Purpose: The aim of the present study was to evaluate factors predicting the recurrence pattern after the administration of temozolomide (TMZ), initially concurrent with radiotherapy (RT) and subsequently as maintenance therapy, which has become standard treatment for patients with newly diagnosed glioblastoma (GBM). Patients and Methods: Ninety-five patients with newly diagnosed GBM were treated with RT plus TMZ (75 mg/m²/d) followed by maintenance TMZ cycles (150 to 200 mg/m² for 5 days every 28 days). Assessable MGMT methylation status and magnetic resonance imaging follow-up were mandatory in all cases. Results: After a median follow-up of 18.9 months (range, 6.6 to 44.8 months), 79 patients (83%) had recurrence: inside the RT field in 57 patients (72.2%), outside in 17 patients (21.5%), and at RT margin in five patients (6.3%). MGMT status was correlated with the site of recurrence, which occurred inside, or at the margin of, the RT field in 51 patients (85%) with MGMT unmethylated status and in 11 patients (57.9%) with MGMT methylated status (P = .01). Recurrences outside the RT field occurred after a longer time interval than those inside the RT field (14.9 v 9.2 months, P = .02). Conclusion: After the administration of TMZ concomitant with and adjuvant to RT in patients with GBM, the pattern of, and time to, recurrence are strictly correlated with MGMT methylation status.

O⁶-methylguanine DNA-methyltransferase (MGMT) promoter methylation status is a prognostic factor in newly diagnosed glioblastoma patients. However, it is not yet clear whether, and if so how, MGMT methylation status may change. Moreover, it is unknown whether the prognostic role of this epigenetic feature is retained during the disease course. A retrospective analysis was made using a database of 614 glioblastoma patients treated prospectively from January 2000 to August 2008. We evaluated only patients who met the following inclusion criteria: age ≥18 years; performance status 0-2; histological diagnosis of glioblastoma at both first and second surgery for recurrence; postoperative treatment consisting of: (i) radiotherapy (RT) followed by adjuvant temozolomide (TMZ) until 2005 and (ii) TMZ concurrent with and adjuvant to RT after 2005; a time interval ≥3 months between first and second surgery. MGMT status was evaluated at first and second surgery in all 44 patients (M:F 32:12, median age: 49 years, range: 27–67 years). In 38 patients (86.4%), MGMT promoter status was assessable at both first and second surgery. MGMT methylation status, changed in 14 patients (37%) of second surgery samples and more frequently in methylated than in unmethylated patients (61.5% vs 24%, P = .03). The median survival was significantly influenced only by MGMT methylation status determined at first surgery (P = .04). Significant changes in MGMT methylation status during the course of GBM occur more frequently in MGMT methylated than unmethylated cases. MGMT methylation status determined at first surgery appears to be of prognostic value; however, it is not predictive of outcome following second surgery.

Hobnail variant of papillary thyroid carcinoma (HPTC) represents a recently described, aggressive and rare group of thyroid tumors with poorly understood pathogenesis. Molecular data about this group of cancers are few, and a more detailed molecular characterization of these tumors is needed. The main objective of the study is to define a comprehensive molecular typing of HPTC. Eighteen patients affected by HPTC, including eighteen primary tumors and four lymph node metastases, were screened forNRAS,KRAS,HRAS,BRAF,TP53,PIK3CA,hTERT,PTEN,CDKN2A,EGFR,AKT1,CTNNB1andNOTCH1gene mutations. Sequencing is conducted on the MiSEQ system, and molecular data are compared with clinical-pathologic data and follow-up. The patients include 14 women and 4 men. Ages range from 23 to 87 years. All 18 primary tumors of HPTC showed ≥30% hobnail features.BRAFandTP53mutations are by far the most common genetic alterations in primary HPTC (72.2% and 55.6%, respectively), followed byhTERT(44.4%),PIK3CA(27.8%),CTNNB1(16.7%),EGFR(11.1%),AKT1(5.5%) andNOTCH1(5.5%). The mutational pattern in primary tumors and metastasis was usually maintained. Univariate Cox regression analyses with bootstrap procedure indicated a significantly increased mortality risk in patients harboringBRAFmutation andBRAFmutation associated withTP53and/orPIK3CAmutations. The detection of these multiple mutations appears to allow the identification of a subset of more aggressive tumors within the group and to bear information that should be useful for prognostic stratification of these patients including the planning of adjuvant therapy.