Miriam Nuño

Acromegaly Clinical Trial Methodology Impact on Reported Biochemical Efficacy Rates of Somatostatin Receptor Ligand Treatments: A Meta-Analysis

Introduction: Biochemical efficacy of somatostatin receptor ligand (SRL) treatment in acromegaly is defined by metrics for GH and IGF-1 control. Since the earliest therapeutic trials, biochemical control criteria, medical formulations, and assay techniques have evolved. Materials and Methods: We searched PubMed for English-language trials published from 1974 to 2012 evaluating 10 or more patients, with a duration of more than 3 months and biochemical control as a key objective. We used a random-effects model to compare biochemical outcomes for octreotide and lanreotide trials according to study design characteristics. Results: A total of 4464 patients were enrolled in the analyzed trials; 4125 were treated, and 3787 completed study treatment. Overall achieved control rates were 56% for mean GH and 55% for IGF-1 normalization. Treatment duration was significantly related to both GH (P < .001) and IGF-1 control (P = .02). Prior SRL therapy (P = .01), and year of study publication (P = .03) were related to biochemical control for GH but not IGF-1. No statistically significant differences in GH or IGF-1 response rates were observed for multicenter vs single center, retrospective vs prospective, study drug, and preselection for SRL responsiveness. Dosing scheme, GH response criterion, or switch study design were also not statistically significant in determining GH or IGF-1 response rate. Conclusions: Clinical design characteristics anticipated to impart efficacy bias including switching, preselection for SRL responsiveness, and retrospective design had no statistically significant impact on efficacy determination. Later year of publication, study duration, and prior SRL use are significant efficacy determinants for acromegaly trial outcomes.

Fluorescence lifetime spectroscopy for guided therapy of brain tumors

This study evaluates the potential of time-resolved laser induced fluorescence spectroscopy (TR-LIFS) as intra-operative tool for the delineation of brain tumor from normal brain. Forty two patients undergoing glioma (WHO grade I-IV) surgery were enrolled in this study. A TR-LIFS prototype apparatus (gated detection, fast digitizer) was used to induce in-vivo fluorescence using a pulsed N2 laser (337 nm excitation, 0.7 ns pulse width) and to record the time-resolved spectrum (360-550 nm range, 10 nm interval). The sites of TR-LIFS measurement were validated by conventional histopathology (H&E staining). Parameters derived from the TR-LIFS data including intensity values and time-resolved intensity decay features (average fluorescence lifetime and Laguerre coefficients values) were used for tissue characterization and classification. 71 areas of tumor and normal brain were analyzed. Several parameters allowed for the differentiation of distinct tissue types. For example, normal cortex (N=35) and normal white matter (N=12) exhibit a longer-lasting fluorescence emission at 390 nm (τ390=2.12±0.10 ns) when compared with 460 nm (τ460=1.16±0.08 ns). High grade glioma (grades III and IV) samples (N=17) demonstrate emission peaks at 460 nm, with large variation at 390 nm while low grade glioma (I and II) samples (N=7) demonstrated a peak fluorescence emission at 460 nm. A linear discriminant algorithm allowed for the classification of low-grade gliomas with 100% sensitivity and 98% specificity. High-grade glioma demonstrated a high degree of heterogeneity thus reducing the discrimination accuracy of these tumors to 47% sensitivity and 94% specificity. Current findings demonstrate that TR-LIFS holds the potential to diagnose brain tumors intra-operatively and to provide a valuable tool for aiding the neurosurgeon-neuropathologist team in to rapidly distinguish between tumor and normal brain during surgery.

Loss of PTEN is not associated with poor survival in newly diagnosed glioblastoma patients of the temozolomide era.

