Spinal ganglioglioma is a rare low-grade, slow-growing tumor of the central nervous system affecting mostly children and young adults. After surgery, some patients show tumor recurrence and/or malignant transformation. Gangliogliomas harbor molecular deficiencies such as mutations in the B-rapidly accelerated fibrosarcoma ( BRAF ) gene, resulting in activation of a downstream signaling pathway and cancer development. Vemurafenib is a BRAF inhibitor used to treat patients with BRAF V600E -mutated cancer. Although a few studies have reported the clinical responses in gangliogliomas, the sequence and duration of treatment have not been established. We describe a case of an adult with a progressive BRAF V600E mutant spinal cord ganglioglioma 9 years after surgery who was treated with vemurafenib. This treatment resulted in a partial response within 2 months, which was sustained for more than a year. The patient then decided to stop treatment because of side effects. Despite this decision, the tumor showed no sign of progression 21 months after treatment discontinuation. This is the first reported case of a response to vemurafenib in an adult with progressive spinal cord BRAF V600E -mutated ganglioglioma which was sustained after treatment discontinuation.

INTRODUCTIONTemozolomide and concomitant radiotherapy followed by temozolomide has been used as a standard therapy for the treatment of newly diagnosed glioblastoma multiform since 2005. A search for prognostic factors was conducted in patients with glioblastoma routinely treated by this strategy in our institution.METHODSThis retrospective study included all patients with histologically proven glioblastoma diagnosed between June 1, 2005, and January 1, 2012, in the Franche-Comté region and treated by 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 six cycles of maintenance temozolomide (150–200 mg/m2, five consecutive days per month). The primary aim was to identify prognostic factors associated with overall survival (OS) in this cohort of patients.RESULTSOne hundred three patients were included in this study. The median age was 64 years. The median OS was 13.7 months (95% confidence interval, 12.5–15.9 months). In multivariate analysis, age over 65 years (hazard ratio [HR] = 1.88; P = 0.01), Medical Research Council (MRC) scale 3–4 (HR = 1.62; P = 0.038), and occurrence of postoperative complications (HR = 2.15; P = 0.028) were associated with unfavorable OS.CONCLUSIONSThis study identified three prognostic factors in patients with glioblastoma eligible to the standard chemotherapy and radiotherapy treatment. Age over 65 years, MRC scale 3–4, and occurrence of postoperative complications were associated with unfavorable OS. A simple clinical evaluation including these three factors enables to estimate the patient prognosis. MRC neurological scale could be a useful, quick, and simple measure to assess neurological status in glioblastoma patients.

Fig. 1 Global concordances between local and remote neurologists (top panel), and local and remote non-neurologists (bottom panel) (regression line model, validated by the Kendall coefficient).

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2005 Background: TERT, a subunit of the telomerase complex, is largely expressed in almost all cancers. Among those cancers, glioblastomas (GBM) harbor the highest incidence of activating mutations within the TERT promoter (over 85% of patients). This high incidence underlies the potential role of TERT in oncogenesis, and points out TERT as a highly relevant tumor target in GBM. UCPvax is a therapeutic vaccine composed of two CD4 helper peptides derived from TERT, combined with the montanide adjuvant. We conducted a phase IIa trial to test the immunogenicity, safety and efficacy of UCPvax in patients with newly diagnosed GBM. Methods: Key inclusion criteria were: histologically confirmed, non-mutated IDH1 glioblastoma, unmethylated MGMT promoter status, previous treatment with concomitant radiotherapy and temozolomide (TMZ), Karnofsky Performance status (KPS) ≥ 70%, steroids < 10mg/ day equivalent prednisone, and lymphocytes count ≥ 0.8 x 109/L. One month after completion of radiation/TMZ, patients started UCPvax vaccinations on days 1, 8, 15, 29, 36 and 43, then every two months until tumor progression, without additional cure of TMZ. Peripheral blood mononuclear cells were collected before treatment, at 1 and 2 months after treatment and, at each vaccination boost. The primary endpoint was an anti-TERT specific CD4 T-cell response measured ex vivo in peripheral blood using IFN-gamma ELISPOT at 2 months. Secondary endpoints included safety, overall survival (OS) and progression-free survival (PFS). Results: Thirty-one adult patients (median age 60-yr old, median KPS 90%) were included in this study. All patients received at least one vaccination, and vaccinations were given for 4.5 months on average (min 2– max 14). At baseline, only one patient had a pre-existing anti-TERT CD4 T-cell response (3%). After immunizations, de novo induction and/or amplification of an anti-TERT response were found in 29/30 pts (97%). An epitope spread response against other tumor-associated antigens was detected in 12/25 pts (48%). No severe (grade 3–4) toxicity was attributable to the vaccination. All patients developed local skin reactions (≤ grade 2), 16 patients complained of transient asthenia (≤grade 2), and 13 patients experienced local pain (≤grade 2). In the intent-to-treat population (n=31), the PFS was 8.9 months (95% CI: 7.6–10.6) and the median OS was 17.9 months (95% CI: 16–23). Two years after diagnosis, 26 % of the patients were still alive. OS was significantly improved in the patients developing an epitope spread response vs the others (19.3 vs 15.8 months, respectively, p=0.03). Conclusions: UCPVax is highly immunogenic and provides an interesting OS rate in this population of poor prognosis, unmethylated MGMT GBM patients. These data support further clinical studies of UCPvax in GBM patients. Clinical trial information: NCT04280848 .

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