A phase II trial of temozolomide and IFN-alpha in patients with advanced renal cell carcinoma.

The combination of temozolomide (TEM) and interferon-alpha (IFN-alpha) previously demonstrated a 30% response rate in metastatic melanoma. A single institution, phase II trial evaluating the efficacy of TEM/IFN in patients with advanced renal cell carcinoma (RCC) was conducted. Safety and tumor response were the main outcomes. Eligible patients received 200 mg/m(2)/day TEM orally on days 1-5 every 28 days, with IFN 2.5 million U/m(2)/day subcutaneously (s.c.) three alternate days/week for days 1-15 first cycle, then 5 million U/m(2)/day s.c. 3 alternate days/week throughout each 28-day cycle. Efficacy was evaluated every 8 weeks, and dose-limiting toxicities (DLTs) were treated with dose reductions of the culprit drug. Sixteen patients (ages 37-67) were initially enrolled. Of the 14 evaluable patients, there was one minor response. Best response was stable disease, with 7 patients remaining on study for > or =6 months. Five were alive for more than 2 years, and 2 remain alive at 45 and 50 months after enrollment. DLTs included TEM-induced myelosuppression and IFN-induced fever/chills. Other toxicities were mild to moderate (grades 1-3). The combination of TEM/IFN proved quite tolerable. This regimen appears inactive in terms of response in this population with poor prognosis, but the patients with stable disease > or =6 months remain of interest.     

Local endometrial injury and IVF outcome: a systematic review and meta-analysis

A systematic review was conducted of the influence of local endometrial injury (LEI) on the outcome of the subsequent IVF cycle. MEDLINE, EMBASE, the Cochrane Library, National Research Register, ISI Conference Proceedings, ISRCTN Register and Meta-register were searched for randomized controlled trials to October 2011. The review included all trials comparing the outcome of IVF treatment in patients who had LEI in the cycle preceding their IVF treatment with controls in which endometrial injury was not performed. The main outcome measures were clinical pregnancy and live birth rates. In total, 901 participants were included in two randomized (n = 193) and six non-randomized controlled studies (n = 708). The quality of the studies was variable. Meta-analysis showed that clinical pregnancy rate was significantly improved after LEI in both the randomized (relative risk, RR, 2.63, 95% CI 1.39–4.96, P = 0.003) and non-randomized studies (RR 1.95, 95% CI 1.61–2.35, P < 0.00001). The improvement did not reach statistical significance in the one randomized study which reported the live birth rate (RR 2.29, 95% CI 0.86–6.11). Robust randomized trials comparing a standardized protocol of LEI before IVF treatment with no intervention in a well-defined patient population are needed.The endometrium is the lining of the womb where the embryo implants. Endometrial surface injury is a simple office procedure. We reviewed the literature to find out if performing endometrial surface injury before an IVF treatment cycle improves its outcome. Our review found that when endometrial surface injury was performed before an IVF treatment cycle, there was a significant improvement in the outcome of that treatment cycle. We recommend this question is addressed in a well-conducted randomized study to confirm the findings of our review.     

An Integrative Model of Subcortical Auditory Plasticity

In direct conflict with the concept of auditory brainstem nuclei as passive relay stations for behaviorally-relevant signals, recent studies have demonstrated plasticity of the auditory signal in the brainstem. In this paper we provide an overview of the forms of plasticity evidenced in subcortical auditory regions. We posit an integrative model of auditory plasticity, which argues for a continuous, online modulation of bottom-up signals via corticofugal pathways, based on an algorithm that anticipates and updates incoming stimulus regularities. We discuss the negative implications of plasticity in clinical dysfunction and propose novel methods of eliciting brainstem responses that could specify the biological nature of auditory processing deficits.     

Seizure Frequency Can Alter Brain Connectivity: Evidence from Resting-State fMRI

BACKGROUND AND PURPOSE:The frequency of seizures is an important factor that can alter functional brain connectivity. Analysis of this factor in patients with epilepsy is complex because of disease- and medication-induced confounders. Because patients with hot-water epilepsy generally are not on long-term drug therapy, we used seed-based connectivity analysis in these patients to assess connectivity changes associated with seizure frequency without confounding from antiepileptic drugs.MATERIALS AND METHODS:Resting-state fMRI data from 36 patients with hot-water epilepsy (18 with frequent seizures [>2 per month] and 18 with infrequent seizures [≤2 per month]) and 18 healthy age- and sex-matched controls were analyzed for seed-to-voxel connectivity by using 106 seeds. Voxel wise paired t-test analysis (P < .005, corrected for false-discovery rate) was used to identify significant intergroup differences between these groups.RESULTS:Connectivity analysis revealed significant differences between the 2 groups (P < .001). Patients in the frequent-seizure group had increased connectivity within the medial temporal structures and widespread areas of poor connectivity, even involving the default mode network, in comparison with those in the infrequent-seizure group. Patients in the infrequent-seizure group had focal abnormalities with increased default mode network connectivity and decreased left entorhinal cortex connectivity.CONCLUSIONS:The results of this study suggest that seizure frequency can alter functional brain connectivity, which can be visualized by using resting-state fMRI. Imaging features such as diffuse network abnormalities, involvement of the default mode network, and recruitment of medial temporal lobe structures were seen only in patients with frequent seizures. Future studies in more common epilepsy groups, however, will be required to further establish this finding.

