Impact of the per-operatory application of GLIADEL wafers (BCNU, carmustine) in combination with temozolomide and radiotherapy in patients with glioblastoma multiforme: Efficacy and toxicity

Purpose

For the last few years wafers of Gliadel have been inserted into the operation cavity in patients with glioblastoma multiforme. This is followed by concurrent radio-chemotherapy with temozolomide (TMZ) according to the Stupp protocol. Only a few studies have investigated this kind of treatment regimen and the impact in terms of survival and toxicity of the combination of Gliadel with TMZ and radiotherapy.

Methods and materials

From November 2006 to January 2010, 24 patients with a newly diagnosed glioblastoma have undergone a tumour resection which was considered to be macroscopically complete in 12 cases and with tumour residue in another 12 cases. The mean age at the moment of diagnosis was 60.25 years and the median age 63.Twenty-three patients underwent subsequently concurrent radio-chemotherapy with TMZ followed by cycles of elevated doses of TMZ as an adjuvant treatment. One patient had adjuvant radiotherapy alone followed by adjuvant chemotherapy. Thirteen were able to receive 6 or more cycles of adjuvant TMZ. Seven patients had received less than 6 cycles of TMZ as an adjuvant therapy. Two patients did not receive adjuvant TMZ at all.

Results

The median overall survival of our group was 19.2 months and the median progression free survival was 12.3 months. Overall survival for the macroscopically complete-resection patients was 14 months, and 12.85 months in subtotal-resection patients. The median OS was 14.25 months for patients PS 0 – 1 at the moment of diagnosis and 12.65 for PS 2 patients. Chemotherapy with TMZ had to be stopped prematurely in 10 cases due to haematotoxicity, digestive toxicity or early relapse.

Conclusions

The concomitant use of surgery with implantation of BCNU wafers and radio-chemotherapy seems to be well tolerated. Despite the small number of patients treated in our group, particular attention should be paid to the potential haematological consequences of this multimodal treatment regimen.     

Clinical outcome of concomitant chemoradiotherapy followed by adjuvant temozolomide therapy for glioblastaomas: Single-center experience

Introduction

The use of radiotherapy plus temozolomide administered concomitantly with and after radiotherapy for glioblastoma was recently shown to improve median and 2-year survival in a large international multicenter study. To compare this result in routine clinical practice, an audit of the management and outcome of patients with glioblastoma at our institute was performed.

Methods

A total of 79 patients with pathologically confirmed glioblastoma were treated with radiotherapy (daily fractions of 2 Gy for a total of 60 Gy) combined with temozolomide at a dose of 75 mg/m² per day, followed by 6 cycles of adjuvant temozolomide (150–200 mg/m², 5 consecutive days per month). The primary end point was overall survival (OS). Secondary endpoints included progression-free survival (PFS) and toxicity. We evaluated the clinical outcome of concomitant chemoradiotherapy for newly diagnosed glioblastomas at a single institute in Korea.

Results

The median age was 52 years (15–76 years), 47 patients were male and 32 patients were female. 92.4% of the patients had undergone debulking surgery. The median overall survival (OS) was 18.3 months (95% CI, 16.3–20.1 months), and the time to progression was 6.7 months (95% CI, 5.2–8.3 months). The 1-year and 2-year survival rates were 70.1% and 37.1%, respectively. In the retrospective analysis, the patients with a post-operative KPS over 80 showed more prolonged survival than those who had a KPS less 80 (23.1 months vs. 13.4 months; p < 0.001). Age and extent of surgery did not emerge as significant factors. Twenty-four patients (30%) were treated with low-dose continuous temozolomide therapy after the tumor had recurred. Hematologic toxicity was the main adverse effect, occurring in seven patients (8.8%). Patients with lymphopenia were not reported.

Conclusions

This study is the largest study of radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in Korean patients, who share a common genetic feature. The median and 2-year survival outcomes in this study are comparable to the previous reports. However, for the recurrent glioblastomas refractory to temozolomide, further clinical trials using other agents should be studied continuously in the future.     

