Impact of discontinuing tremor suppressing medications following thalamic deep brain stimulation

BackgroundMany essential tremor patients continue to require tremor suppressing medications following deep brain stimulation. The true incidence of medication usage in the years following surgery remains unclear, and the use of medications has not been included in the post-operative analyses of tremor severity and also quality of life.MethodsAmong 28 essential tremor patients treated with deep brain stimulation at a single center between January 2002 and April 2010, we analyzed the prevalence and dosage of pre-operative tremor suppressing medications versus post-operative medications at 12 and 36 months following surgery. We also assessed the influence of medication continuation on clinical outcome measures, such as the Fahn-Tolosa-Marin Tremor Rating Scale, and the 36 item short-form health quality of life survey.ResultsBoth unilateral and bilateral deep brain stimulation resulted in a decrease in primidone use (p = 0.0082, 0.046, respectively), and bilateral deep brain stimulation patients used less tremor suppressing medications 36 months following surgery (p = 0.02). The decision to discontinue primidone after surgery resulted in a non-significant long-term improvement in tremor motor score (23 points versus 15 points, p = 0.19), and did not significantly influence the physical and mental composite quality of life scores (p = 0.81, 0.23, respectively).ConclusionsBilateral deep brain stimulation effectively eliminated the need for tremor suppressing medications, while unilateral stimulation was not as effective in reducing medication usage. Clinicians and patients should be aware that discontinuation of primidone after surgery may worsen tremor in unilateral deep brain stimulation cases, but discontinuation will not likely impact quality of life.     

High Infection Rate Outcomes in Long-bone Tumor Surgery with Endoprosthetic Reconstruction in Adults: A Systematic Review

Background

Limb salvage surgery (LSS) with endoprosthetic replacement is the most common method of reconstruction following bone tumor resection in the adult population. The risk of a postoperative infection developing is high when compared with conventional arthroplasty and there are no appropriate guidelines for antibiotic prophylaxis.

Questions/purposes

We sought to answer the following questions: (1) What is the overall risk of deep infection and the causative organism in lower-extremity long-bone tumor surgery with endoprosthetic reconstruction? (2) What antibiotic regimens are used with endoprosthetic reconstruction? (3) Is there a correlation between infection and either duration of postoperative antibiotics or sample size?

Methods

We conducted a systematic review of the literature for clinical studies that reported infection rates in adults with primary bony malignancies of the lower extremity treated with surgery and endoprosthetic reconstruction. The search included articles published in English between 1980 and July 2011.

Results

The systematic literature review yielded 48 studies reporting on a total of 4838 patients. The overall pooled weighted infection rate for lower-extremity LSS with endoprosthetic reconstruction was approximately 10% (95% CI, 8%–11%), with the most common causative organism reported to be Gram-positive bacteria in the majority of cases. The pooled weighted infection rate was 13% after short-term postoperative antibiotics and 8% after long-term postoperative antibiotics. There was no correlation between sample size and infection rate.

Conclusions

Infection rates of 10% are high when compared with rates for conventional arthroplasty. Our results suggest that long-term antibiotic prophylaxis decreases the risk of deep infection. However, the data should be interpreted with caution owing to the retrospective nature of the studies.     

Adoptive transfer of immature myeloid cells lacking NF‐κB p50 (p50‐IMC) impedes the growth of MHC‐matched high‐risk neuroblastoma

High‐risk neuroblastomas harbor abundant myeloid cells that suppress antitumor immunity and support tumor growth. Macrophages lacking the inhibitory NF‐κB p50 subunit adopt a pro‐inflammatory phenotype. We now report that murine 9464D neuroblastoma cells, which express high levels of exogenous MYCN, grow slower in syngeneic p50(f/f);Lys‐Cre mice that lack p50 in macrophages and neutrophils, compared with p50(f/f) littermates. Tumors in p50(f/f);Lys‐Cre mice possess increased numbers of total and activated CD4⁺ and CD8⁺ T cells, and depletion of both of these T‐cell populations accelerates tumor growth. Anti‐PD‐1 T‐cell checkpoint blockade, or DNA methyltransferase and histone deacetylase inhibition, further slows tumor growth. In addition, adoptive transfer of immature myeloid cells lacking NF‐κB p50 (p50‐IMC), generated either from the bone marrow of p50^−/− mice or via nucleofection of a p50 sgRNA:Cas9 complex into wild‐type hematopoietic progenitors, also slowed growth of MHC‐matched 9464D tumors but not of MHC‐mismatched Neuro2A tumors. These findings further validate the utility of targeting myeloid NF‐κB p50 as a strategy for cancer therapy and demonstrate activity of p50‐IMC generated by gene editing of syngeneic marrow cells, a cell product relevant to clinical translation.     

