Marc Polivka

Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions.

PURPOSE To determine the response rate of low-grade oligodendroglial tumors (LGOT) to temozolomide (TMZ) as initial treatment and to evaluate the predictive value of chromosome 1p deletion on the radiologic response. PATIENTS AND METHODS Adult patients with pathologically proven LGOT with progressive disease on magnetic resonance imaging (MRI) were eligible for the study. TMZ was administered at the starting dose of 200 mg/m2/d for 5 days, repeated every 28 days. Response was evaluated clinically and by central review of MRIs. Chromosome 1p and 19q deletions were detected by the loss of heterozygosity technique. RESULTS Sixty consecutive patients were included in the study. At the time of analysis, the median number of TMZ cycles delivered was 11. Clinically, 51% of patients improved, particularly those with uncontrolled epilepsy. The objective radiologic response rate was 31% (17% partial response and 14% minor response), whereas 61% of patients had stable disease and 8% experienced disease progression. The median time to maximum tumor response was 12 months (range, 5 to 20 months). Myelosuppression was the most frequent side effect, with grade 3 to 4 toxicity in 8% of patients. Loss of chromosome 1p was associated with objective tumor response (P < .004). CONCLUSION TMZ is well tolerated and provides a substantial rate of response in LGOT. Chromosome 1p loss is correlated with radiographic response and could be a helpful marker for guiding therapeutic decision making in LGOT.

Temozolomide for low-grade gliomas Predictive impact of 1p/19q loss on response and outcome

Objective: To evaluate the predictive impact of chromosome 1p/19q deletions on the response and outcome of progressive low-grade gliomas (LGG) treated with up-front temozolomide (TMZ) chemotherapy. Methods: Adult patients with measurable, progressive LGG (WHO grade II) treated with TMZ delivered at the conventional schedule (200 mg/m2/day for 5 consecutive days, repeated every 28 days) were retrospectively evaluated for response by central review of MRI-s. Chromosome 1p and 19q deletions were detected by the loss of the heterozygosity technique (LOH). Results: A total of 149 consecutive patients were included in this retrospective, single center observational study. The median number of TMZ cycles delivered was 14 (range 2 to 30). Seventy-seven patients (53%) experienced an objective response (including 22 [15%] cases of partial response and 55 [38%] cases of minor response), 55 (37%) patients had stable disease, and 14 (10%) had a progressive disease. The median time to maximum tumor response was 12 months (range 3 to 30 months). The median progression-free survival (PFS) was 28 months (95% CI: 23.4 to 32.6). Material for genotyping was available for 86 patients. Combined 1p/19q LOH was present in 42% of the cases and was significantly associated with a higher rate (p = 0.02) and longer objective response to chemotherapy (p = 0.017), and both longer PFS (p = 4.10−5) and overall survival (p = 0.04). Conclusion: Low-grade gliomas respond to temozolomide and loss of chromosome 1p/19q predicts both a durable chemosensitivity and a favorable outcome.

Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

Purpose: Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance. Experimental Design: We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n = 29) and whole-exome sequencing (n = 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis. Results: All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P = 0.006 and P = 0.01) and CDKN2A homozygous deletion (P = 0.02 and P = 0.01) were significantly associated with shorter progression-free survival and overall survival. Conclusions: Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-κB signaling pathway, which may be promising targets for future therapeutic strategies. Clin Cancer Res; 18(19); 5203–11. ©2012 AACR.

Chromosome 1p loss: a favorable prognostic factor in low-grade gliomas.

Search for loss of heterozygosity on chromosomes 1p, 9p, 10q, and 19q, epidermal growth factor receptor (EGFR) gene amplification, and p53 expression was performed in a series of 131 low‐grade gliomas. The profile of molecular changes, clinical findings, and histology were subsequently correlated with the course of the disease, mainly progression‐free survival. When these parameters were considered as candidate variables in a multivariate analysis, only loss of heterozygosity on chromosome 1p was associated with increased progression‐free survival (hazard ratio, 0.521), indicating a major favorable prognostic role of this genetic alteration in low‐grade gliomas. Ann Neurol 2005;58:322–326

Prognostic stratification of patients with anaplastic gliomas according to genetic profile.