Hypo-fractionated IMRT for patients with newly diagnosed glioblastoma multiforme: A 6 year single institutional experience

Objectives

Glioblastoma (GBM) is the most common malignant primary brain tumour in adults. Surgery and radiotherapy constitute the cornerstones for the therapeutic management of GBM. The standard treatment today is maximal surgical resection followed by concomitant chemo-radiation therapy followed by adjuvant TMZ according to Stupp protocol. Despite the progress in neurosurgery, radiotherapy and oncology, the prognosis still results poor.In order to reduce the long time of standard treatment, maintaining or improving the clinical results, in our institute we have investigated the effects of hypo-fractionated radiation therapy for patients with GBM.

Patients and methods

Sixty-seven patients affected by GBM who had previously undergone surgical resection (total, subtotal or biopsy) were enrolled between October 2005 and December 2011 in a single institutional study of hypo-fractionated intensity modulated radiation therapy (IMRT) followed or not by adjuvant chemotherapy with TMZ (6–12 cycles). The most important eligibility criteria were: biopsy-proven GBM, KPS ≥ 60, age ≥ 18 years, no previous brain irradiation, informed consensus. Hypo-fractionated IMRT was delivered to a total dose of 25 Gy in 5 fractions prescribed to 70% isodose. Response to treatment, OS, PFS, toxicity and patterns of recurrence were evaluated, and sex, age, type of surgery, Karnofsky performance status, Recursive Partitioning Analysis (RPA) classification, time between surgery and initiation of radiotherapy were evaluated as potential prognostic factors for survival.

Results

All patients have completed the treatment protocol. Median age was 64.5 years (range 41–82 years) with 31 females (46%) and 36 males (54%). Median KPS at time of treatment was 80. The surgery was gross total in 38 patients and subtotal in 14 patients; 15 patients underwent only biopsy.No grade 3–4 acute or late neurotoxicity was observed. With median follow-up of 14.9 months, the median OS and PFS were 13.4 and 7.9 months, respectively.

Conclusions

The hypo-fractionated radiation therapy can be used for patients with GBM, resulting in favourable overall survival, low rates of toxicity and satisfying QoL. Future investigations are needed to determine the optimal fractionation for GBM.     

Anti-aquaporin-4 antibody in Chinese patients with central nervous system inflammatory demyelinating disorders

Objective

To determine seroprevalence of aquaporin-4 (AQP4) antibody in Chinese patients with central nervous system (CNS) inflammatory demyelinating disorders.

Methods

AQP4 antibody was detected by anti-AQP4 antibody assay. We measured seroprevalence in 200 patients with neuromyelitis optica (NMO, n = 44), multiple sclerosis (MS, n = 46), transverse myelitis (TM, n = 44), optic neuritis (ON, n = 13), acute disseminated encephalomyelitis (ADEM, n = 2), and other neurological diseases (OND, n = 51).

Results

AQP4 antibody seropositivity was 88.6% in patients with NMO, 4.3% in patients with MS, 30.8% in patients with ON and 51.7% in patients with LETM (longitudinally extensive TM). No patients with acute partial TM, ADEM, OND were positive for AQP4 antibody. Sensitivity of the test was 88.6% (95% CI 80–95) in patients with NMO. Specificity is 97.9% (95% CI 95.1–100) in 46 MS patients, with 51 OND patients as the control group. If the patients with recurrent ON, LETM were considered high risk for NMO (n = 37) and the remaining patients (n = 119) were considered controls, the sensitivity of this assay would be 48.6% (95% CI 33.4–64.1) and the specificity 97.5% (95% CI 94.7–100).

Conclusion

This study confirms that AQP4 antibody is a sensitive and specific biomarker for discrimination between NMO and other CNS autoimmune diseases.     

Effectiveness of home rehabilitation program for ischemic stroke upon disability and quality of life: a randomized controlled trial

Background

To develop and examine the effectiveness of individual 6-month home rehabilitation program in ischemic stroke patients upon disability and quality of life at 2 years.

