A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients.

Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 × 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29-75) and median KPS was 90 (70-100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2-47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter.

Antiepileptic drugs for preventing seizures in people with brain tumors.

BACKGROUND: Seizures can present at any time before or after diagnosis of a brain tumor. The risk of seizures varies by tumor type and its location in the brain. For a long time we believed that preventing seizures with antiepileptic drugs (seizure prophylaxis) was effective and necessary, but the supporting evidence was little and mixed. Such evidence was the basis for previous reviews to conclude that seizure prophylaxis was ineffective in people with brain tumors. OBJECTIVES: To estimate the effectiveness of seizure prophylaxis in people with brain tumors, and to estimate the adverse event rates in the identified clinical trials. SEARCH STRATEGY: A search strategy that included free-text and MeSH terms in LILACS, EMBASE, PubMed, CENTRAL, and The Cochrane Library (1966 to 2007). SELECTION CRITERIA: Controlled clinical trials with random allocation, blinded or unblinded, and placebo or observation in the control groups. DATA COLLECTION AND ANALYSIS: We screened the articles, extracted the data, and rated the validity of each trial to assess the risk of bias. Our primary outcome was the occurrence of a first seizure. The secondary outcome was adverse events. We pooled the aggregate data for each outcome into a random-effects model meta-analysis using the relative risk (RR). For adverse events, we also included the number needed to harm (NNH) using the absolute risk increase to compute the NNH. MAIN RESULTS: There was no difference between the treatment interventions and the control groups in preventing a first seizure in participants with brain tumors. The risk of an adverse event was higher for those on antiepileptic drugs than for participants not on antiepileptic drugs (NNH 3; RR 6.10, 95% CI 1.10 to 34.63; P = 0.046). AUTHORS' CONCLUSIONS: The evidence is neutral, neither for nor against seizure prophylaxis, in people with brain tumors. These conclusions apply only for the antiepileptic drugs phenytoin, phenobarbital, and divalproex sodium. The decision to start an antiepileptic drug for seizure prophylaxis is ultimately guided by assessment of individual risk factors and careful discussion with patients.

Systemic administration of local anesthetic agents to relieve neuropathic pain.

BACKGROUND: Lidocaine, mexiletine, tocainide, and flecainide are local anesthetics which give an analgesic effect when administered orally or parenterally. Early reports described the use of intravenous lidocaine or procaine to relieve cancer and postoperative pain (Keats 1951; Gilbert 1951; De Clive-Lowe 1958; Bartlett 1961). Interest reappeared decades later when patient series and clinical trials reported that parenteral lidocaine and its oral analogs tocainide, mexiletine, and flecainide relieved neuropathic pain in some patients (Boas 1982; Lindblom 1984; Petersen 1986; Dunlop 1988; Bach 1990; Awerbuch 1990). With the recent publication of clinical trials with high quality standards, we have reviewed the use of systemic lidocaine and its oral analogs in neuropathic pain to update our knowledge, to measure their benefit and harm, and to better define their role in therapy. OBJECTIVES: To evaluate pain relief and adverse effect rates between systemic local anesthetic-type drugs and other control interventions. SEARCH STRATEGY: We searched MEDLINE (1966 through 15 May 2004), EMBASE (January 1980 to December 2002), Cancer Lit (through 15 December 2002), Cochrane Central Register of Controlled Trials (2nd Quarter, 2004), System for Information on Grey Literature in Europe (SIGLE), and LILACS, from January 1966 through March 2001. We also hand searched conference proceedings, textbooks, original articles and reviews. SELECTION CRITERIA: We included trials with random allocation, that were double blinded, with a parallel or crossover design. The control intervention was a placebo or an analgesic drug for neuropathic pain from any cause. DATA COLLECTION AND ANALYSIS: We collected efficacy and safety data from all published and unpublished trials. We calculated combined effect sizes using continuous and binary data for pain relief and adverse effects as primary and secondary outcome measurements, respectively. MAIN RESULTS: Thirty-two controlled clinical trials met the selection criteria; two were duplicate articles. The treatment drugs were intravenous lidocaine (16 trials), mexiletine (12 trials), lidocaine plus mexiletine sequentially (one trial), and tocainide (one trial). Twenty-one trials were crossover studies, and nine were parallel. Lidocaine and mexiletine were superior to placebo [weighted mean difference (WMD) = -11; 95% CI: -15 to -7; P <0.00001], and limited data showed no difference in efficacy (WMD = -0.6; 95% CI: -7 to 6), or adverse effects versus carbamazepine, amantadine, gabapentin or morphine. In these trials, systemic local anesthetics were safe, with no deaths or life-threatening toxicities. Sensitivity analysis identified data distribution in three trials as a probable source of heterogeneity. There was no publication bias. AUTHORS' CONCLUSIONS: Lidocaine and oral analogs were safe drugs in controlled clinical trials for neuropathic pain, were better than placebo, and were as effective as other analgesics. Future trials should enroll specific diseases and test novel lidocaine analogs with better toxicity profiles. More emphasis is necessary on outcomes measuring patient satisfaction to assess if statistically significant pain relief is clinically meaningful.