Behind the unquestionable clinical and electroencephalographic manifestations of an epileptic seizure, there lie several molecular, metabolic, cellular, and hemodynamic events that alter the function of the brain in a complex manner. These alterations may be transient, but many such events can have a cumulative effect, resulting in psychological and memory deficits, personality changes, and reduced functioning in patients with epilepsy. Advances in neurophysiology, functional imaging, and computational neurosciences have made it possible to derive models mathematically to describe such complex diseases.Disease-state network analysis with resting-state fMRI is becoming increasingly popular because of its superior spatial resolution, nondependence on task, ease of acquisition, and ability to visualize whole-brain functional networks, which are amenable to long-term changes related to disease states.¹ Application of connectivity principles to these data has promoted research in various aspects of epileptic seizures, and there has been overwhelming report of decreased connectivity around the seizure-onset zone^2–6 and the default mode network (DMN) by several groups.^7,8 In 2012, Jehi⁷ and Morgan et al⁹ reported that connectivity patterns were different in patients with right and left mesial temporal sclerosis and that there was decreased connectivity between the regions of the DMN and the hippocampus and amygdala in patients with mesial temporal sclerosis. Similarly, hemispheric connectivity analysis in patients with unilateral mesial temporal sclerosis revealed decreased local and intrahemispheric connectivity and increased interhemispheric connectivity.¹⁰ In contradistinction to the aforementioned results, there have been reports on increased hippocampal connectivity that was presumed to be a compensatory mechanism because it linearly correlated with a disease duration of >10 years.^1–4,6 Graph-theory analysis of resting-state fMRI data from patients with epilepsy also revealed decreased functional nodal topologic properties of the DMN that were positively correlated with disease duration.^8,11–14 Regional homogeneity analysis of resting-state fMRI data was even used as a presurgical tool for seizure identification in patients with MR-negative focal epilepsy.¹⁵ Thus, various models of data analysis have helped in understanding epilepsy further, and now there is increasing interest in using these models to reclassify epilepsy as a focal epileptogenic area^10,15 or as a network of seizure-generating areas.^16–18Gower''s clinical observation that “seizures beget seizures” in 1881 triggered several studies, especially animal models that addressed the genesis of epilepsy. Kindling is a phenomenon in which the repetition of subconvulsive electrical stimuli results in a progressive epileptic state and an increased frequency of seizures.^19,20 Kindling is a continuous temporal process that remodels the mechanisms and circuits in the brain. Early changes, beginning with modulation of presynaptic and postsynaptic functioning in glutamate, N-methyl-d-aspartate, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and late changes, including mossy fiber sprouting, synaptogenesis/neurogenesis, and neurotrophic factor regulation, are known to occur as a result of kindling.^20–22 The increased risk for seizure recurrence with increasing numbers of seizures was first demonstrated clinically by Hauser and Lee.²³ The effects of seizure frequency and chronic epilepsy have been studied sparsely by using imaging techniques.¹ For example, Widjaja et al²⁴ found no significant correlation with seizure frequency, age of seizure onset, or duration of epilepsy in a group of children with medically refractory epilepsy.Apart from other disease-related confounders such as type of seizure, duration of epilepsy, age of onset, family history of epilepsy, etc, each of which can induce connectivity differences independently, a major limitation of interpreting the results of functional connectivity in patients with epilepsy is the use of antiepileptic drugs. Patients with hot-water epilepsy (HWE) present with a history of complex partial seizures clinically suggestive of temporal lobe onset with or without secondary generalization. Most patients are drug naive at their first evaluation, which provided us an opportunity to study networks that were affected by seizure frequency and matched for other disease-related confounders but not antiepileptic drugs. On the basis of the phenomenon of kindling, we hypothesized that seizures can alter brain connectivity and that the frequency of seizures can influence the magnitude of this alteration. We predicted that patients with a higher seizure frequency would have widespread changes in comparison with patients with a lower seizure frequency. We used seed-to-voxel–based resting-state fMRI connectivity in 36 drug-naive patients with HWE who were comparable in terms of various factors such as age, sex, education, and epilepsy-related confounders. We hope that such quantifiable noninvasive in vivo evidence further enhances knowledge of the etiopathogenesis of HWE and, if applicable to refractory epilepsy, can identify such patients early to avoid time-consuming trial-and-error methods of pharmacotherapy and facilitate early intervention to minimize cognitive deficits.     

Risk factors associated with lymphedema after lymph node dissection in melanoma patients

Background

Secondary lymphedema is a frequent complication after lymphadenectomy in melanoma patients, although few studies in melanoma adequately characterize risk factors for lymphedema, and of these, sample size is limited. This study aims to identify risk factors associated with the lymphedema after axillary lymph node dissection (ALND) and inguinal lymph node dissection (ILND) in a more robust cohort of melanoma patients.

Methods

We identified 269 ALND or ILND melanoma patients treated between 2008 and 2014. Demographic, clinical, and postoperative data were collected by review of the electronic medical record. Univariate and multivariate analysis were used to determine independent predictors of lymphedema.

Results

Fifty-six (20.8%) of the patients developed lymphedema after lymph node dissection with a median staging group of 3. ILND (odds ratio [OR] = 4.506, P < .001, 95% confidence interval [CI]: 2.289 to 8.869) and peripheral vascular disease (PVD; OR = 3.849, P = .020, 95% CI: 1.237 to 11.975) were significant predictors of lymphedema in multivariate analysis. Obese body mass index approached significance (OR = 1.802, P = .069, 95% CI: .955 to 3.399).

Conclusions

PVD and ILND were the 2 factors associated with the highest risk of lymphedema in melanoma surgery with PVD increasing risk 2-fold in ILND patients and 3-fold in ALND patients. These findings may improve surgeon-patient communication of care goals and surgical risk assessment.