Health-related quality of life and cognitive failures in patients with lower-grade gliomas treated with radiotherapy.

PURPOSE: Patients with lower grade (grade 2 and 3) glioma (LGG) frequently experience prolonged clinical course after multimodal therapy (including surgery, radiotherapy (RT), and chemotherapy). There is therefore significant concern about the potential long-term impact of the disease and treatments on quality of life (QOL) and cognitive functioning. In this context, we evaluated health related QOL and cognitive failures in LGG patients previously treated in our RT department. PATIENTS AND METHODS: Adult LGG patients previously treated with RT were prospectively included. Patients were evaluated based on standardized questionnaires [i.e., EORTC QLQ-C30, EORTC QLQ-BN20, and cognitive failures questionnaire (CFQ)]. RESULTS: Forty-eight patients were included. Median time elapsed since the end of RT was 59.5 months (range: 4-297). Based on EORTC QLQ-C30 and QLQ-BN20, the most prevalent HRQOL issues were impaired cognitive functioning (50% of the patients), impaired emotional functioning (47.9%), financial difficulties (43.7%), fatigue (43.7%), future uncertainty (39.6%), and impaired physical functioning (35.4%). Based on the CFQ, 35.4% of the patients showed increased tendency to cognitive failures. CONCLUSION: Patients with LGG frequently experience impairments in HRQOL and cognitive failures after treatment (including RT). Further efforts are therefore warranted to improve the QOL and cognitive outcome of these patients.

Glioblastoma surgery with and without intraoperative MRI at 3.0T.

BACKGROUND: Gross total or near total resection (GTR/NTR; resection ≥95%) of glioblastoma (GBM) seems correlated with a longer survival. Intraoperative MRI (ioMRI) is one method to evaluate the extent of resection (EOR) in order to improve it during the same anesthesia. We compared GBM resections using a 3.0T ioMRI and then without considering the EOR, safety, survival and discussed the indications for using this expensive modality. METHODS: Between March 2006 and November 2011, 56 GBM resections were performed using an ioMRI, and 38 without (control group). The only criterion in order to have access to the ioMRI was its availability. We compared the variables EOR, Karnofsky Performance Scale scores and survival in both groups. RESULTS: In the ioMRI group, 15 patients (26.8%) underwent an immediate second resection increasing the GTR rate of 10.7% and the GTR/NTR rate of 8.9%. There was a significant difference between the use of an ioMRI and the control group in reaching a larger EOR (P=0.049, Fisher's exact test). The effect of using the ioMRI or not on the overall survival, with EOR as covariate, was not significant (P=0.147, Likelihood ratio test). However, the EOR alone had a significant effect on survival (P=0.049, Wald test), with a shorter survival for the patients with a partial resection (PR) than a GTR/NTR (Hazard ratio=1.6, 95% CI HR: 1.00-2.69), with a median overall survival of 15.26 months (95% CI: 12.34-19.08) for the GTR/NTR subgroup versus 10.26 months (95% CI: 6.64-15.82) for the PR subgroup. Multivariate regression analysis also identified age, sex and adjuvant chemotherapy as factors significantly associated with overall survival. CONCLUSIONS: A 3.0T ioMRI improved the quality of resection by 17.8% and increased the GTR/NTR rate by 8.9% up to 73.2% without additional morbidity. A GTR/NTR improves survival duration by about 50%. Thus, it remains reasonable to increase the EOR to reach GTR/NTR using an intraoperative control. However, ioMRI should be limited to the cases for which a GTR/NTR seems preoperatively possible.

Influenza A antigen exposure selects dominant Vbeta17+ TCR in human CD8+ cytotoxic T cell responses.

During acute human viral infections, such as influenza A, specific cytotoxic T lymphocytes (CTL) are generated which aid virus clearance. We have observed that in HLA-A*0201+ subjects, CTL expressing Vbeta17+ TCR and recognizing a peptide from the influenza A matrix protein (M1(58-66)) dominate this response. In experimental models of infection such dominance can be due to inheritance of a restricted T cell repertoire or acquired consequent on expansion of CTL bearing an optimum TCR conformation against the MHC-peptide complex. To examine how influenza A infection might influence the development of TCR Vbeta17 expansion, we studied influenza A-specific CTL in a cross-sectional study of 82 HLA-A*0201+ individuals from birth (cord blood) to adulthood. Primary M1(58-66) -specific CTL were detected in cord blood, but their TCR were diverse and depletion of Vbeta17+ cells did not abrogate specific cytotoxicity. In contrast following natural influenza A infection, TCR Vbeta17+ CTL dominated to the extent that only one of nine adult CTL lines retained any functional activity after in vitro depletion of Vbeta17+ CTL. These results suggest that the dominance of Vbeta17+ TCR among adult M1(58-66)-specific CTL results from maturation and focussing of the response driven by exposure to influenza, and have implications for optimum immunization strategies.