Methods

This is a prospective randomized controlled trial (RCT) in 60 patients with recent ischemic stroke. They were randomly assigned to receive either home rehabilitation program once a month for 6 months with audiovisual materials (intervention group) or usual care (control group). We collected outcome data after discharge from the hospital until 2 years. The Barthel index (BI), the modified Rankin Scale (mRS) and utility index (EQ-5D) were measured for function, disability and quality of life respectively.

Results

At 2 years, the BI was significantly improved in the intervention group more than the control group: 97.2 ± 2.8 vs. 76.4 ± 9.4, p < 0.001. The good outcome, defined as BI 95–100, or mRS 0 or 1. For BI, there were 29 patients (96.7%) in intervention group vs 12 patients (42.9%) in usual care group (95% CI, 42.0, 85.0, p = 0.03). For mRS, there were 28 patients (93.3%) in intervention group vs 9 patients (32.1%) in usual care group (95% CI, 38.2, 87.0, p = 0.02). Number needed to treat for good outcome in mRS was 2.0 (95% CI: 1.0, 1.3). The mean (SD) of utility index in intervention group and control group were 0.9 ± 0.02 and 0.7 ± 0.04 respectively (p = 0.03). There was no significant interaction in baseline characteristics and treatment outcome.

Conclusions

Early home rehabilitation program in the first 6 months period after ischemic stroke leads to more rapid improvement in function, reducing disability and increase quality of life than usual care.     

Continuous Low-Dose Temozolomide Chemotherapy and Microvessel Density in Recurrent Glioblastoma

Objective

The purpose of this study was to evaluate the clinical efficacy of continuous low-dose temozolomide (TMZ) chemotherapy for recurrent and TMZ-refractory glioblastoma multiforme (GBM) and to study the relationship between its efficacy and microvessel density within the tumor.

Methods

Thirty patients who had recurrent GBM following Stupp''s regimen received TMZ daily at 50 mg/m²/day until tumor progression between 2007 and 2013. The median duration of continuous low-dose TMZ administration was 8 weeks (range, 2-64).

Results

The median progression-free survival (PFS) of continuous low-dose TMZ therapy was 2 months (range, 0.5-16). At 6 months, PFS was 20%. The median overall survival (OS) from the start of this therapy to death was 6 months (95% CI : 5.1-6.9). Microvessel density of recurrent tumor tissues obtained by reoperation of 17 patients was 22.7±24.1/mm² (mean±standard deviation), and this was lower than that of the initial tumor (61.4±32.7/mm²) (p-value=0.001). It suggests that standard TMZ-chemoradiotherapy reduces the microvessel density within GBM and that recurrences develop in tumor cells with low metabolic burden. The efficacy of continuous low-dose TMZ could not be expected in recurrent GBM cells in poor angiogenic environments.

Conclusion

The efficacy of continuous low-dose TMZ chemotherapy is marginal. This study suggests the need to develop further treatment strategies for recurrent and TMZ-refractory GBM.     

Non-conventional risk factors were associated with infarct patterns in ischemic stroke

Objective

Diffusion-weighted imaging (DWI) infarct patterns can play a useful role in the management of ischemic stroke patients, particularly in identifying index stroke mechanisms. Novel vascular risk factors like high sensitivity C-reactive protein (hs-CRP) and the metabolic syndrome have recently been shown to be of prognostic importance following ischemic stroke. We aimed to determine the relationship between these novel factors and infarct patterns noted on DWI.

Methods

A total of 886 patients with acute cerebral infarcts within the MCA territory were prospectively studied. Using the DWI data the patients were divided into four groups: cortical, small (<1 cm) superficial, border-zone, and deep infarcts patterns. The independent associations of various infarct DWI patterns vs. hs-CRP and presence of the metabolic syndrome were evaluated after adjusting for the confounders.

Results

hs-CRP was highest among patients with cortical infarcts, while the metabolic syndrome was most frequent in patients with border-zone infarcts. Compared to the lowest quartile of hs-CRP level, those in the highest quartile were more likely to have the cortical pattern (OR, 3.55; 95% CI, 1.92–6.56; P < 0.001), and less likely to have the deep infarct pattern (OR, 0.49; 95% CI, 0.29–0.81; P = 0.006) in logistic regression analyses. There was an independent association between presence of the metabolic syndrome and the border-zone pattern (OR, 1.75; 95% CI, 1.12–2.73; P = 0.013).

