Emeline Tabouret

FDG-PET predicts survival in recurrent high-grade gliomas treated with bevacizumab and irinotecan

Prognosis of recurrent high-grade glioma (HGG) is poor, although bevacizumab has been documented in that context. This study aimed to determine the independent prognostic value of fluorodeoxyglucose (FDG)-PET on progression-free survival (PFS) and overall survival (OS) of recurrent HGG after combined treatment with bevacizumab and irinotecan, compared with other documented prognostic variables. Twenty-five adult patients with histologically proven HGG were included at recurrence. Brain FDG-PET imaging was performed within 6 weeks of starting chemotherapy with bevacizumab and irinotecan. Response based on MRI was assessed every 2 months according to revised assessment in Neuro-Oncology (RANO) criteria. Median PFS and OS were 4 months (range, 0.9-10.4 months) and 7.2 months (range, 1.2-41.7 months), respectively. At 6 months, PFS and OS rate were 16.0% and 72.0%. FDG uptake was the most powerful predictor of both PFS and OS, using either univariate or multivariate analysis, among all variables tested: histological grade, Karnofsky performance status, steroid intake, and number of previous treatments. Moreover, FDG uptake was also prognostic of response to bevacizumab-based therapy. This study provides the first evidence that pretreatment FDG-PET can serve as an imaging biomarker in recurrent HGG for predicting survival following anti-angiogenic therapy with bevacizumab.

Reassessment of scoring systems and prognostic factors for metastatic spinal cord compression

BACKGROUND CONTEXT The incidence of metastatic spinal cord compression (MSCC) is increasing, paralleling increasing life expectancy of patients. However, management of MSCC and relevance of scoring systems remain controversial. PURPOSE The aims of our study were to analyze the feasibility and outcomes of spinal surgery, to identify prognostic factors for survival, and to assess the accuracy of scoring systems in patients with malignancies associated with MSCC. STUDY DESIGN Retrospective analysis of all patients with MSCC operated in our institution. METHODS Outcomes of surgery, prognostic factors for survival, and relevance of Tomita and Tokuhashi scores were investigated. RESULTS One hundred forty-eight patients were included: 66% were hyperalgic (pain score >6) and Frankel score (FS) was decreased in 49%. Seventy-three percent of patients had laminectomy with spinal fixation. After surgery, pain decreased in 75% of cases, FS was improved in 31%, and 92% of patients were ambulatory. Postoperative complication rate was 16%. Median overall survival (OS) was 8.9 months (95% confidence interval, 4.4-13). Only Tokuhashi score was relevant, but predictive accuracy of survival was just 51%. In univariate analyses, hyperalgia (p=.001), primary tumor site, extrabone metastases (p<.001), Karnofsky performance status (KPS) less than 70 (p<.001), poor American Society of Anesthesiologist (ASA) score (p<.001) or FS (p=.01), and absence of postoperative chemotherapy (p<.001) were associated with shorter OS. In multivariate analysis, only extrabone metastases (p=.004), KPS (p=.001), and ASA score (p=.007) remained significantly associated with OS. CONCLUSIONS Surgery for MSCC is associated with limited morbidity, improved autonomy, and pain relief. Usual scores do not seem relevant, whereas ASA score, KPS, and extrabone metastases are significantly associated with OS.

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.

Systemic treatments for brain metastases from breast cancer, non-small cell lung cancer, melanoma and renal cell carcinoma: an overview of the literature.

The frequency of metastatic brain tumors has increased over recent years; the primary tumors most involved are breast cancer, lung cancer, melanoma and renal cell carcinoma. While radiation therapy and surgery remain the mainstay treatment in selected patients, new molecular drugs have been developed for brain metastases. Studies so far report interesting results. This review focuses on systemic cytotoxic drugs and, in particular, on new targeted therapies and their clinically relevant activities in brain metastases from solid tumors in adults.

Supratentorial clear cell ependymomas with branching capillaries demonstrate characteristic clinicopathological features and pathological activation of nuclear factor-kappaB signaling

