was determined at 0.5 x 10(9)/kg. The median overall survival (OS) and progression-free survival (PFS) times were longer in patients who received an A-ALC >/=0.5 x 10(9)/kg vs A-ALC <0.5 x 10(9)/kg (76 vs 17 months, P<0.0001; 49 vs 10 months, P<0.0001, respectively). Multivariate analysis demonstrated A-ALC to be an independent prognostic indicator for OS and PFS. These data support our hypothesis that ALC-15 and survival are dependent upon the dose of infused A-ALC in NHL.     

Elevated monoclonal and polyclonal serum immunoglobulin free light chain as prognostic factors in B‐ and T‐cell non‐Hodgkin lymphoma

The serum immunoglobulin free light chain (FLC) assay quantitates free kappa (κ) and lambda (λ) light chains. FLC elevations in patients with diffuse large B‐cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and chronic lymphocytic leukemia (CLL) are associated with an inferior survival. These increases in FLC can be monoclonal (as in myeloma) or polyclonal. The goal was to estimate the frequency of these elevations within distinct types of B‐cell and T‐cell non‐Hodgkin lymphoma (NHL) and whether the FLC measurements are associated with event‐free survival (EFS). We studied serum for FLC abnormalities using normal laboratory reference ranges to define an elevated κ or λ FLC. Elevations were further classified as polyclonal or monoclonal. Four hundred ninety‐two patients were studied: 453 B‐cell and 34 T‐cell NHL patients. Twenty‐nine % (142/453) of patients had an elevated FLC of which 10% were monoclonal elevations. Within B‐cell NHL, FLC abnormalities were most common in lymphoplasmacytic (79%), mantle cell (68%), and lymphomas of mucosa associated lymphoid tissue (31%); they were least common in follicular (15%). The hazard ratio (HR) for EFS in all patients was 1.41 (95% CI; 1.11–1.81); in all B‐cell NHL the HR was 1.44 (95% CI 1.11–1.96); in all T‐cell NHL the HR was 1.17 (95% CI 0.55–2.49). FLC abnormalities predicted an inferior OS (HR = 2.75, 95% CI: 1.93–3.90, P < 0.0001). The serum FLC assay is useful for prognosis in both B‐cell and T‐cell types of NHL. In B‐cell NHL further discrimination between a monoclonal and polyclonal elevation may be helpful and should be analyzed in prospective clinical trials. Am. J. Hematol. 89:1116–1120, 2014. © 2014 Wiley Periodicals, Inc.     

Segmental-Dependent Intestinal Drug Permeability: Development and Model Validation of In Silico Predictions Guided by In Vivo Permeability Values

The goal of this work was to develop an in silico model that allows predicting segmental-dependent permeability throughout the small intestine (SI). In vivo permeability of 11 model drugs in 3 SI segments (jejunum, mid-SI, ileum) was studied in rats, creating a data set that reflects the conditions throughout the SI. Then, a predictive model was developed, combining physicochemical drug properties influencing the underlying mechanism of passive permeability: Log p, polar surface area, M_W, H-bond count, and Log f_u, with microenvironmental SI conditions. Excellent correlation was evident between the predicted and experimental data (R² = 0.914), with similar predictability in each SI segment. Log p and Log f_u were identified as the major determinants of permeability, with similar contribution. Total H-bond count was also a significant determinant, followed by polar surface area and M_W. Leaving out any of the model parameters decreased its predictability. The model was validated against 5 external drugs, with excellent predictability. Notably, the model was able to predict the segmental-dependent permeability of all drugs showing this trend experimentally. Model predictability was better in the high-permeability versus low-permeability range. Overall, our approach of constructing a straightforward in silico model allowed reliable predictions of segmental-dependent intestinal permeability, providing new insights into relative effects of drug-related factors and gastrointestinal environment on permeability.     

Deficits in motor performance after pedunculopontine lesions in rats – impairment depends on demands of task

Anatomically and functionally located between basal ganglia and brainstem circuitry, the pedunculopontine tegmental nucleus (PPTg) is in a pivotal position to contribute to motor behavior. Studies in primates have reported akinesia and postural instability following destruction of the PPTg. In humans, the PPTg partially degenerates in Parkinson's disease and stimulation of this region is under investigation as a possible therapeutic. Studies in rats report no crude motor impairment following PPTg lesion, although a detailed assessment of the role of the PPTg in rat motor function has not been reported. Our studies applied motor tests generally used in rodent models of Parkinson's disease to rats bearing either excitotoxic damage to all neuronal populations within PPTg, or selective destruction of the cholinergic subpopulation created with the toxin Dtx‐UII. Neither lesion type altered baseline locomotion. On the rotarod, excitotoxic lesions produced a persistent impairment on the accelerating, but not fixed speed, conditions. In the vermicelli handling task (a quantitative measure of fine motor control and effective behavioral sequencing) excitotoxic lesions produced no single impairment, but globally increased the number of normal and abnormal behaviors. In contrast, depletion of cholinergic PPTg neurons produced impairment on the accelerating rotarod but no changes in vermicelli handling. Together, these results show that while PPTg lesions produce no impairment in the execution of individual motor actions, impairments emerge when the demands of the task increase. Results are discussed in terms of PPTg acting as part of a rapid action selection system, which integrates sensory information into motor output.