Conclusions

hs-CRP levels and metabolic derangements are independently associated with infarct pattern in acute ischemic stroke, and may be the potential targets for lessening the clinical impact of certain infarct patterns.     

Postsurgical infection after myelomeningocele repair: a multivariate analysis of 60 consecutive cases

Objective

We investigate the demographic, clinical and surgical variables associated with wound and ventriculoperitoneal (VP) shunt infections in a well-defined group of patients submitted to neurosurgical myelomeningocele repair.

Methods

We analyzed the data of sixty consecutive patients with a myelomeningocele diagnosis submitted to neurosurgical repair between January 2002 and December 2005. Multiple logistic regression analysis identified clinical, demographic and neurosurgical variables that were independently associated with the occurrence of wound and VP shunt infections.

Results

Seven patients (11.7%) developed wound infections after myelomeningocele repair and two (3.3%) presented with sepsis unrelated to the neurosurgical procedures. Forty-six patients (76.7%) received a VP shunt and nine of them (19.6%) had VP shunt infection. There was a non-significant trend (p = 0.09) for a higher association between thoracic than lumbar or sacral topography and the occurrence of any type of infection. Among patients who underwent VP shunt placement, there was a non-significant trend for a higher association between VP shunt infection and thoracic topography compared to lumbar or sacral regions (adjusted OR 4.3; CI 95% 0.7–24.7; p = 0.10). Evans’ index scores higher than 70 were ten times more associated with VP shunt infection (adjusted OR 10.5; CI 95% 1.6–67.4; p = 0.01) than lower scores.

Conclusion

The thoracic topography of myelomeningocele has a trend for a higher association with infection in general and VP shunt infection. Evans’ index scores higher than 70 were independently associated with VP shunt infection.     

Malignant glioma grade 3 and 4: How relevant is timing of radiotherapy?

Aims and background

The aim of this study is to determine prognostic factors that influence further outcome in patients with glioma.

Methods

Between 01/2002 and 08/2008, 153 patients with malignant gliomas of WHO-grade 3 or 4 who were treated with external beam radiotherapy with or without chemotherapy.

Results

In univariate analysis, following factors were ascertained as statistically significant prognostic parameters: grade (p = 0.000), time between operation and radiotherapy >24 days (p = 0.044) for progression-free survival; grade (p = 0.000), age < 58 years (p = 0.001), extent of surgery (p = 0.011), time between operation and radiotherapy >24 days (p = 0.009), overall treatment time >68 days (p = 0.003), use of chemotherapy (p = 0.015) for overall survival. A longer time period between resection and start of radiotherapy showed to be associated with improved outcome. After multivariate analysis, only grade (p = 0.000) remained a statistically significant factor for progression-free and grade (p = 0.000) and use of chemotherapy (p = 0.031) for overall survival.

Conclusions

We were able to recognize grade and use of chemotherapy as statistically significant prognostic determinants, but not time intervals or overall treatment time.     

Factors affecting the diagnostic delay in amyotrophic lateral sclerosis

Background

Although amyotrophic lateral sclerosis (ALS) is a relentlessly progressive disorder, early diagnosis allows a prompt start with the specific drug riluzole and an accurate palliative care planning. ALS at onset may however mimic several disorders, some of them treatable (e.g., multifocal motor neuropathy) or epidemiologically more frequent (e.g., cervical myelopathy).

Objective

To study the delay from onset to diagnosis in a cohort of ALS patients and to the variables that may affect it.

Methods

We performed a retrospective analysis of the diagnostic delays in a cohort of 260 patients affected by ALS (M/F = 1.32) followed at our tertiary referral ALS Center between 2000 and 2007.