BACKGROUND Clear cell ependymoma is one of the 4 main histological subtypes of ependymomas defined by the World Health Organization (WHO) classification of tumors of the CNS. DNA methylation profiling can distinguish 4 subgroups of intracranial ependymomas, including supratentorial (ST) ependymomas with Yes-associated protein 1 fusion (YAP1), ST ependymomas with fusion of v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), posterior fossa ependymomas with balanced genome, and posterior fossa ependymomas with chromosomal instability. In addition, trisomy 19 is a genomic hallmark of ependymomas with rich branching capillaries. However, the relation of histological and molecular subtypes is unclear. METHODS Here, we report a series of 20 ependymomas histologically defined by clear cells and branching capillaries. RESULTS We observed a strong male predominance. Median age at surgery was 10.4 years (range, 0.8-68.4). All cases were ST, cortical, contrast enhancing, and most often frontal, cystic, and calcified. All tumors qualified as WHO grade III. Some of them exhibited neuronal differentiation. Trisomy 19 was recorded in 13 cases. All samples strongly accumulated p65RelA protein within nuclei, indicating pathological activation of the nuclear factor-kappaB pathway. We identified causative C11ORF95-RELA fusion in almost all cases. Median progression-free survival and overall survival were 11.4 years (95% CI: 5.1-17.8) and not reached, respectively. CONCLUSION ST clear cell ependymomas with branching capillaries display characteristic clinicopathological features and are associated with pathological activation of nuclear factor-kappaB signaling, which may indicate a potential novel target for therapy in these patients.

Rituximab-lenalidomide-dexamethasone induces complete and durable remission in relapsed refractory diffuse large B-cell non-Hodgkin lymphoma.

Since the first and subsequent reports of its efficacy in myelodysplastic syndrome and multiple myeloma, there has been growing interest in lenalidomide as an anti-lymphoma therapy. Data emerging from initial clinical trials has demonstrated that lenalidomide has significant activity against different subtypes of aggressive B-cell lymphoma [1,2]. Two phase 2 studies of lenalidomide monotherapy in patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL; diffuse large B-cell [DLBCL], grade 3 follicular lymphoma, mantle-cell [MCL], and transformed NHL) were conducted in the USA (NHL-002) [3] and internationally (CC-5013-NHL003) [4]. The first study (49 patients) demonstrated a 35% overall response rate (ORR), which included 12% of patients with complete response, and a median duration of response (DR) of 10.4 months. The larger (217 patients) CC-5013-NHL-003 study confirmed these results in a similar patient population. Clinical responses were histologic subtypedependent and most prominent in MCL: ORR was 53%, with 20% CR and 33% PR. Median duration of response was 13.7 months and median progressionfree survival (PFS) was 5.6 months [5]. The results in patients with DLBCL (n1⁄4 108) were less encouraging, with ORR of 28%, short median PFS of 2.3 months, and median DR of 4.5 months. However, given the dismal prognosis of patients with relapsed DLBCL, this activity prompted us to utilize a lenalidomide-based combination in a single patient. Herein we report the case of a patient with DLBCL who was refractory to four previous lines of conventional immuno-chemotherapy, but achieved a remarkable sustained complete remission to treatment using the combination of lenalidomide with rituximab and dexamethasone. A 65-year-old male presented with 2 months’ history of abdominal pain and diarrhea. Colonoscopy revealed a left colon tumor, and biopsy showed histopathological features of DLBCL: proliferation of large immunoblastic and centroblastic cells expressing CD20 but also BCL2 and MUM1 without expression of CD10 and BCL6. The disease was classified by immunochemistry as ‘non-germinal center B-cell’ (non-GCB) according to the Hans decision tree [6]. The patient was staged as Ann Arbor IV, and received eight cycles of standard RCHOP-21 chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, 21day cycle). Complete response was confirmed by fluorodeoxyglucose positron emission tomographycomputed tomography (FDG PET-CT) and biopsy at the end of chemotherapy. The first relapse of DLBCL occurred 7 months later, and was confirmed by a new colon biopsy. The patient received two cycles of R-DHAC-21 (rituximab, carboplatin, cytarabine, and dexamethasone) as second-line treatment. After two cycles, the colonoscopy remained

Predictive biomarkers investigated in glioblastoma

Glioblastoma is the most aggressive primary brain tumor in adults. Consequently, new therapeutic strategies are needed. Tumor response to cytotoxic chemotherapy is heterogeneous across patients. Interestingly, predictive biomarkers of response to these classic chemotherapeutic agents have been identified in neuro-oncology (i.e., 1p/19q co-deletion, IDH mutation and O6-methylguanine DNA-methyltransferase promoter methylation). The most emblematic biomarker in glioblastoma is O6-methylguanine DNA-methyltransferase promoter methylation that predicts response to temozolomide. In parallel, innovative drugs are emerging. Some of these agents have shown some activity but in a limited number of glioblastoma patients. One of the major challenges is to identify molecular predictors of response to these smart drugs for an efficient personalized medicine. These novel agents have been tested in clinical trials enrolling glioblastoma patients. Although none of them has been validated prospectively in Phase III clinical trials, interesting molecular predictors of response to these drugs have been investigated and are presented in this review, which also reports more advanced biomarkers.

