Tumor-Infiltrating T Cells Correlate with NY-ESO-1-Specific Autoantibodies in Ovarian Cancer

BACKGROUND: Tumor-infiltrating CD8+ T cells are correlated with prolonged progression-free and overall survival in epithelial ovarian cancer (EOC). A significant fraction of EOC patients mount autoantibody responses to various tumor antigens, however the relationship between autoantibodies and tumor-infiltrating T cells has not been investigated in EOC or any other human cancer. We hypothesized that autoantibody and T cell responses may be correlated in EOC and directed toward the same antigens. METHODOLOGY AND PRINCIPAL FINDINGS: We obtained matched serum and tumor tissue from 35 patients with high-grade serous ovarian cancer. Serum samples were assessed by ELISA for autoantibodies to the common tumor antigen NY-ESO-1. Tumor tissue was examined by immunohistochemistry for expression of NY-ESO-1, various T cell markers (CD3, CD4, CD8, CD25, FoxP3, TIA-1 and Granzyme B) and other immunological markers (CD20, MHC class I and MHC class II). Lymphocytic infiltrates varied widely among tumors and included cells positive for CD3, CD8, TIA-1, CD25, FoxP3 and CD4. Twenty-six percent (9/35) of patients demonstrated serum IgG autoantibodies to NY-ESO-1, which were positively correlated with expression of NY-ESO-1 antigen by tumor cells (r = 0.57, p = 0.0004). Autoantibodies to NY-ESO-1 were associated with increased tumor-infiltrating CD8+, CD4+ and FoxP3+ cells. In an individual HLA-A2+ patient with autoantibodies to NY-ESO-1, CD8+ T cells isolated from solid tumor and ascites were reactive to NY-ESO-1 by IFN-gamma ELISPOT and MHC class I pentamer staining. CONCLUSION AND SIGNIFICANCE: We demonstrate that tumor-specific autoantibodies and tumor-infiltrating T cells are correlated in human cancer and can be directed against the same target antigen. This implies that autoantibodies may collaborate with tumor-infiltrating T cells to influence clinical outcomes in EOC. Furthermore, serological screening methods may prove useful for identifying clinically relevant T cell antigens for immunotherapy

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

Factors influencing the incidence of lamotrigine-related skin rash

OBJECTIVE: To determine the incidences of serious and nonserious lamotrigine-related rash, determine the risk factors for lamotrigine-related rash, and evaluate the impact on the incidence of rash of the manufacturer's recommendation to reduce the starting dose of lamotrigine. METHODS: This was a retrospective case record survey at five tertiary referral epilepsy centers in the UK. The risk factors for lamotrigine-related rash were identified by logistic regression. The independent factors tested were gender, age, epilepsy type, concurrent medication, and starting dose of lamotrigine. The incidences of rash before and after the recommendation of reduction in starting dose were compared by χ 2 analysis. RESULTS: A total of 1050 patients were included. The incidences of serious and nonserious rash were 1.1% (95% CI 0.5% to 1.8%) and 7% (95% CI 5.5% to 8.6%), respectively. Females were at higher risk of developing rash than were males, with a relative risk of 1.8 (95% CI 1.2 to 2.8). The starting dose of lamotrigine was reduced in response to the manufacturer's recommendation, and there was a significant reduction (p = 0.045) in the incidence of serious rash, from 1.5% (12/805) to 0% (0/245). However, there was no reduction in the overall incidence of lamotrigine-related rash, with 63/805 (8%) before and 23/245 (9%) after the recommendation. CONCLUSIONS: Failure to detect a reduction in the incidence of lamotrigine-related rash since the new (reduced) recommended starting dose of lamotrigine may arise from failure to reduce the starting dose below a critical threshold level, incomplete compliance with current recommendations, or insufficient sample size. The results of this and other studies show that the starting dose of lamotrigine is a significant factor affecting the incidence of rash; furthermore, this study also shows that significant reduction in the incidence of serious rash can be achieved by reducing the starting dose. Therefore, clinicians should not deviate from the recommendations.link_to_subscribed_fulltex

Adverse event monitoring in lamotrigine patients: A pharmacoepidemiologic study in the United Kingdom

