Giannini, Caterina

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly encountered in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. A small group of ATRT stands out clinically, because these tumors are located in the sellar region of adults. To investigate if sellar region ATRT in adults represents a molecular distinct entity, we characterized molecular alterations in 7 sellar region ATRTs in adults as compared with 150 pediatric ATRTs and 47 pituitary adenomas using SMARCB1 sequencing, multiplex ligation-dependent probe amplification and fluorescence in situ hybridization as well as DNA methylation profiling. The median age of the 6 female and 1 male patients was 56 years. On histopathologic examination, all tumors were malignant rhabdoid tumors showing loss of SMARCB1/INI1 protein expression. Two cases displayed compound heterozygous SMARCB1 point mutations, 3 cases showed heterozygous SMARCB1 deletions with point mutations of the other allele and 1 case a homozygous SMARCB1 deletion; in 1 case, underlying SMARCB1 alterations could not be identified. On unsupervised hierarchical cluster analysis of DNA methylation profiles, sellar region ATRTs did not form a distinct group, but clustered with ATRT-MYC, 1 of 3 recently described molecular subgroups of ATRT. On analysis of DNA methylation array intensity data, only 1 sellar region ATRT showed characteristic features of pediatric ATRT-MYC, that is, major copy number losses affecting the SMARCB1 region. In conclusion, these results suggest that sellar region ATRTs in adults form a clinically distinct entity with a different mutational spectrum, but epigenetic similarities with pediatric ATRTs of the ATRT-MYC subgroup.

BACKGROUNDMitogen‐activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)‐dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR‐2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma.METHODSPatients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts‐of‐3 design. The 2‐stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)–naive patients and patients who progressed after prior VEGFi.RESULTSThe MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression‐free survival at 6 months [PFS6]) in the VEGFi‐naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi‐naive patients and in 73.9% of the prior VEGFi patients.CONCLUSIONSThe limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single‐agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455‐63. © 2018 American Cancer Society.

We report a case of low‐grade fibromyxoid sarcoma arising within the median nerve. A 31‐year‐old woman presented with symptoms of carpal tunnel syndrome and an enlarging mass in her right palm over 1 year. MRI demonstrated a mass associated with the right median nerve with solid and cystic components. At surgery, the mass was located within the epineurium, could be bluntly dissected from the nerve fascicles, and was suspected to be a schwannoma. A 3.4 cm, tan‐pink, glistening, smooth, homogenous mass was submitted to pathology. Microscopically, the tumor was a solid and cystic circumscribed nodule with a dense fibrous pseudocapsule. The tumor cells were uniformly bland and spindle‐shaped, with small, hyperchromatic oval nuclei and were embedded in an alternating fibrous and myxoid stroma with a prominent curvilinear vasculature and perivascular sclerosis. The differential diagnosis for this lesion included myxoid neurofibroma, schwannoma, soft tissue perineurioma, low‐grade malignant peripheral nerve sheath tumor and low‐grade fibromyxoid sarcoma. The tumor cells expressed MUC4, GLUT‐1, and vimentin and were negative for S‐100 protein, epithelial membrane antigen, smooth muscle actin, desmin, claudin‐1, neurofilament and SOX10. Fluorescence in situ hybridization, with a break‐apart probe strategy, demonstrated FUS rearrangement, consistent in this morphological context with the low‐grade fibromyxoid sarcoma‐associated FUS‐CREB3L2 or FUS‐CREB3L1 fusions. Low‐grade fibromyxoid sarcoma is exceptionally rare in the peripheral nerve, with only a single previously reported case. Nonetheless, as our case illustrates, this entity must be included in the differential diagnosis of unusual intraneural mesenchymal tumors. As in all other locations, intraneural low‐grade fibromyxoid sarcomas should be excised with negative margins. Patients with this disease require long‐term clinical follow‐up, given this tumor's propensity for very late distant metastases to the lungs and other sites.

Abstract BACKGROUND Stereotactic radiosurgery (SRS) is a commonly performed procedure for patients with intracranial meningiomas. OBJECTIVE To describe the clinical features of patients with radiation-induced cavernous malformations (RICM) after single-fraction meningioma SRS. METHODS Retrospective study of patients having single-fraction SRS for intracranial meningioma at our center from 1990 through 2009, and 1 patient who had single-fraction SRS elsewhere. Patients were excluded if they refused research authorization (n = 7), had a World Health Organization Grade II or III meningioma (n = 65), had a genetic predisposition for tumor development (n = 52), had prior or concurrent radiation therapy (n = 49), or had less than 2 yr of magnetic resonance imaging follow-up after SRS (n = 77). The median follow-up of the remaining 426 patients was 7.9 yr (range, 2-24.9). RESULTS Three RICM (0.7%) were identified at 2, 10, and 21 yr after SRS. Two patients were asymptomatic, whereas 1 patient had a brainstem hemorrhage causing facial weakness and numbness. The risk of developing an RICM after SRS was 0.2% at 5 yr and 0.9% at 15 yr. All patients were observed and remained stable without additional bleeding in follow-up of 7, 12.8, and 2 yr, respectively. A fourth patient developed progressive neurological dysfunction starting 7 yr after SRS at another center and was treated for several years with bevacizumab without improvement. Surgical resection was performed 11.5 yr after SRS and histologic examination was consistent with an RICM. CONCLUSION The risk of RICM after single-fraction SRS for intracranial meningiomas is very low, but the latency period noted until their detection emphasizes the need for extended imaging follow-up after SRS of benign lesions.

Abstract Objectives To develop and evaluate a real-time methylation-specific polymerase chain reaction (RT-MSP) MGMT assay, with a particular focus on small biopsies and indeterminate testing results. Methods We assessed formalin-fixed paraffin-embedded glioblastoma or gliosarcoma specimens (n = 641). A test-validation group (n = 51) with previously obtained reference laboratory (RL) results was used to determine performance characteristics of the RT-MSP assay. An indeterminate (equivocal) category was established for cases that could not be clearly classified as positive or negative. Results Overall agreement of RT-MSP and RL results was 91% (41/45 nonindeterminate cases). Discordant cases were tested by pyrosequencing, and results were most concordant with RT-MSP. Among cases with limited amounts of tissue (n = 7), six yielded valid results by RT-MSP (all negative); the single invalid result consisted of a stereotactic biopsy specimen obtained 14 years prior. A subset of indeterminate cases obtained during clinical testing (n = 18/575 [3%]) was also evaluated by pyrosequencing and showed a heterogeneous pattern of methylation across the eight interrogated CpG sites. Conclusions The RT-MSP assay that we developed in-house is a robust clinical detection method for the heterogeneous process of MGMT promoter methylation in glioblastoma.