Leptomeningeal Gliomatosis: A Single Institution Study of 31 Patients.

BACKGROUND/AIM: Secondary leptomeningeal gliomatosis (LG) is a rare and severe progression pattern of glioma. Our objective was to evaluate the characteristics and outcome of patients with LG. PATIENTS AND METHODS: We retrospectively reviewed 31 patients diagnosed with secondary LG. At the time of LG diagnosis, the median age of patients was 45 years. The histological grade was IV in 20 patients and II to III in 11 patients. As a first-line of therapy for LG, 22 patients received an oncological treatment: i) BCNU-temozolomide (TMZ) (n=15), ii) other type of chemotherapy (n=7), and iii) no treatment (supportive care) (n=9). RESULTS: Following LG diagnosis, the median progression-free survival (PFS) and overall survival (OS) were 1.8 months [95% confidence interval (CI)=0.9-2.7] and 2.1 months (95%CI=1.3-3), respectively. The univariate analyses showed an improved OS with age of less than 45 years (p<0.001), a prolonged interval from the initial glioma diagnosis (IGD) to LG diagnosis (p=0.003), BCNU-TMZ as the preferred first-line treatment for LG out of the three options (p=0.008), and Karnofsky performance status (KPS) ≥70 (p=0.012). Prolonged interval from IGD to LG diagnosis (HR=5.839) and BCNU-TMZ as the chosen first-line treatment for LG (HR=6.635) remained significant in the multivariate analyses as well. Among the 22 treated patients, the median OS was significantly higher (p=0.008) with the BCNU-TMZ treatment (5.7 months; 95%CI=4.2-7.1), compared to other types of treatment offered (2 months; 95%CI=1.1-2.9). CONCLUSION: The time interval from the IGD to the LG diagnosis is a potential prognostic factor for LG. BCNU-TMZ may be a therapeutic option in the present setting.

Takayasu disease presenting as malignant pyoderma gangrenosum in a child with relapsing polychondritis.

A 7-year-old Lebanese girl with recently diagnosed relapsing polychondritis had a 1-month history of several painful ulcerations involving her entire body. Skin biopsy was consistent with the diagnosis of pyoderma gangrenosum. She was hospitalized and started on intravenous steroids with partial improvement. During her hospital stay, she developed right wrist drop. Radiologic studies revealed a large aortic aneurysm and an axillary aneurysm compressing the right brachial nerve plexus. Pathology of the resected aortic anyeurism confirmed the diagnosis of Takayasu's arteritis. The patient was started on infliximab therapy with complete resolution of her skin lesions and improvement in hand function.

Relationships Between Dose Intensity, Toxicity, and Outcome in Patients with Oligodendroglial Tumors Treated with the PCV Regimen.

BACKGROUND/AIM: The drug combination of procarbazine, lomustine (CCNU) and vincristine (PCV) has been associated with efficacy in oligodendroglial gliomas (OG) when added to radiotherapy as the first line of treatment, despite the important toxicity of this treatment schedule. The aim of the present study was to analyze the tolerance, feasibility and impact of the dose intensity of the PCV regimen on outcome for patients with OG. PATIENTS AND METHODS: We retrospectively reviewed all patients with OG receiving PCV (CCNU=110 mg/m(2)) who were referred to our two Institutions. The total dose and dose adaptation, cycle delay, dose intensity, toxicity and discontinuation of CCNU were analyzed. Impacts on the outcome were evaluated. RESULTS: Between 2007 and 2011, 89 patients received PCV. PCV was administered at relapse in 73% of patients. Only 37% completed six cycles, 13.4% discontinued PCV because of toxicity, the other patients discontinued due to tumor progression. Cycle delay and dose reduction were observed for 62% and 70% patients, respectively. Grade 3 and 4 toxicities were observed in 38% and 8% patients, respectively. Among patients whose disease did not progress under the PCV regimen, discontinuation due to toxicity was significantly correlated to poor progression-free survival (PFS: p=0.023, hazard ratio=2.354) and poor overall survival (OS: p=0.021, hazard ratio=5.093). A factor that negatively impacted PFS was the absence of CCNU dose adaptation (p=0.001), while OS was negatively impacted by the absence of cycle delay (p=0.049) and grade 3/4 toxicities (p=0.045). CONCLUSION: Despite the efficacy of the PCV regimen, significant toxicity is associated with this schedule, which appears to impact its feasibility and efficacy. The optimal PCV schedule with the appropriate CCNU dose-intensity adaptation should be redefined taking into account this finding.

Association of matrix metalloproteinase 2 plasma level with response and survival in patients treated with bevacizumab for recurrent high-grade glioma.

