Citations

Secondary, radiation-induced neoplasms represent a significant long-term risk after radiation treatment, and radiation-induced sarcomas (RAS) have an especially poor prognosis. These have rarely been reported after irradiation for pituitary adenomas.

We present a case of an intramedullary melanotic schwannoma (IMS) of the thoracic spinal cord. To our knowledge, this is the seventh reported case of an IMS of the central nervous system. Schwannomas are benign nerve sheath tumors of neural crest origin composed entirely of well differentiated Schwann cells that typically occur in peripheral nerves. Both the intramedullary location and the melanotic component of the reported lesion make it exceedingly rare. We will present our case, theories as to the origin of these tumors, clues in radiographic identification, and current clinical follow-up recommendations.

Abstract BACKGROUND: Ventral spinal epidural meningeal cysts are rare entities for which the pathogenesis is poorly understood. OBJECTIVE: We present the clinical, radiographic, surgical, and pathologic findings of 4 patients with extensive ventral spinal epidural meningeal cysts and review the relevant literature. In addition, we discuss a suspected mechanism for pathogenesis. METHODS: Four patients with anterior spinal epidural meningeal cysts are retrospectively reviewed. RESULTS: Ventral spinal epidural meningeal cysts are often large, extending on average from C2 to L1 in our series. Patients typically present with a prolonged course of symptoms and signs, including segmental muscle weakness and atrophy, subtle myelopathy, mild to moderate spinal pain, and headache. Histopathologic analysis of the cyst wall demonstrates collagenous tissue consistent with dura but without arachnoid features. Dynamic computed tomographic myelography is the study of choice for localization of the primary dural defect. Patient symptoms and neurological deficits routinely improve after appropriate surgical intervention. CONCLUSION: Diverse signs and symptoms herald the presentation of ventral spinal meningoceles. Intraoperative, radiographic, and pathological findings are all suggestive of an intradural dissection as the etiology. Hence, they may be more appropriately named “ventral spinal intradural dissecting meningoceles.” Definitive treatment involves identification and obliteration of the dural defect.

Abstract Purpose: Only a limited number of genetic studies have been conducted in primary central nervous system lymphomas (PCNSL), partly due to the rarity of the tumors and the very limited amount of available tissue. In this report, we present the first molecular characterization of copy number abnormalities (CNA) of newly diagnosed PCNSL by array-based comparative genomic hybridization (aCGH) in formalin-fixed paraffin-embedded (FFPE) specimens and compare the results with matched, frozen tumor specimens. Experimental Design: We conducted aCGH in FFPE tissues from PCNSL. Results were compared with matched, paired, frozen tumors. Results: Our analysis confirmed the good to fair quality and reliability of the data generated from limited amounts of tumoral FFPE tissue. Overall, all PCNSL cases were characterized by highly complex karyotypes, with a median of 23 CNAs per patient (range, 17–47). Overall, 20 chromosomal regions were recurrently found in more than 40% of cases. Deletions of 6p21, 6q, and 9p21.3 and gain of 12q12-q24.33 were the commonest CNAs. Other minimal affected regions were defined, and novel recurrent CNAs affecting single genes were identified in 3q26.32 (TBL1XR1) and 8q12.1 (TOX). Conclusions: The results obtained are encouraging. Larger archival tissue collections can now be analyzed to complement the still fragmented knowledge we have of the genetic basis of the PCNSL. Clin Cancer Res; 17(13); 4245–53. ©2011 AACR.

Abstract Introduction. PCNSL is an aggressive primary brain tumor characterized by a perivascular accumulation of malignant cells that have lymphoid characteristics. As there is significantly less information regarding the molecular pathogenesis of PCNSL in comparison with systemic lymphomas the aim of this study was to perform a comprehensive high-resolution genomic analysis in a cohort of PCNSL cases to better characterize the disease at chromosomal and gene level. Material and Methods. Specimens from 7 EBV- and HIV-negative and presumed immunocompetent PCNSL patients with sufficient frozen tissue for DNA extraction were studied. Copy-number abnormalities were analyzed by array CGH using SurePrint G3 (1 million probes) microarray (Agilent). B-cell differentiation status was characterized by immunostains for CD10, MUM-1, and CD138. Results. PCNSL cases were characterized by highly complex genomes with a median of 23 copy-number abnormalities per patient (range 16-49). Twenty-four chromosomal regions were affected in recurrent deletions and 19 in copy-number gains. Gain of 12q12-q24.33 and losses of 9p21.3 and 6q were the most common abnormalities, found in five of the seven patients. There was not a deleted region on 6q unique to all cases, with 6q14.1-q14.3, 6q16.3-q22.2 and 6q25.3-q26 losses being found in 4 out of 5 cases with 6q deletions. Two regions of interest were biallelically deleted. CDKN2A was the sole gene included in all cases with 9p21.3, being biallelically deleted in two out of 5 cases. TOX and CD58, genes associated with the development and activation of T cells, were also biallelically affected. Focal monoallelic deletions affecting negative regulators of the NFkB signaling pathway (MAP4K1, TANK, TAX1BP1, TRIB3), cell cycle (RB1) and immune-cell regulation (SIRPB1, CBLB, NFATC2) were also identified. Overall, a total of 22 genes were included in homozygous deletions in at least one case. Several chromosomal breakpoints were identified inside genes that encode transcription factors previously identified as being part of fusion protein in other hematological malignancies (FOXP1, ETV6 and NCOA2). Conclusion. This pilot study showed evidence for a highly complex genome, mainly characterized by abnormalities affecting a plethora of genes involved in lymphocyte development, activation and NF-kB signaling pathways regulation. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 331.