There is a need to improve the current, controversial, and poorly reproducible classification of anaplastic gliomas, which represent a highly heterogeneous entity in terms of survival.

Contrast enhancement in 1p/19q-codeleted anaplastic oligodendrogliomas is associated with 9p loss, genomic instability, and angiogenic gene expression

BACKGROUND The aim of this study was to correlate MRI features and molecular characteristics in anaplastic oligodendrogliomas (AOs). METHODS The MRI characteristics of 50 AO patients enrolled in the French national network for high-grade oligodendroglial tumors were analyzed. The genomic profiles and IDH mutational statuses were assessed using high-resolution single-nucleotide polymorphism arrays and direct sequencing, respectively. The gene expression profiles of 25 1p/19q-codeleted AOs were studied on Affymetrix expression arrays. RESULTS Most of the cases were frontal lobe contrast-enhanced tumors (52%), but the radiological presentations of these cases were heterogeneous, ranging from low-grade glioma-like aspects (26%) to glioblastoma-like aspects (22%). The 1p/19q codeletion (n = 39) was associated with locations in the frontal lobe (P = .001), with heterogeneous intratumoral signal intensities (P = .003) and with no or nonmeasurable contrast enhancements (P = .01). The IDH wild-type AOs (n = 7) more frequently displayed ringlike contrast enhancements (P = .03) and were more frequently located outside of the frontal lobe (P = .01). However, no specific imaging pattern could be identified for the 1p/19q-codeleted AO or the IDH-mutated AO. Within the 1p/19q-codeleted AO, the contrast enhancement was associated with larger tumor volumes (P = .001), chromosome 9p loss and CDKN2A loss (P = .006), genomic instability (P = .03), and angiogenesis-related gene expression (P < .001), particularly for vascular endothelial growth factor A and angiopoietin 2. CONCLUSION In AOs, the 1p/19q codeletion and the IDH mutation are associated with preferential (but not with specific) imaging characteristics. Within 1p/19q-codeleted AO, imaging heterogeneity is related to additional molecular alterations, especially chromosome 9p loss, which is associated with contrast enhancement and larger tumor volume.

Digestive smooth muscle mitochondrial myopathy in patients with mitochondrial-neuro-gastro-intestinal encephalomyopathy (MNGIE).

We report 3 new cases of Mitochondrial-Neuro-Gastro-Intestinal Encephalomyopathy (MNGIE) (or Pseudo-Obstruction-Leukoencephalopathy-Intestinal-Pseudoobstruction Syndrome [POLIP]), a rare disease that associates chronic intestinal pseudo-obstruction (CIPO) and neurological symptoms. A review of the 72 reported cases together with these 3 cases revealed that this condition was associated with (a) a specific cluster of neurological symptoms including leukoencephalopathy (96%), polyneuropathy (96%), ophthalmoplegia (91%) and hearing loss (55%); (b) a CIPO syndrome with the presence of small bowel diverticulae (53%); and (c) mitochondrial cytopathy in 36 of the 37 tested patients (2 of our 3 cases), and thymidine phosphorylase gene mutations in all the 37 tested patients (2 of our cases). The etiology of POLIP/MNGIE syndrome appears therefore to be due to a mitochondrial cytopathy secondary to thymidine phosphorylase gene mutation(s). In 3 cases, including 2 of our 3 patients, mitochondrial abnormalities were evidenced at the ultrastructural level in digestive smooth muscle demonstrating that the pathogenesis of gastrointestinal involvement was directly related to mitochondrial alterations in digestive smooth muscle cells.