Introduction Pre-temozolomide studies demonstrated that loss of the tumor suppressor gene PTEN held independent prognostic significance in GBM patients. We investigated whether loss of PTEN predicted shorter survival in the temozolomide era. The role of PTEN in the PI3K/Akt pathway is also reviewed. Methods Patients with histologically proven newly diagnosed GBM were identified from a retrospective database between 2007 and 2010. Cox proportional hazards analysis was used to calculate the independent effects of PTEN expression, age, extent of resection, Karnofsky performance scale (KPS), and treatment on overall survival. Results Sixty-five percent of patients were men with median age of 63 years, and 70% had KPS≥80. Most patients (81%) received standard treatment (temozolomide with concurrent radiation). A total of 72 (47%) patients had retained PTEN expression. Median overall survival (OS) was 19.1 months (95% CI: 15.0–22.5). Median survival of 20.0 months (95% CI: 15.0–25.5) and 18.2 months (95% CI: 13.0–25.7) was observed in PTEN retained and PTEN loss patients, respectively (p = .71). PTEN loss patients were also found to have amplifications of EGFR gene more frequently than patients with retained PTEN (70.8% vs. 47.8%, p = .01). Multivariate analysis showed that older age (HR 1.64, CI: 1.02–2.63, p = .04), low KPS (HR 3.57, CI: 2.20–5.79, p<.0001), and lack of standard treatment (HR 3.98, CI: 2.38–6.65, p<.0001) yielded worse survival. PTEN loss was not prognostic of overall survival (HR 1.31, CI: 0.85–2.03, p = .22). Conclusions Loss of expression of PTEN does not confer poor overall survival in the temozolomide era. These findings imply a complex and non-linear molecular relationship between PTEN, its regulators and effectors in the tumorigenesis of glioblastoma. Additionally, there is evidence that temozolomide may be more effective in eradicating GBM cancer cells with PTEN loss and hence, level the outcomes between the PTEN retained and loss groups.

Contingency management among homeless, out-of-treatment men who have sex with men

Homeless men who have sex with men are a particularly vulnerable population with high rates of substance dependence, psychiatric disorders, and HIV prevalence. Most need strong incentives to engage with community-based prevention and treatment programs. Contingency management (CM) was implemented in a community HIV prevention setting and targeted reduced substance use and increased health-promoting behaviors over a 24-week intervention period. Participants in the CM condition achieved greater reductions in stimulant and alcohol use (χ(2) = 27.36, p < .01) and, in particular, methamphetamine use (χ(2) = 21.78, p < .01) and greater increases in health-promoting behaviors (χ(2) = 37.83, p < .01) during the intervention period than those in the control group. Reductions in substance use were maintained to 9- and 12-month follow-up evaluations. Findings indicate the utility of CM for this high-risk population and the feasibility of implementing the intervention in a community-based HIV prevention program.

Prognosis of patients with multifocal glioblastoma: a case-control study

OBJECT The prognosis of patients with glioblastoma who present with multifocal disease is not well documented. The objective of this study was to determine whether multifocal disease on initial presentation is associated with worse survival. METHODS The authors retrospectively reviewed records of 368 patients with newly diagnosed glioblastoma and identified 47 patients with multifocal tumors. Each patient with a multifocal tumor was then matched with a patient with a solitary glioblastoma on the basis of age, Karnofsky Performance Scale (KPS) score, and extent of resection, using a propensity score matching methodology. Radiation and temozolomide treatments were also well matched between the 2 cohorts. Kaplan-Meier estimates and log-rank tests were used to compare patient survival. RESULTS The incidence of multifocal tumors was 12.8% (47/368). The median age of patients with multifocal tumors was 61 years, 76.6% had KPS scores ≥ 70, and 87.2% underwent either a biopsy or partial resection of their tumors. The 47 patients with multifocal tumors were almost perfectly matched on the basis of age (p = 0.97), extent of resection (p = 1.0), and KPS score (p = 0.80) compared with 47 patients with a solitary glioblastoma. Age (>65 years), partial resection or biopsy, and low KPS score (<70) were associated with worse median survival within the multifocal group. In the multifocal group, 19 patients experienced tumor progression on postradiation therapy MRI, compared with 11 patients (26.8%) with tumor progression in the unifocal group (p = 0.08). Patients with multifocal tumors experienced a significantly shorter median overall survival of 6 months (95% CI 4-10 months), compared with the 11-month median survival (95% CI 10-19 months) of the matched solitary glioblastoma group (p = 0.02, log-rank test). Two-year survival rates were 4.3% for patients with multifocal tumors and 29.0% for the unifocal cohort. Patients with newly diagnosed multifocal tumors were found to have an almost 2-fold increase in the hazard of death compared with patients with solitary glioblastoma (hazard ratio 1.8, 95% CI 1.1-3.1; p = 0.02). Tumor samples were analyzed for expression of phosphorylated mitogen-activated protein kinase, phosphatase and tensin homolog, O(6)-methylguanine-DNA methyltransferase, laminin β1 and β2, as well as epidermal growth factor receptor amplification, and no significant differences in expression profile between the multifocal and solitary glioblastoma groups was found. CONCLUSIONS Patients with newly diagnosed multifocal glioblastoma on presentation experience significantly worse survival than patients with solitary glioblastoma. Patients with multifocal tumors continue to pose a therapeutic challenge in the temozolomide era and magnify the challenges faced while treating patients with malignant gliomas.