Hyperactive Transforming Growth Factor‐β1 Signaling Potentiates Skeletal Defects in a Neurofibromatosis Type 1 Mouse Model

Dysregulated transforming growth factor beta (TGF‐β) signaling is associated with a spectrum of osseous defects as seen in Loeys‐Dietz syndrome, Marfan syndrome, and Camurati‐Engelmann disease. Intriguingly, neurofibromatosis type 1 (NF1) patients exhibit many of these characteristic skeletal features, including kyphoscoliosis, osteoporosis, tibial dysplasia, and pseudarthrosis; however, the molecular mechanisms mediating these phenotypes remain unclear. Here, we provide genetic and pharmacologic evidence that hyperactive TGF‐β1 signaling pivotally underpins osseous defects in Nf1^flox/?;Col2.3Cre mice, a model which closely recapitulates the skeletal abnormalities found in the human disease. Compared to controls, we show that serum TGF‐β1 levels are fivefold to sixfold increased both in Nf1^flox/?;Col2.3Cre mice and in a cohort of NF1 patients. Nf1‐deficient osteoblasts, the principal source of TGF‐β1 in bone, overexpress TGF‐β1 in a gene dosage–dependent fashion. Moreover, Nf1‐deficient osteoblasts and osteoclasts are hyperresponsive to TGF‐β1 stimulation, potentiating osteoclast bone resorptive activity while inhibiting osteoblast differentiation. These cellular phenotypes are further accompanied by p21‐Ras–dependent hyperactivation of the canonical TGF‐β1–Smad pathway. Reexpression of the human, full‐length neurofibromin guanosine triphosphatase (GTPase)‐activating protein (GAP)‐related domain (NF1 GRD) in primary Nf1‐deficient osteoblast progenitors, attenuated TGF‐β1 expression levels and reduced Smad phosphorylation in response to TGF‐β1 stimulation. As an in vivo proof of principle, we demonstrate that administration of the TGF‐β receptor 1 (TβRI) kinase inhibitor, SD‐208, can rescue bone mass deficits and prevent tibial fracture nonunion in Nf1^flox/?;Col2.3Cre mice. In sum, these data demonstrate a pivotal role for hyperactive TGF‐β1 signaling in the pathogenesis of NF1‐associated osteoporosis and pseudarthrosis, thus implicating the TGF‐β signaling pathway as a potential therapeutic target in the treatment of NF1 osseous defects that are refractory to current therapies. © 2013 American Society for Bone and Mineral Research.     

Impact of Adjuvant Radiotherapy on Survival after Pancreatic Cancer Resection: An Appraisal of Data from the National Cancer Data Base

Purpose

The impact of adjuvant radiotherapy for pancreatic adenocarcinoma (PAC) remains controversial. We examined effects of adjuvant therapy on overall survival (OS) in PAC, using the National Cancer Data Base (NCDB).

Methods

Patients with resected PAC from 1998 to 2002 were queried from the NCDB. Factors associated with receipt of adjuvant chemotherapy (ChemoOnly) versus adjuvant chemoradiotherapy (ChemoRad) versus no adjuvant treatment (NoAdjuvant) were assessed. Cox proportional hazard modeling was used to examine effect of adjuvant therapy type on OS. Propensity scores (PS) were developed for each treatment arm and used to produce matched samples for analysis to minimize selection bias.