BACKGROUND: A predictive marker of bevacizumab activity is an unmet medical need. We evaluated the predictive value of selected circulating prebiomarkers involved in neoangiogenesis and invasion on patient outcome in recurrent high-grade glioma treated with bevacizumab. METHODS: Analyzed in plasma were a set of 11 prebiomakers of interest (vascular endothelial growth factor receptor [VEGF]; VEGF receptor 2; basic fibroblast growth factor; stromal cell derived factor 1; placenta growth factor; urokinase-type plasminogen activator; plasminogen activator inhibitor 1; matrix metalloproteinases 2, 7, and 9; and adrenomedulline), using ELISA, at baseline and 2 weeks after bevacizumab initiation in a prospective cohort of 26 patients (Cohort 1). Correlations were validated in a separate retrospective cohort (Cohort 2; n = 50) and tested in cohort patients treated with cytotoxic agents without bevacizumab (Cohort 3; n = 34). Dosages were correlated to objective response, progression-free survival (PFS), and overall survival (OS). RESULTS: In Cohort 1, high MMP2 baseline level was associated with a probability of objective response of 83.3% versus 15.4% for low MMP2 level (P = .001). In multivariate analysis, baseline level of MMP2 correlated with PFS (hazard ratio, 3.92; 95% confidence interval [CI]:1.46-10.52; P = .007) and OS (hazard ratio, 4.62; 95% CI: 1.58-13.53; P = .005), as decrease of VEGF (P = .038 for PFS and P = .013 for OS) and MMP9 (P = .016 for PFS and P = .025 for OS). In Cohort 2, MMP2, but not MMP9, confirmed its predictive significance. In Cohort 3, no association was found between MMP2, MMP9, and outcome. CONCLUSION: In patients with recurrent high-grade glioma treated with bevacizumab, but not with cytotoxic agent, high MMP2 plasma levels are associated with prolonged tumor control and survival. MMP2 should be tested in randomized clinical trials that evaluate bevacizumab efficacy, and its biological role reassessed.

GJB6, of which mutations underlie Clouston syndrome, is a potential direct target gene of p63.

BACKGROUND: Clouston syndrome is a rare autosomal dominant condition characterized by hypotrichosis, nail dystrophy, and occasionally palmoplantar keratoderma. The disease is caused by mutations in GJB6 gene, which encodes a gap junction protein connexin 30 (Cx30). OBJECTIVE: To disclose the molecular basis of Clouston syndrome in a Lebanese-German family, and also to determine precise expression of Cx30 in normal skin of humans and mice, as well as transcriptional regulation for the GJB6 expression. METHODS: We searched for mutations in the GJB6 gene using DNA of the family members with Clouston syndrome. We performed immunostaining to localize the Cx30 expression in normal human skin and mouse embryos. In addition, we did a series of in vitro studies to investigate if the GJB6 could be a direct transcriptional target gene of p63. RESULTS: We identified a recurrent heterozygous mutation c.31G>C (p.Gly11Arg) in the GJB6 gene in the Lebanese-German family with Clouston syndrome. Immunostaining in normal human skin sections demonstrated predominant expression of Cx30 in hair follicles, nails, and palmoplantar epidermis, which partially overlapped with p63 expression. We also showed co-expression of Cx30 and p63 in developing mouse hair follicles and nail units. In cultured cells, the GJB6 expression was significantly upregulated by ΔNp63α isoform. Further in vitro analyses suggested that ΔNp63α was potentially involved in the GJB6 expression via binding to the sequences in intron 1 of the GJB6 gene. CONCLUSION: Our data further underscore the crucial roles of Cx30 in morphogenesis and development of skin and its appendages.

Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: an ANOCEF phase II trial.

PURPOSE: The management of glioblastoma multiforme (GBM) in elderly patients with poor performance status is not well established. A trial evaluating the efficacy and safety of temozolomide alone in this population was undertaken. PATIENTS AND METHODS: Patients age 70 years or older with newly diagnosed GBM and postoperative Karnofsky performance score (KPS) less than 70 were eligible for this nonrandomized phase II trial. Treatment consisted of 150 to 200 mg/m(2)/d temozolomide for 5 days every 4 weeks until disease progression. Radiotherapy was not administered. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), safety, quality of life, and cognition. RESULTS: Seventy patients (median age, 77 years; median KPS, 60) were enrolled between July 2007 and February 2009. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 13% and 14% of patients, respectively. Median PFS was 16 weeks (95% CI, 10 to 20 weeks), and median OS was 25 weeks (95% CI, 19 to 28 weeks), comparing favorably with a 12- to 16-week OS expected from a purely supportive approach. Twenty-three patients (33%) improved their KPS by 10 or more points, and 18 (26%) became capable of self-care (KPS ≥ 70). Overall quality of life and cognition improved over time before disease progression. In the 31 tumors evaluated for O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, a methylated status indicated longer PFS (26 v 11 weeks; P = .03) and OS (31 v 19 weeks; P = .03). CONCLUSION: Temozolomide has an acceptable tolerance in elderly patients with GBM and KPS less than 70. It is associated with improvement of functional status in 33% of patients and appears to increase survival compared with supportive care alone, especially in patients with methylated MGMT promoter.