Encephalitis with Infiltration by CD8+ Lymphocytes in HIV Patients Receiving Combination Antiretroviral Treatment

We report the neuropathological findings in 10 HIV‐infected patients treated by combination antiretroviral therapy who developed subacute encephalopathy of rapidly progressive onset. Brain biopsy showed encephalitic lesions variably associated with myelin loss and slight axonal damage. There was inconstant, weak expression of HIV protein p24; tests for other pathogens were negative. The most striking feature was diffuse, perivascular and intraparenchymal infiltration by CD8+ T‐lymphocytes. Six patients improved after the treatment. Four had an unfavorable outcome and died within a year. Post‐mortem in one case confirmed HIV leukoencephalitis with p24‐positive multinucleated giant cells, associated with acute demyelinating encephalomyelitis (ADEM) in the cerebellum. There was diffuse infiltration by CD8+ lymphocytes; CD4+ cells were virtually absent. These cases may represent a specific clinicopathological entity, of which a few comparable cases have been already described. They can be included in the wide framework of immune reconstitution disease. Such syndromes have been described with opportunistic infections, but only seldom with HIV infection of the central nervous system (CNS). Our findings support the hypothesis that CD8+ cytotoxic lymphocytes can be harmful in immune reconstitution disease, particularly in the absence of CD4+ lymphocytes. CD8 cytotoxicity produces an acutization of a smoldering infection and/or an immunopathological reaction similar to ADEM.

Pineocytoma and Pineal Parenchymal Tumors of Intermediate Differentiation Presenting Cytologic Pleomorphism: A Multicenter Study

Cytologic pleomorphism has been described in a limited number of benign pineal tumors, namely pineocytoma (PC) and pineal parenchymal tumors (PPTs) of intermediate differentiation (PPTID). We examined the clinicopathologic features in a retrospective series of 14 cases (seven females and seven males aged from 10 to 65 years) of pleomorphic PPT. Seven cases were PC, with no mitoses and with areas of tumoral cells forming large pineocytomatous rosettes and other areas with giant cells containing hyperchromatic nuclei. The other seven were PPTID, presenting few mitoses (≤2), a Ki67 proliferation index between 3% and 7%, and predominantly composed of small neoplastic cells and scattered giant cells, sometimes multinucleated. In the 14 tumors, the proportion of pleomorphic areas was variable. Most tumoral cells showed extensive neuronal differentiation with strong expression of neuron‐specific enolase, synaptophysin and neurofilaments. Some of the neoplastic cells expressed S100 protein. The follow‐up period ranged from 1.2 to 13 years and only one PC and one PPTID progressed after stereotactic biopsy or incomplete resection. The lack of invasiveness and the low proliferation index of these tumors suggest a benign clinical course despite the marked pleomorphism, the latter of which can lead to upgrading.

Neuronal phosphorylated RNA-dependent protein kinase in Creutzfeldt-Jakob disease.

The mechanisms of neuronal apoptosis in Creutzfeldt-Jakob disease (CJD) and their relationship to accumulated prion protein (PrP) are unclear. A recent cell culture study showed that intracytoplasmic PrP may induce phosphorylated RNA-dependent protein kinase (PKRp)-mediated cell stress. The double-stranded RNA protein kinase PKR is a proapoptotic and stress kinase that accumulates in degenerating neurons in Alzheimer disease. To determine whether neuronal apoptosis in human CJD is associated with activation of the PKRp signaling pathway, we assessed in situ end labeling and immunocytochemistry for PrP, glial fibrillary acidic protein, CD68, activated caspase 3, and phosphorylated PKR (Thr451) in samples of frontal, occipital, and temporal cortex, striatum, and cerebellum from 6 patients with sporadic CJD and 5 controls. Neuronal immunostaining for activated PKR was found in all CJD cases. The most staining was in nuclei and, in contrast to findings in Alzheimer disease, cytoplasmic labeling was not detected. Both the number and distribution of PKRp-positive neurons correlated closely with the extent of neuronal apoptosis, spongiosis, astrocytosis, and microglial activation and with the phenotype and disease severity. There was no correlation with the type, topography, or amount of extracellular PrP deposits. These findings suggest that neuronal apoptosis in human CJD may result from PKRp-mediated cell stress and are consistent with recent studies supporting a pathogenic role for intracellular or transmembrane PrP.