Anticonvulsants for neuropathic pain syndromes: mechanisms of action and place in therapy.

Neuropathic pain, a form of chronic pain caused by injury to or disease of the peripheral or central nervous system, is a formidable therapeutic challenge to clinicians because it does not respond well to traditional pain therapies. Our knowledge about the pathogenesis of neuropathic pain has grown significantly over last 2 decades. Basic research with animal and human models of neuropathic pain has shown that a number of pathophysiological and biochemical changes take place in the nervous system as a result of an insult. This property of the nervous system to adapt morphologically and functionally to external stimuli is known as neuroplasticity and plays a crucial role in the onset and maintenance of pain symptoms. Many similarities between the pathophysiological phenomena observed in some epilepsy models and in neuropathic pain models justify the rational for use of anticonvulsant drugs in the symptomatic management of neuropathic pain disorders. Carbamazepine, the first anticonvulsant studied in clinical trials, probably alleviates pain by decreasing conductance in Na+ channels and inhibiting ectopic discharges. Results from clinical trials have been positive in the treatment of trigeminal neuralgia, painful diabetic neuropathy and postherpetic neuralgia. The availability of newer anticonvulsants tested in higher quality clinical trials has marked a new era in the treatment of neuropathic pain. Gabapentin has the most clearly demonstrated analgesic effect for the treatment of neuropathic pain, specifically for treatment of painful diabetic neuropathy and postherpetic neuralgia. Based on the positive results of these studies and its favourable adverse effect profile, gabapentin should be considered the first choice of therapy for neuropathic pain. Evidence for the efficacy of phenytoin as an antinociceptive agent is, at best, weak to modest. Lamotrigine has good potential to modulate and control neuropathic pain, as shown in 2 controlled clinical trials, although another randomised trial showed no effect. There is potential for phenobarbital, clonazepam, valproic acid, topiramate, pregabalin and tiagabine to have antihyperalgesic and antinociceptive activities based on result in animal models of neuropathic pain, but the efficacy of these drugs in the treatment of human neuropathic pain has not yet been fully determined in clinical trials. The role of anticonvulsant drugs in the treatment of neuropathic pain is evolving and has been clearly demonstrated with gabapentin and carbamazepine. Further advances in our understanding of the mechanisms underlying neuropathic pain syndromes and well-designed clinical trials should further the opportunities to establish the role of anticonvulsants in the treatment of neuropathic pain.

Primitive reflexes in a case-control study of patients with advanced human immunodeficiency virus type 1.

This study estimated the frequency of nine primitive reflexes (PR) and assessed their possible clinical value in a group of patients with acquired immunodeficiency syndrome. We studied 78 patients with human inmunodeficiency type 1 (HIV-1) infection in WHO clinical stage 3 or 4 and 81 matched seronegative controls. All participants were examined using a standardized neurological examination and the Mini-Mental State Examination. Cognitive impairment and PR was found in 36% of patients but in none of the controls (P<0.0001; logistic regression odds ratio: 14.7). Overall, PR were 2-36 times more frequent in patients with HIV-1 infection. This association was stronger for the glabellar, snout, Rossolimo, and digital signs. At least two PR were observed in 92% of patients vs. 8% of controls (P<0.0001; 95% confidence interval: 68%-100%; logistic regression odds ratio: 10.8). These data support the association of PR with cognitive decline in patients with advanced HIV-1 infection without overt neurological disease. Larger follow-up studies with multivariate techniques are needed to identify which PRs are useful as indicators of HIV-1-associated cognitive/motor complex and minor neurocognitive disorders.

Validity of colposcopy to identify and grade squamous intraepithelial lesions among Venezuelan women.

To assess the validity of colposcopy to correctly detect and grade squamous intraepithelial lesions (SIL) in Venezuelan women, we did a prospective, nonrandomized and cross sectional study on patients referred with low-grade and high-grade SIL. After a second cervical smear, they were colposcopically evaluated and biopsied. The outcome measures were interobserver variation, sensitivity, specificity, and predictive values. Ninety-nine patients were evaluable. Colposcopy had poor agreement with repeat cervical smears, and moderate to good agreement with conization biopsy (kappa = 0.55; 95% C.I.: 0.45 to 0.65), with a sensitivity of 0.87, a specificity of 0.69, a positive predictive value of 0.85 and a negative predictive value of 0.71 for high-grade SIL. The criterion of colposcopic vascular atypias was accurate enough to detect and grade SIL, showing good agreement with histopathology. Because of the disparity of results in previous reports, only a carefully designed, randomized study will settle this question.