Longitudinal Impedance Variability in Patients with Chronically Implanted DBS Devices

BACKGROUND Deep brain stimulation (DBS) is an effective therapy for advanced movement disorders, but its optimal use is still controversial. One factor that could play a role in the proper delivery of therapeutic stimulation by current DBS devices is the variability of the impedance at the interface between the electrode surface and surrounding tissue. OBJECTIVE To analyze variability and trends in the impedance of chronically-implanted DBS electrodes in subjects with movement disorders. METHODS We reviewed impedance values from medical records of DBS patients at an academic tertiary-care movement disorders center. The standard deviation of data recorded within individual subjects and single contacts were used as measures of longitudinal impedance variability. A generalized linear mixed model (GLMM) determined if a number of effects had significant influences on impedance. RESULTS We analyzed 2863 impedance measurements from 94 subjects. Median variability, for subjects with follow-up from 6 months to 5 years (n = 77), was 194 Ω for individual subjects and 141 Ω for individual contacts, with a range spanning from 18 to over 600 Ω. The GLMM, incorporating all subjects (n = 94), identified time, electrical activity, implanted target, contact position on the electrode and side of implantation as significant predictors of impedance. Age and disease duration at surgery, gender or ethnicity were not significant predictors. CONCLUSIONS Our analysis suggests that a significant amount of impedance variability can be expected in chronically implanted DBS electrodes and indicates a number of factors with possible predictive value. Further studies are needed to link impedance characteristics to clinical outcomes.

Unplanned readmissions and survival following brain tumor surgery.

OBJECT Research on readmissions has been influenced by efforts to reduce hospital cost and avoid penalties stipulated by the Centers for Medicare and Medicaid Services. Less emphasis has been placed on understanding these readmissions and their impact on patient outcomes. This study 1) delineates reasons for readmission, 2) explores factors associated with readmissions, and 3) describes their impact on the survival of glioblastoma patients. METHODS The authors conducted a retrospective review of 362 cases involving patients with glioblastoma undergoing biopsy or tumor resection at their institution between 2003 and 2011. Reasons for re-hospitalization were characterized according to whether or not they were related to surgery and considered preventable. Multivariate analyses were conducted to identify the effect of readmission on survival and determine factors associated with re-hospitalizations. RESULTS Twenty-seven (7.5%) of 362 patients experienced unplanned readmissions within 30 days of surgery. Six patients (22.2%) were readmitted by Day 7, 14 (51.9%) by Day 14, and 20 (74.1%) by Day 21. Neurological, infectious, and thromboembolic complications were leading reasons for readmission, accounting for, respectively, 37.0%, 29.6%, and 22.2% of unplanned readmissions. Twenty-one (77.8%) of the 27 readmissions were related to surgery and 19 (70.4%) were preventable. The adjusted hazard ratio of mortality associated with a readmission was 2.03 (95% CI 1.3-3.1). Higher-functioning patients (OR 0.96, 95% CI 0.9-1.0) and patients discharged home (OR 0.21, 95% CI 0.1-0.6) were less likely to get readmitted. CONCLUSIONS An overwhelming fraction of documented unplanned readmissions were considered preventable and related to surgery. Patients who were readmitted to the hospital within 30 days of surgery had twice the risk of mortality compared with patients who were not readmitted.