Results

The median time from onset to diagnosis was 11 months (range: 6–21) for the whole ALS cohort, 10 months (range: 6–15) in bulbar-onset (n = 65) and 12 months (range: 7–23) in spinal-onset (n = 195) patients (p = 0.3). 31.1% of patients received other diagnoses before ALS and this led to a significant delay of the correct diagnosis in this group (other diagnoses before ALS, n = 81: median delay, 15 months [9.75–24.25] vs ALS, n = 179, median delay, 9 months [6–15.25], p < 0.001).

Conclusions

The diagnostic delay in ALS is about one year, besides the growing number of tertiary centres and the spread of information about the disease through media and internet. Cognitive errors based on an incorrect use of heuristics might represent an important contributing factor. Furthermore, the length of the differential diagnosis from other disorders and delays in referral to the neurologist seems to be positively associated with the delay in diagnosis.     

The incidence of pulmonary embolism (PE) after spinal fusions

Background

Pulmonary embolism (PE) is a rare but serious event that may occur after spinal surgery.

Objective

To correlate PE incidence after spinal arthrodesis with surgical approach, region of spine operated, and primary spinal pathology. To identify PE incidence trends in this population.

Methods

The Nationwide Inpatient Sample was queried using ICD-9 codes (81.01–81.08) for spinal fusion procedures over a 21-year period (1988–2008). Other data points included PE occurrence, surgical approach, spinal region, surgical indication, and mortality. Multivariate and relational analyses were performed.

Results

4,505,556 patients were identified and 9530 had PE (incidence = 0.2%). PE patients had higher odds of combined A/P surgical approaches than posterior approaches (OR = 1.97; 95% CI = 1.66–2.33), and PE incidence was higher in thoracic versus cervical or lumbar fusions (OR = 2.54; 95% CI = 2.14–3.02). PE was more likely with vertebral fracture (OR = 1.85; 95% CI = 1.53–2.23) and SCI with vertebral fracture (OR = 4.59; 95% CI = 3.72–5.70) than without trauma. Between 1988 and 2008, the PE incidence remained stable for patients with intervertebral disk degeneration and scoliosis, but increased for patients with vertebral fracture, and SCI with vertebral fracture. There was greater inpatient mortality with occurrence of a PE (OR = 12.92; 95% CI = 10.55–14.41).

Conclusion

Although the incidence of PE in spinal arthrodesis patients is only 0.2%, there is a higher incidence after combined A/P approaches, thoracic procedures, and trauma surgical procedures. Despite the overall PE incidence remaining stable since 1988, incidence steadily increased among trauma patients. Further research is needed to explain these trends, given the context of changing patient populations and improving surgical techniques and prophylaxis measures. Greater caution and prophylaxis among trauma patients may be warranted.     

Association of genetic polymorphisms in the type II deiodinase gene with bipolar disorder in a subset of Chinese population

Objective

Genetic factors play a critical role in the etiology of bipolar disorder (BPAD). Previous studies suggested an association between thyroid dysfunction and BPAD. We hypothesize that genetic variations in the type II deiodinase (DIO2) gene that possibly alter the bioactivity of thyroid hormones are associated with BPAD.

Method

A case–control association study was conducted in a subset of Chinese Han population. Two single nucleotide polymorphisms (SNP), open reading frame a (ORFa)-Gly3Asp (rs12885300) and Thr92Ala (rs225014) with potential functions on the activity of DIO2, were selected. The frequencies of allele, genotype and haplotype of the two SNPs were compared between the BPAD patients and the control group.

Results

Statistical significance between the BPAD patients and the control group was observed for the allele (χ² = 7.746, P = 0.005, df = 1) and genotype frequencies (χ² = 8.158, P = 0.017, df = 2) at the locus of ORFa-Gly3Asp, and for the allele (χ² = 15.838, P = 7.00e−005, df = 1) and genotype frequencies (χ² = 17.236, P = 0.0002, df = 2) at Thr92Ala. Distribution of allele 3Gly and 92Ala were significantly higher in the BPAD patients, with odds ratios of 1.489 [95% confidence interval (CI) = 1.124–1.973] and 1.616 [95% CI = 1.275–2.048], respectively. Individuals with two copies of the variant 3Gly or 92Ala were at greater risk of BPAD than individuals with one copy (dose–response manner). Haplotypes ORFa-3Asp-92Ala and ORFa-3Gly-92Ala indicated higher susceptibility for BPAD with odds ratios of 3.759 (95% CI = 2.013–7.020) and 1.292 (95% CI = 1.017–1.642), respectively, while ORFa-3Asp-92Thr probably played a protective role with an odds ratio of 0.395 (95% CI = 0.284–0.549).