Results

From 1998 to 2002, a total of 11,526 patients underwent resection of PAC. Of these, 1,029 (8.9 %) received ChemoOnly, 5,292 (45.9 %) received ChemoRad, and 5,205 (45.2 %) received NoAdjuvant. On univariate analysis, factors associated with improved OS included: younger age, higher income, higher facility volume, lower tumor stage and grade, negative margins and nodes, and absence of adjuvant therapy. On multivariate analysis with matched PS, factors independently associated with improved OS included: younger age, higher income, higher facility volume, later year of diagnosis, smaller tumor size, lower tumor stage, and negative tumor margins and nodes. ChemoRad had the best OS (hazard ratio 0.70, 95 % confidence interval 0.61–0.80) in a PS matched comparison with ChemoOnly (hazard ratio 1.04, 95 % confidence interval 0.93–1.18) and NoAdjuvant (index).

Conclusions

Adjuvant chemotherapy with radiotherapy is associated with improved OS after PAC resection in a large population from the NCDB. On the basis of these analyses, radiotherapy should be a part of adjuvant therapy for PAC.     

Stroke and the “Stroke Belt” in Dialysis: Contribution of Patient Characteristics to Ischemic Stroke Rate and Its Geographic Variation

Geographic variation in stroke rates is well established in the general population, with higher rates in the South than in other areas of the United States. ESRD is a potent risk factor for stroke, but whether regional variations in stroke risk exist among dialysis patients is unknown. Medicare claims from 2000 to 2005 were used to ascertain ischemic stroke events in a large cohort of 265,685 incident dialysis patients. A Poisson generalized linear mixed model was generated to determine factors associated with stroke and to ascertain state-by-state geographic variability in stroke rates by generating observed-to-expected (O/E) adjusted rate ratios for stroke. Older age, female sex, African American race and Hispanic ethnicity, unemployed status, diabetes, hypertension, history of stroke, and permanent atrial fibrillation were positively associated with ischemic stroke, whereas body mass index >30 kg/m² was inversely associated with stroke (P<0.001 for each). After full multivariable adjustment, the three states with O/E rate ratios >1.0 were all in the South: North Carolina, Mississippi, and Oklahoma. Regional efforts to increase primary prevention in the “stroke belt” or to better educate dialysis patients on the signs of stroke so that they may promptly seek care may improve stroke care and outcomes in dialysis patients.Stroke is a catastrophic health event and a leading cause of disability. It represents a particularly heavy burden for the long-term dialysis population, in whom stroke rates are substantially higher than in the general population.¹ In the general population, there is substantial geographic variability in stroke rates, with the southeastern United States having long been recognized as a “stroke belt” of higher stroke mortality rates.^2–4 However, whether a stroke belt of increased ischemic stroke incidence exists in dialysis patients has not been formally studied.Although one might suspect that the same factors contributing to ischemic stroke risk in the general population also apply to dialysis patients, there are several reasons to posit that this might not be the case. First, unlike the general population, dialysis patients across the United States have consistent access to insurance and frequent contact with health care providers, who routinely measure their BP, irrespective of geographic location. Second, the nature of vascular disease differs between dialysis and nondialysis patients, so different pathophysiologic mechanisms may be operative in the two populations.⁵ Third, dialysis patients fundamentally represent a “survivor cohort” relative to individuals with (predialysis) CKD and its attendant cardiovascular disorders, suggesting that epidemiologic trends evident in one population might not be found in the other.⁶ Accordingly, it is uncertain whether there is substantial geographic variation in stroke risk among dialysis patients and what factors might, in part, explain such a finding.To address this gap in knowledge, we constructed a large cohort of incident dialysis patients to determine whether ischemic stroke rates vary by geography and how differences in stroke rates might be explained by patient characteristics. We reasoned that uncovering the existence of geographic variability in the stroke rates of dialysis patients might provide direction for focused health care efforts in regions at elevated risk, such as screening new dialysis patients for symptoms that might be referable to old strokes, lowering the threshold for investigating cerebrovascular disease, or educating dialysis patients on the importance of seeking immediate care for stroke-type symptoms.