Purpose: This postmarketing surveillance study of lamotrigine (LTG) was performed to provide complementary data to large-scale Prescription-Event Monitoring study with a retrospective case records survey in five tertiary referral epilepsy centres in the United Kingdom. Methods: Adverse events were recorded and compared with those of two other new antiepileptic drugs (AEDs), gabapentin (GBP) and vigabatrin (VGB). All deaths were followed up and standardised mortality ratios (SMRs) were calculated. Serious adverse events were assessed individually. Results: A total of 2.701 patients was identified as being exposed to LTG and/or the comparators. It was necessary to exclude 1,326 patients because LTG and/or comparators had been commenced outside the study centres. The adverse events with LTG reported by this study were similar to those reported in the literature. Skin rash was the major adverse event. Life-threatening hepatic failure, acute exacerbation of ulcerative colitis, disseminated intravascular coagulation, and renal failure were reported. No death could be directly attributed to the use of LTG. The SMR was slightly higher than that reported in the literature: this probably reflects severity of epilepsy in the study population. Conclusions: The safety profile of LTG was similar to that in the large-scale Prescription-Event Monitoring study and generally acceptable. Life-threatening adverse reactions were rare.link_to_subscribed_fulltex

A pharmacoepidemiologic study of factors influencing the outcome of treatment with lamotrigine in chronic epilepsy

Purpose: To identify prognostic factors for freedom from seizures and long-term retention of treatment in patients receiving lamotrigine (LTG). Methods: A multicenter, retrospective, case record study of 1,050 patients with chronic epilepsy was carried out. Logistic regression and Cox regression analyses were used to identify clinical features associated with freedom from seizures and retention of treatment, respectively. Long-term retention rates of LTG therapy were estimated using Kaplan-Meier survival analysis. Results: The 1,050 patients with chronic epilepsy were included in the study. Patients with generalized epilepsy (p = 0.01), who were not receiving carbamazepine (CBZ; p = 0.02) were more likely to become seizure-free. Sixty percent of patients continued on LTG therapy >1 year and estimated retention at 8 years was 38%. Patients with generalized epilepsy (p = 0.002), patients receiving concurrent sodium valproate (VPA; p < 0.0001), those not previously exposed to gabapentin and vigabatrin (p < 0.0001), and those in whom the starting dose was lower (p < 0.0012), were more likely to remain on long-term treatment with LTG. The relationships with exposure to other antiepileptic drugs remained significant in patients with focal and with generalized epilepsy when considered separately. Conclusions: The best results from LTG treatment in terms of freedom from seizures and long-term retention of treatment were obtained in patients with generalized epilepsy. Retention of treatment was enhanced by VPA not only in generalized but also in focal epilepsy. The importance of a low starting dose of LTG was again confirmed. The apparent negative effect of CBZ in patients taking LTG merits further investigation.link_to_subscribed_fulltex

The long-term use of gabapentin, lamotrigine, and vigabatrin in patients with chronic epilepsy

Purpose: To compare the long-term retention of gabapentin (GBP), lamotrigine (LTG), and vigabatrin (VGB) by patients with chronic epilepsy and the reasons for treatment discontinuation. To assess the likelihood of seizure freedom, seizure-related injury/hospital admission and mortality after these drags were commenced. Methods: This was a retrospective case- records survey in five tertiary referral epilepsy centres in the U.K. The retention times on treatment (from initiation to discontinuation) for the different antiepileptic drugs (AEDs) were compared by using Kaplan-Meier survival analysis and Cox regression. Incidences of seizure freedom and seizure-related injury/hospital admissions and standardised mortality ratios were calculated. Results: There were 1,375 patients with chronic epilepsy included; 361 were taking GBP, 1,050 LTG, and 713 VGB. The retention of GBP, LTG, or VGB was <40% at 6 years. Fewer than 4% of patients become seizure free while taking one of the drugs. There was no reduction in mortality or seizure-related injury/admission. Conclusions: The impact of these new AEDs on chronic epilepsy can be described only as modest. This view may be revised, however, as more experience is gained with new drugs in previously untreated patients.link_to_subscribed_fulltex

Severe persistent visual field constriction associated with vigabatrin (multiple letters) [7]

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