Conclusion

Data generated from this study supported our hypothesis that genetic variations of the DIO2 gene were associated with BPAD and suggested further consideration on the possible involvement of these functionally active variants in the pathophysiology of BPAD.     

Clinical safety and primary efficacy of bone marrow mesenchymal cell transplantation in subacute spinal cord injured patients

Background

In recent years, some studies were conducted to evaluate the effects of stem cells from different sources on patients with spinal cord injury (SCI). This study was carried out to evaluate the feasibility and therapeutic potential of autologous bone marrow cell (BMC) transplantation in 11 complete spinal cord injured patients at thoracic level.

Methods and materials

This nonrandomized clinical trial compared the results of autologous BMC transplantation into cerebrospinal fluid (CSF) via lumbar puncture (LP) in 11 patients having complete SCI, with 20 patients as control group who received conventional treatment without BMC transplantation. The patients underwent preoperative and follow-up neurological assessments using the American Spinal Injury Association (ASIA) impairment scale. Then, the participants were followed for 12–33 months.

Results

Eleven patients with the mean age of 33.2 ± 8.9 years and 20 patients with the mean age of 33.5 ± 7.2 years were enrolled in the study and in the control group, respectively. None of the patients in the study and control group experienced any adverse reaction and complications, neither after routine treatment nor after cell transplantation. Five patients out of 11 (45.5%) in the study group and three patients in the control group (15%) showed marked recovery, but the result was statistically borderline (P = 0.095).

Conclusion

We conclude that transplantation of autologous BMC via LP is a feasible and safe technique, but at the moment, no clear answer can be given regarding the clinical potential, despite a potential tendency to treat SCI patients, observed through statistics.     

Bandpass filter settings differentially affect measurement of P50 sensory gating in children and adults

Objective

This study investigated the effect of four different bandpass filter settings on measures of the P50 component and the signal-to-noise ratios (SNR) of averaged ERPs obtained from a sensory gating paradigm employing paired-click stimuli.

Methods

Participants were adults (n = 18) 20–55 years old and children (n = 25) 5–10 years old who were free of neurological disorders.

Results

Results show that the filter settings (0.23–75 Hz, 10–50 Hz, 10–75 Hz, and 10–200 Hz) differentially affected the P50 amplitude, noise power and SNR measures of the conditioning and test clicks, and P50 T/C ratios.

Conclusions

The 10–50 Hz filter setting may be optimal in studies that include only adults as these settings resulted in the smallest mean P50 T/C ratio, a reasonable standard deviation (SD) for the ratio, and the highest SNRs. The 10–200 Hz filter may be the best for studying young children as this setting had the smallest mean and SD of P50 T/C ratios for these participants.

Significance

In studies that include both adults and children investigators are advised to use the 10–200 Hz filter setting because the smaller variability of sensory gating in the child group helps ensure better homogeneity of variance measures between the groups.     

Frequency-domain EEG source analysis for acute tonic cold pain perception

Objective

To investigate electrocortical responses to tonic cold pain by frequency-domain electroencephalogram (EEG) source analysis, and to identify potential electrocortical indices of acute tonic pain.

Methods

Scalp EEG data were recorded from 26 healthy subjects under tonic cold pain (CP) and no-pain control (NP) conditions. EEG power spectra and the standardized low-resolution brain electromagnetic tomography (sLORETA) localized EEG cortical sources were compared between the two conditions in five frequency bands: 1–4 Hz, 4–8 Hz, 8–12 Hz, 12–18 Hz and 18–30 Hz.