Object Supratentorial cortical ependymomas (CE) are rare, with 7 cases reported. The lesions, typically occurring in the superficial cortex in young adults and associated with a history of seizures, are not fully characterized. Furthermore, their relationship with the recently described angiocentric glioma (AG) is still being debated. This study was undertaken to summarize the authors' experience with CEs. Methods Between 1997 and 2009, 202 cases of ependymoma were surgically treated at the Mayo Clinic, 49 of which were supratentorial. Among these, 9 CE cases were retrospectively identified. Clinical, imaging, and pathological features of each case were reviewed. Results Tumors arose from the frontal (5 cases), parietal (3), and occipital (1) lobes. No tumor occurred in the temporal lobe, despite its reported association with seizures. The mean age at presentation was 27 ± 19 years (± SD) and age at resection was 36 ± 16 years. The mean size of the lesion was 16 ± 14 cm3. Seizures were the presenting symptom in 78%. Cross-sectional imaging in 8 cases was characterized by a heterogeneous mass with multiple cystlike areas and enhancement of the soft-tissue component. Gross-total resection was achieved in 8 of 9 tumors. Pathologically, 6 were low-grade (WHO Grade II) and 3 were anaplastic (WHO Grade III) ependymomas. All tumors exhibited the focal presence of perivascular pseudorosettes, but only 1 (11%) exhibited the focal presence of a true rosette. A bipolar spindle cell component resembling AG was present in 3 (33%) and “Schwannian-like” nodules in 2 (22%). Subpial aggregation and peripheral infiltration were present in 4 cases (44%). With a mean postsurgery follow-up of 62 ± 38 months, only 2 lesions recurred locally after imaging-confirmed gross-total resection, both being Grade III. In 5 (71%) of 7 patients presenting with seizures an Engel Class I outcome was achieved. Conclusions Cortical ependymomas represent a rare type of ependymoma occurring superficially in the cortex. Morphologically, these tumors are protean, varying from classic to epithelioid, clear cell, and tanycytic. Some also exhibited features typical of AG. Most tumors were low grade and cured with resection. Anaplastic tumors occur and may recur locally despite provision of radiation therapy. Cortical ependymomas frequently, but not always, present with seizures, but despite their high association with epilepsy, none occurred in the temporal lobe in any of the authors' 9 patients. Overall, CEs appear to have a relatively favorable prognosis compared with other supratentorial ependymomas.

Abstract Purpose: The mammalian target of rapamycin (mTOR) functions within the phosphoinositide 3-kinase/Akt signaling pathway as a critical modulator of cell survival. Methods: The mTOR inhibitor temsirolimus (CCI-779) was combined with chemoradiotherapy in glioblastoma multiforme (GBM) patients in a dose-escalation phase I trial. The first 12 patients were treated with CCI-779 combined with radiation/temozolomide and adjuvant temozolomide. A second cohort of 13 patients was treated with concurrent CCI-779/radiation/temozolomide followed by adjuvant temozolomide monotherapy. Results: Concomitant and adjuvant CCI-779 was associated with a high rate (3 of 12 patients) of grade 4/5 infections. By limiting CCI-779 treatment to the radiation/temozolomide phase and using antibiotic prophylaxis, the rate of infections was reduced, although 2 of 13 patients developed exacerbation of pre-existing fungal or viral infections. Dose-limiting toxicities were observed in 2 of 13 patients with this modified schedule. Weekly CCI-779 (50 mg/week) combined with radiation/temozolomide is the recommended phase II dose and schedule. The immune profile of patients in the second cohort was assessed before, during, and after CCI-779 therapy. There was robust suppression of helper and cytotoxic T cells, B cells, natural killer, cells and elevation of regulatory T cells during CCI-779/radiation/temozolomide therapy with recovery to baseline levels during adjuvant temozolomide of cytotoxic T cells, natural killer cells, and regulatory T cells. Conclusions: The increased infection rate observed with CCI-779 combined with chemoradiotherapy in GBM was reduced with antibiotic prophylaxis and by limiting the duration of CCI-779 therapy. The combined suppressive effects of CCI-779 and temozolomide therapy on discrete immune compartments likely contributed to the increased infectious risks observed. Clin Cancer Res; 16(22); 5573–80. ©2010 AACR.

Purpose Vorinostat, a histone deacetylase inhibitor, represents a rational therapeutic target in glioblastoma multiforme (GBM). Patients and Methods Patients with recurrent GBM who had received one or fewer chemotherapy regimens for progressive disease were eligible. Vorinostat was administered at a dose of 200 mg orally twice a day for 14 days, followed by a 7-day rest period. Results A total of 66 patients were treated. Grade 3 or worse nonhematologic toxicity occurred in 26% of patients and consisted mainly of fatigue (17%), dehydration (6%), and hypernatremia (5%); grade 3 or worse hematologic toxicity occurred in 26% of patients and consisted mainly of thrombocytopenia (22%). Pharmacokinetic analysis showed lower vorinostat maximum concentration and area under the curve (0 to 24 hours) values in patients treated with enzyme-inducing anticonvulsants, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy end point, with nine of the first 52 patients being progression-free at 6 months. Median overall survival from study entry was 5.7 months (range, 0.7 to 28+ months). Immunohistochemical analysis performed in paired baseline and post-vorinostat treatment samples in a separate surgical subgroup of five patients with recurrent GBM showed post treatment increase in acetylation of histones H2B and H4 (four of five patients) and of histone H3 (three of five patients). Microarray RNA analysis in the same samples showed changes in genes regulated by vorinostat, such as upregulation of E-cadherin (P = .02). Conclusion Vorinostat monotherapy is well tolerated in patients with recurrent GBM and has modest single-agent activity. Histone acetylation analysis and RNA expression profiling indicate that vorinostat in this dose and schedule affects target pathways in GBM. Additional testing of vorinostat in combination regimens is warranted.