Functional differences between influenza A-specific cytotoxic T lymphocyte clones expressing dominant and subdominant TCR.

We have shown that the dominance of CD8+ T cells expressing TCR Vbeta17 in the adult HLA-A*0201-restricted influenza A/M1(58-66)-specific response is acquired following first antigen exposure. Despite the acquired dominance of Vbeta17+ cells, subdominant M1(58-66)-specific clones expressing non-Vbeta17+ TCR persist in all individuals. To determine whether the affinity of the expressed TCR for the HLA-A*0201/M1(58-66) complex could influence functional properties, M1(58-66)-specific clones expressing subdominant (non-Vbeta17+) TCR were compared to cytotoxic T lymphocyte (CTL) clones expressing dominant (Vbeta17+) TCR. The Vbeta17+ CTL required up to 10,000-fold lower amounts of M1 peptide to mediate lysis compared to CTL clones expressing other Vbeta gene segments. All Vbeta17+ CTL clones tested bound HLA-A*0201/M1(58-66) tetramer, but two of three CTL clones expressing other TCR did not bind tetramer. The inability of non-Vbeta17+ CTL to bind tetramer did not correlate with phenotype, CD8 dependence or with cytokine production profiles. This suggests a limitation for the use of tetramers in examining subdominant T cell responses. Together these findings suggest that Vbeta17+ CTL which dominate the HLA-A*0201-restricted CTL response against influenza A are not functionally distinct from subdominant non-Vbeta17+ CTL. The dominance of Vbeta17+ CTL is likely to result from a competitive advantage due to superior CTL avidity for the HLA-A*0201/M1(58-66) complex.

Minocycline-induced lupus: clinical features and response to rechallenge.

OBJECTIVE: To describe the spectrum of clinical features in patients with minocycline-induced lupus (MIL) and determine their response to rechallenge. METHODS: The clinical features and laboratory findings of 23 patients with MIL were recorded. Ten patients were rechallenged, and their C-reactive protein (CRP) levels were monitored. RESULTS: All subjects complained of polyarthralgia; three had metacarpophalangeal and proximal interphalangeal joint synovitis and one had bilateral knee effusions. Elevated hepatic transaminases were noted in eight subjects. Cutaneous vasculitis was a feature in two cases. None had renal or central nervous system disease, although five patients complained of impaired concentration and poor memory and a single patient had a peripheral sensory neuropathy. The following serological abnormalities were detected: antinuclear antibodies (19/23 patients); antibodies to double-stranded DNA (4/23); perinuclear antineutrophil cytoplasmic antibodies (10/15); IgG anti-cardiolipin antibodies (6/23); hypergammaglobulinaemia (12/19). Anti-histone antibodies were negative in 9/9 cases. Rechallenge resulted in rapid recurrence of symptoms and elevation of CRP levels. CONCLUSION: MIL is associated with a wide spectrum of clinical and serological features. The diagnosis can be confirmed by rechallenge, which results in rapid reappearance of symptoms and a rise in CRP.

CD8high+ (CD57+) T cells in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the development and T cell receptor (TCR) usage of CD8+, CD57+ T cells in rheumatoid arthritis (RA) patients. METHODS: Three-color flow cytometry using monoclonal antibodies (MAb) to CD8, CD57 and different TCR V beta gene products. RESULTS: The proportion of CD8+ T cells expressing CD57 (CD57/CD8) was significantly higher in RA patients compared with age-matched controls. Expanded TCR V beta populations were more frequent, and were found in both RA patient-derived CD8high+ (CD57+) and CD8+, CD57- populations. TCR V beta 5+ and TCR V beta 13+ expansions were present at high frequency (5 of 26 and 7 of 26, respectively). TCR V beta expansions in CD8high+ (CD57+) lymphocytes from RA patients were significantly larger than those in age-matched controls (expansion index 2.38 +/- 0.28, n = 41 and 1.63 +/- 0.09, n = 32, respectively), and were stable over time. CONCLUSION: RA leads to an increase in the frequency of expanded CD8+ T cell subsets expressing selected TCR, due to expansion of TCR V beta + populations in CD8high+ (CD57+) T cells. Their restricted TCR usage suggests potential specificity for RA antigens and, therefore, a potential role in the pathogenesis of RA.

Stroke and transient ischaemic attacks in association with substance abuse in a young man.

A 22-year-old man with a five-year history of drug and alcohol abuse presented with a left hemiparesis preceded by three transient ischaemic attacks, two of which occurred whilst smoking cannabis. Substance abuse was the only identifiable risk factor for cerebrovascular disease.

Silent myocardial infarction in Wegener's granulomatosis.

Histological cardiac abnormalities in Wegener's granulomatosis can frequently be demonstrated at post-mortem examination, but clinically significant cardiac involvement is rare. We describe a massive silent myocardial infarction leading to intractable heart failure and death in a young man with Wegener's granulomatosis, occurring at a time when other features of the disease were responding to aggressive immunosuppression.