Results

In line with the EEG power spectral results, the source power significantly differed between the CP and NP conditions in 8–12 Hz (CP < NP) and 18–30 Hz (CP > NP) in extensive brain regions. Besides, there were also significantly different 4–8 Hz and 12–18 Hz source activities between the two conditions. Among the significant source activities, the left medial frontal and left superior frontal 4–8 Hz activities, the anterior cingulate 8–12 Hz activity and the posterior cingulate 12–18 Hz activity showed significant negative correlations with subjective pain ratings.

Conclusions

The brain’s perception of tonic cold pain was characterized by cortical source power changes across different frequency bands in multiple brain regions. Oscillatory activities that significantly correlated with subjective pain ratings were found in the prefrontal and cingulate regions.

Significance

These findings may offer useful measures for objective pain assessment and provide a basis for pain treatment by modulation of neural oscillations at specific frequencies in specific brain regions.     

History of depressive and/or anxiety disorders as a predictor of treatment response: A post hoc analysis of a 12-week, randomized, double-blind, placebo-controlled trial of paroxetine controlled release in patients with fibromyalgia

Background

Despite of a high comorbidity of depressive and/or anxiety disorders with fibromyalgia, information on the clinical implications of this comorbidity is limited but antidepressants are commonly prescribed to treat fibromyalgia in clinical practice. We investigated whether a history of depressive and/or anxiety disorders was associated with response to paroxetine controlled release (CR) in the treatment of fibromyalgia.

Methods

One hundred sixteen (116) fibromyalgia subjects were randomized to receive paroxetine CR or placebo for 12 weeks. The primary outcome was treatment response defined as ≥ 25% reduction in the Fibromyalgia Impact Questionnaire (FIQ) score. In multivariate logistic regression, we determined if a history of depression and/or anxiety disorders was an independent predictor of response to paroxetine CR.

Results

In logistic regression, the history of depression and/or anxiety did not predict treatment response as measured by ≥ 25% reduction in Fibromyalgia Impact Questionnaire (FIQ) score (OR = 0.66, 95% CI = .29–1.49, Wald = 0.97, p = 0.32), while the drug status (paroxetine CR) was significantly associated with treatment response (OR = 2.57, CI = 1.2–5.61, Wald = 5.5, p = 0.02).

Conclusion

A significant proportion of patients with fibromyalgia had a history of anxiety and or depressive disorders. However response to treatment of fibromyalgia symptoms with paroxetine CR was not associated with a history of depressive and/or anxiety disorders. Our findings need to be confirmed in more adequately-powered and well-designed subsequent studies.     

Mismatch negativity and low frequency oscillations in schizophrenia families

Objective

Theta-alpha range oscillations have been associated with MMN in healthy controls. Our previous studies showed that theta-alpha activities are highly heritable in schizophrenia patients’ families. We aimed to test the hypothesis that theta-alpha activities may contribute to MMN in schizophrenia patients and their family members.

Methods

We compared MMN and single trial oscillations during MMN in 95 patients, 75 first-degree relatives, 87 controls, and 34 community subjects with schizophrenia spectrum personality (SSP) traits.

Results

We found that (1) MMN was reduced in patients (p < 0.001) and SSP subjects (p = 0.047) but not in relatives (p = 0.42); (2) there were augmented 1–20 Hz oscillations in patients (p = 0.02 to <0.001) during standard and deviant stimuli; (3) theta-alpha (5–12 Hz) oscillations had the strongest correlation to MMN in controls and relatives (ΔR² = 21.4–23.9%, all p < 0.001), while delta (<5 Hz) showed the strongest correlation to MMN in schizophrenia and SSP trait subjects; and, (4) MMN (h² = 0.56, p = 0.002) and theta-alpha (h² = 0.55, p = 0.004) were heritable traits.

Conclusions

Low frequency oscillations have a robust relationship with MMN and the relationship appears altered by schizophrenia; and schizophrenia patients showed augmented low frequency activities during the MMN paradigm.

Significance

The results encourage investigation of low frequency oscillations to elucidate the neurophysiological pathology underlying MMN abnormalities in schizophrenia.     