Survival and prognostic factors of anaplastic gliomas.

BACKGROUND The prognosis of patients with anaplastic glioma tumors is relatively favorable compared with patients with glioblastoma multiforme. OBJECTIVE To estimate survival differences between anaplastic astrocytoma (AA) and anaplastic oligodendroglioma (AO) patients and factors associated with survival prognosis. METHODS A nationwide cohort of grade III glioma patients diagnosed between 1990 and 2008 was studied using the Surveillance, Epidemiology, and End Results registry. Multivariate Cox proportional hazard models evaluated the role of patient and clinical characteristics on overall survival. RESULTS A total of 1766 patients with AA and 570 patients with AO were studied. The median overall survival was 15 and 42 months among AA and AO patients, respectively. Age increments of 10 years implicated a 50% increase in mortality hazards among AA (hazard ratio [HR], 1.49; P < .001) and AO (HR, 1.51; P < .001) patients. Among AA patients, radiation (HR, 0.62; P < .001), surgery (vs biopsy; HR, 0.73; P < .001), female sex (HR, 0.87; P = .02), and married status (HR, 0.87; P = .02) were associated with a reduction in the hazard of mortality. Longer survival if diagnosed in 2000 relative to 1990 was observed (HR, 0.84; P = .004) in AA patients. Although surgery did not significantly improve survival among AO patients, gross total resection increased the median survival from 40 to 61 months (P = .001) in this cohort. CONCLUSION First-course radiation, younger age, female sex, treatment in recent years, and surgery were associated with improved survival in AA patients. In contrast, age was the most prominent predictor of survival in AO patients. Surgery alone did not seem to benefit AO patients, and gross total resection improved survival by 21 months.

Substance P (SP)-Neurokinin-1 Receptor (NK-1R) Alters Adipose Tissue Responses to High-Fat Diet and Insulin Action

Peripheral administration of a specific neurokinin-1 receptor (NK-1R) antagonist to mice leads to reduced weight gain and circulating levels of insulin and leptin after high-fat diet (HFD). Here, we assessed the contribution of substance P (SP) and NK-1R in diet-induced obesity using NK-1R deficient [knockout (KO)] mice and extended our previous findings to show the effects of SP-NK-1R interactions on adipose tissue-associated insulin signaling and glucose metabolic responses. NK-1R KO and wild-type (WT) littermates were fed a HFD for 3 wk, and obesity-associated responses were determined. Compared with WT, NK-1 KO mice show reduced weight gain and circulating levels of leptin and insulin in response to HFD. Adiponectin receptor mRNA levels are higher in mesenteric fat and liver in NK-1 KO animals compared with WT, after HFD. Mesenteric fat from NK-1R KO mice fed with HFD has reduced stress-activated protein kinase/c-Jun N-terminal kinase and protein kinase C activation compared with WT mice. After glucose challenge, NK-1R KO mice remove glucose from the circulation more efficiently than WT and pair-fed controls, suggesting an additional peripheral effect of NK-1R-mediated signaling on glucose metabolism. Glucose uptake experiments in isolated rat adipocytes showed that SP directly inhibits insulin-mediated glucose uptake. Our results further establish a role for SP-NK-1R interactions in adipose tissue responses, specifically as they relate to obesity-associated pathologies such as glucose intolerance and insulin resistance. Our results highlight this pathway as an important therapeutic approach for type 2 diabetes.

The Impact of Inpatient Rehabilitation on Function and Survival of Newly Diagnosed Patients With Glioblastoma

To examine the impact of an inpatient rehabilitation program on functional improvement and survival among patients with newly diagnosed glioblastoma multiforme (GBM) who underwent surgical resection of the brain tumor.