[Nine primitive reflexes in patients with acquired immunodeficiency syndrome (AIDS). Results of a case-control study]. / Nueve reflejos primitivos en enfermos con síndrome de inmunodeficiencia adquirida (SIDA). Resultados de un estudio caso-control.

This study estimated the frequency and assessed the clinical value of nine primitive reflexes (PR) in 78 AIDS cases, comparing them with 81 matched, seronegative controls. All subjects were evaluated with a standardized neurologic examination that included a Mini-Mental State Exam (MMSE). Fifty-six percent had cognitive impairment and PR. Overall, PR were 2-36 times more frequent in cases. Such association was univariately stronger for the glabellar, snout, and Rossolimo signs. Ninety-two percent of cases had > or = 2 PR vs. 8% of controls, who had up to 2 PR (p < 0.0001; 95 CI: 68% to 100%). We were able isolate or show opportunistic pathogens in CSF of 4 out of 43 cases. This study supports the association of PR to cognitive decline in patients with AIDS. Larger, long term follow-up studies with multivariate analysis in Latin America are needed to identify the PR that can serve as reliable indicators of human immunodeficiency virus type 1 (HIV-1)-associated cognitive/motor complex.

Antibody levels against alpha-galactosyl epitopes in sera of patients with squamous intraepithelial lesions and early invasive cervical carcinoma.

We measured serum levels of anti-Gal(alpha 1-->3)Gal and anti-Gal(alpha 1-->2)Gal antibodies in 89 and 91 women, respectively, by using ELISA. These patients had cervical intraepithelial neoplasia (CIN) grades 1 to 3 and early invasive cervical carcinoma (ICC). Our objective was to compare anti-alpha-galactosyl antibody levels among them and with those of normal controls. High levels of anti-Gal(alpha 1-->2)Gal antibodies were detected in 22% of patients (P = 0.006). The mean level was 1.6 times greater than that of controls, without difference among subgroups. Thirty percent of patients had abnormally high anti-Gal levels (P = 0.001). Mean levels were twofold greater than the mean control value. Subsets with human papillomavirus/CIN 1 and CIN 2-3 had high immunoreactivity (P = 0.004). Both antibodies showed a significant correlation (r = 0.53, P < 0.00001). We conclude that 22 to 30% of patients with CIN 1-3 showed significantly high levels of anti-alpha-galactosyl antibodies. This seroreactivity might be related to the abnormal expression of alpha-galactosyl residues at some point of the natural history of human papillomavirus infection of the uterine cervix, suggesting an active immune response by natural antibodies against this virus. Further studies are needed to determine whether anti-alpha-galactosyl antibodies confer protection in human papillomavirus infection.

Multivariate analysis of primitive reflexes in patients with human immunodeficiency virus type-1 infection and neurocognitive dysfunction.

To prove that primitive reflexes are independent markers of symptomatic human immunodeficiency virus type-1 (HIV-1) infection, a case-control study was carried out in a tertiary care, university teaching hospital. Thirty HIV-1-positive symptomatic cases, 30 seropositive asymptomatic controls and 30 HIV-1 seronegative controls consented to participate and were selected consecutively. A single examiner blinded to serostatus administered the Mini-Mental State Exam and a structured neurological exam to each participant. Up to 45% of cases had cognitive impairment. The occurrence of neurologic signs between seropositive cases and seropositive controls was similar, but the number of primitive reflexes was significantly higher in cases (P < 0.001). By multivariate discriminant analysis, all primitive reflexes but two correctly classified 83.3% of all participants (P = 0.0013). The model had a positive predictive value of 97% when motor, mood, and cognitive symptoms were added (P = 0.0001). Primitive reflexes were independent predictors of HIV-1 serostatus, especially for those with cognitive dysfunction. Primitive reflexes should be included in future case definitions of HIV-1-related neurocognitive disorders.

Abnormal expression of galactosyl(alpha 1-->3) galactose epitopes in squamous cells of the uterine cervix infected by human papillomavirus.

This study describes the presence of alpha-galactosyl epitopes on 12 cervical biopsy samples with features of human papillomavirus infection (HPV) and different stages of cervical intraepithelial neoplasia. An avidin-biotin-peroxidase assay with a monoclonal antibody recognizing gal(alpha 1-->3)gal residues was strongly positive in 5 of 12 cases. None of the controls stained (p = 0.02). Immunostaining was intense in the areas with the highest viral load (koilocytes and keratinocytes) and absent in malignant foci. Immunostaining was also absent in normal exo- and endocervical epithelium of 12 controls with no features of HPV infection. A faint background staining in cases and controls was evident, but similar. These initial findings suggest that alpha-galactosyl epitopes are expressed in cervical squamous cells infected with HPV, turning them vulnerable to lysis by natural anti-alpha-galactosyl antibodies.