Disseminated progression of glioblastoma after treatment with bevacizumab

Objectives

Reports of glioblastoma (GBM) progression following treatment with bevacizumab indicate that a subset of patients develop disseminated, often minimally enhancing tumors that differ from the typical pattern of focal recurrence. We have reviewed our institutional experience with bevacizumab for GBM to evaluate the prognostic factors and outcomes of patients with disseminated progression.

Patients and methods

Medical records of patients treated for GBM at the University of California San Francisco from 2005 to 2009 were reviewed. Patients receiving bevacizumab for focal disease were evaluated and imaging was reviewed to identify patients who progressed in a disseminated pattern. Tumor and treatment factors were compared between focal and disseminated progressors to identify predictive factors for dissemination. Clinical outcomes were compared between progression groups.

Results

Seventy-one patients received adjuvant bevacizumab at some point in their disease course in addition to surgical resection and standard chemoradiotherapy. Of these, 12 patients (17%) had disseminated progression after bevacizumab. There were no differences in patient demographics, surgical treatment, or bevacizumab administration between disseminated and focal progressors. Length of bevacizumab treatment for disseminated progressors trended toward increased time (7.4 vs. 5.4 months) but was not statistically significant (p = 0.1). Although progression-free survival and overall survival did not differ significantly between progression groups (median survival from progression was 3.8 vs. 4.6 months, p = 0.5), over 30% of focal progressors had a subsequent resection and enrollment in a surgically based clinical trial, whereas none of the disseminated progressors had further surgical intervention. Compared to previously published reports of GBM dissemination with and without prior bevacizumab treatment, our patients had a rate of disease dissemination similar to the baseline rate observed in patients treated without bevacizumab.

Conclusion

The risk of dissemination does not appear to be considerably increased due to the use of bevacizumab, and the pattern of disease at progression does not affect subsequent survival. Therefore, the risk of dissemination should not influence the decision to treat with bevacizumab, especially for recurrent disease.     

Comparing efficacy and side effects of a weekly intramuscular biogeneric/biosimilar interferon beta-1a with Avonex in relapsing remitting multiple sclerosis: a double blind randomized clinical trial

Objective

We compared the efficacy and safety of two biosimilar forms of interferon beta-1a in the treatment of multiple sclerosis: Avonex (Biogen Idec, USA) and CinnoVex (CinnaGen, Iran).

Methods

In a double blind randomized clinical trial study 84 patients with relapsing remitting multiple sclerosis (RRMS) with Expanded Disability Status Scale (EDSS) score of 0–5.5 were randomly allocated to two groups of 42 subjects.

Results

Twenty-four patients lost to follow-up. Finally, 31 patients (mean ± SD of age = 33.7 ± 7.0; 7 males and 24 females) in the Avonex and 29 patients (mean ± SD of age = 32.2 ± 9.2; 8 males and 21 females) in the CinnoVex group completed full 24 months of study period. Decrease in EDSS was 1.05 ± 0.24, p = 0.62 in the Avonex and 0.16 ± 0.88, p = 1.0 in the CinnoVex group after 12 months and 0.27 ± 1.05, p = 0.46 in the Avonex and 0.16 ± 1.06, p = 1.0 in the CinnoVex group after 24 months. There was no statistically significant difference in attack number between two groups (1.0 ± 1.2 in Avonex and 1.2 ± 1.3 in CinnoVex; p = 0.46). Volume of T2-weighted lesions on MRI showed a progressive significant increase in the 12th month (28056 ± 23693) in Avonex treated patients compared with first image (16353 ± 11172) (p = 0.01). But number of gadolinium-enhancing lesions in CinnoVex showed statistically significant decrease after 12 months (0.08 ± 0.28 vs. 1.00 ± 1.22; p = 0.03). However, there were no significant differences between groups after 24 months. There were no significant differences between 2 groups regarding frequency and duration of most considerable side effects, as well. Neutralizing antibodies were not positive in any patients.

Conclusion

CinnoVex can be used as a safe and effective alternative to Avonex in treatment of RRMS.