MMP2 and MMP9 serum levels are associated with favorable outcome in patients with inflammatory breast cancer treated with bevacizumab-based neoadjuvant chemotherapy in the BEVERLY-2 study

Purpose Addition of bevacizumab to trastuzumab-based neoadjuvant chemotherapy in HER2-positive inflammatory breast cancer (IBC) was associated with favorable outcome in the BEVERLY-2 phase II trial. Circulating levels of matrix metalloproteinases (MMP) 2 and 9 were correlated to high response rate and prolonged survival in high-grade glioma treated with bevacizumab. We examined the prognostic impact of MMP2 and MMP9 serum levels in BEVERLY-2 patients. Experimental design MMP2 and MMP9 serum levels were assessed using ELISA at baseline and before surgery in 45/52 available samples. Correlations were tested with pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Results Baseline (b) MMP2 and MMP9 serum levels were independent from patient characteristics and circulating tumor or endothelial cells, and were not correlated to pCR. High bMMP2 was correlated to better DFS (p=0.001) and OS (p=0.032), while low bMMP9 was correlated to better OS (p=0.022) and tended to be associated with longer DFS (p=0.071). In multivariate analyses, bMMP2 (p=0.003, Hazard Ratio [HR]: 0.115) and bMMP9 (p=0.041, HR: 3.511) remained correlated to DFS. As continuous variables, bMMP2 was associated with relapse (p=0.002) and death (p=0.049), while bMMP9 was associated with death (p=0.035). During treatment, significant increase in MMP2 and decrease in MMP9 levels (p<0.001 for both) were observed in 100% and 87% of patients respectively. Conclusions High bMMP2 and low bMMP9 serum levels were associated with better survival in HER2-positive IBC patients treated with bevacizumab- and trastuzumab-based neoadjuvant chemotherapy. Their predictive value of bevacizumab benefit should be evaluated in a randomized trial.

Assessment of prognostic scores in brain metastases from breast cancer

BACKGROUND Breast cancer (BC) is the second most common cause of brain metastases (BM). Optimal management of BM from BC is still debated. In an attempt to provide appropriate treatment and to assist with optimal patient selection, several specific prognostic classifications for BM from BC have been established. We evaluated the prognostic value and validity of the 6 proposed scoring systems in an independent population of BC patients with BM. METHODS We retrospectively reviewed all consecutive BC patients referred to our institution for newly diagnosed BM between October 1995 and July 2011 (n = 149). Each of the 6 scores proposed for BM from BC (Sperduto, Niwinska, Park, Nieder, Le Scodan, and Claude) was applied to this population. The discriminative ability of each score was assessed using the Brier score and the C-index. Individual prognostic values of clinical and histological factors were analyzed using uni- and multivariate analyses. RESULTS Median overall survival was 15.1 months (95% CI,11.5-18.7). Sperduto-GPA (P < .001), Nieder (P < .001), Park (P < .001), Claude (P < .001), Niwinska (P < .001), and Le Scodan (P = .034) scores all showed significant prognostic value. The Nieder score showed the best discriminative ability (C-index, 0.672; Brier score error reduction, 16.1%). CONCLUSION The majority of prognostic scores were relevant for patients with BM from BC in our independent population, and the Nieder score seems to present the best predictive value but showed a relatively low positive predictive value. Thus, these results remain insufficient and challenge the routine use of these scoring systems.

Primary neurolymphomatosis diagnosis and treatment: A retrospective study

BACKGROUND To discuss the therapeutic approach for primary neurolymphomatosis. METHODS We report all primary neurolymphomatosis cases referred to our institution, with descriptions of clinical, radiological, electrophysiological, histological features and long-term follow-up. We treated all patients with a combination of high-dose methotrexate and alkylating agents. RESULTS Five patients were diagnosed with histologically confirmed primary neurolymphomatosis. The majority of them presented with painful asymmetric sensory-motor neuropathy. Magnetic resonance imaging was abnormal in 4 of 5 patients, as shown with gadolinium enhancements. Electroneuromyography revealed denervation in all 4 cases with contributive examinations. All our patients received a chemotherapy combination of high-dose methotrexate and alkylating agent. Median progression-free survival was 8 months (2 complete responses and 2 partial responses), and overall survival was 24 months. CONCLUSIONS Primary neurolymphomatosis is rare and polymorphic; it represents a difficult diagnosis of neuropathy. In our cohort, treatment with a chemotherapy combination with high-dose methotrexate showed encouraging results.