No abstract

In recent years, important advances have been achieved in the understanding of the molecular biology of glioblastoma multiforme (GBM); thus, complex genetic alterations and genomic profiles, which recurrently involve multiple signaling pathways, have been defined, leading to the first molecular/genetic classification of the disease. In this regard, different genetic alterations and genetic pathways appear to distinguish primary (eg, EGFR amplification) versus secondary (eg, IDH1/2 or TP53 mutation) GBM. Such genetic alterations target distinct combinations of the growth factor receptor-ras signaling pathways, as well as the phosphatidylinositol 3-kinase/phosphatase and tensin homolog/AKT, retinoblastoma/cyclin-dependent kinase (CDK) N2A-p16(INK4A), and TP53/mouse double minute (MDM) 2/MDM4/CDKN2A-p14(ARF) pathways, in cells that present features associated with key stages of normal neurogenesis and (normal) central nervous system cell types. This translates into well-defined genomic profiles that have been recently classified by The Cancer Genome Atlas Consortium into four subtypes: classic, mesenchymal, proneural, and neural GBM. Herein, we review the most relevant genetic alterations of primary versus secondary GBM, the specific signaling pathways involved, and the overall genomic profile of this genetically heterogeneous group of malignant tumors.

We report on a series of 26 patients diagnosed with primary (de novo) plasma cell (PC) leukemia (PCL) in whom we analyzed the clinicobiologic characteristics of the disease together with the immunophenotype, DNA cell content, proliferative index, and numeric chromosomal aberrations of the neoplastic PC, and compared them with 664 multiple myeloma (MM) patients at diagnosis. The median age, sex ratio, and bone lesion extension were similar, but PCL cases displayed a higher prevalence of clinical stage III, extramedullary involvement, and Bence Jones cases, with fewer IgA cases than for MM patients. In addition, according to several prognostic indicators (β2-microglobulin serum level, proportion of S-phase PCs, proteinuria, calcium serum level, lactate dehydrogenase [LDH] and renal function), the incidence of adverse prognostic factors was significantly higher in PCL versus MM. Immunophenotypic expression was similar for CD38, CD138, CD2, CD3, CD16, CD10, CD13, and CD15, but PCL differed from MM in the expression of CD56, CD9 HLA-DR, CD117, and CD20 antigens. Twenty-two PCL cases were diploid and one was hypodiploid, while most MM cases (57%) showed DNA hyperdiploidy. With the fluorescent in situ hydridization (FISH) technique, 12 of 13 PCL cases displayed the numeric aberrations, −13 (86%), ±1 (57%), +18 (43%), and −X in women (25%), but they lacked several numeric aberrations usually found in MM such as +3, +6, +9, +11, and +15. PCL cases had a lower overall response to therapy than MM cases (38% v 63%, P = .01332). Among PCL patients, a trend for a worse response was observed in cases treated with melphalan and prednisone (MP) versus polychemotherapy. Overall survival was significantly worse in PCL versus MM patients (8 v 36 months,P < .0001), but it was significantly better in PCL patients treated with polychemotherapy versus MP (18 v 3 months,P = .0137). By contrast, MM patients did not show significant differences in overall survival according to the treatment used, MP or polychemotherapy. Ten variables seemed to predict survival in PCL patients, but only the β2-microglobulin level and S-phase PCs retained an independent value in multivariate analysis. In summary, our study illustrates that PCs from PCL display singular phenotypic, DNA cell content, and cytogenetic characteristics that lead to a different disease evolution versus MM.

We report on a series of 26 patients diagnosed with primary (de novo) plasma cell (PC) leukemia (PCL) in whom we analyzed the clinicobiologic characteristics of the disease together with the immunophenotype, DNA cell content, proliferative index, and numeric chromosomal aberrations of the neoplastic PC, and compared them with 664 multiple myeloma (MM) patients at diagnosis. The median age, sex ratio, and bone lesion extension were similar, but PCL cases displayed a higher prevalence of clinical stage III, extramedullary involvement, and Bence Jones cases, with fewer IgA cases than for MM patients. In addition, according to several prognostic indicators (β2-microglobulin serum level, proportion of S-phase PCs, proteinuria, calcium serum level, lactate dehydrogenase [LDH] and renal function), the incidence of adverse prognostic factors was significantly higher in PCL versus MM. Immunophenotypic expression was similar for CD38, CD138, CD2, CD3, CD16, CD10, CD13, and CD15, but PCL differed from MM in the expression of CD56, CD9 HLA-DR, CD117, and CD20 antigens. Twenty-two PCL cases were diploid and one was hypodiploid, while most MM cases (57%) showed DNA hyperdiploidy. With the fluorescent in situ hydridization (FISH) technique, 12 of 13 PCL cases displayed the numeric aberrations, −13 (86%), ±1 (57%), +18 (43%), and −X in women (25%), but they lacked several numeric aberrations usually found in MM such as +3, +6, +9, +11, and +15. PCL cases had a lower overall response to therapy than MM cases (38% v 63%, P = .01332). Among PCL patients, a trend for a worse response was observed in cases treated with melphalan and prednisone (MP) versus polychemotherapy. Overall survival was significantly worse in PCL versus MM patients (8 v 36 months,P &lt; .0001), but it was significantly better in PCL patients treated with polychemotherapy versus MP (18 v 3 months,P = .0137). By contrast, MM patients did not show significant differences in overall survival according to the treatment used, MP or polychemotherapy. Ten variables seemed to predict survival in PCL patients, but only the β2-microglobulin level and S-phase PCs retained an independent value in multivariate analysis. In summary, our study illustrates that PCs from PCL display singular phenotypic, DNA cell content, and cytogenetic characteristics that lead to a different disease evolution versus MM.

Based on this risk-stratification classification, different strategies may be adopted for follow-up, and eventually also for treatment, of meningioma patients at different risks for relapse.

In addition to age and histologic grade, abnormalities of chromosome 14 contribute to a better prognostic stratification of meningioma patients at diagnosis. Additional prospective studies in larger series of patients, also including larger numbers of patients who experienced relapse, are necessary to confirm the utility of the proposed predictive model.

No abstract

Tumor recurrence is the major clinical complication in meningiomas, and its prediction in histologically benign/grade I tumors remains a challenge. In this study, we analyzed the prognostic value of specific chromosomal abnormalities and the genetic heterogeneity of the tumor, together with other clinicobiological disease features, for predicting early relapses in histologically benign/grade I meningiomas. A total of 149 consecutive histologically benign/grade I meningiomas in patients who underwent complete tumor resection were prospectively analyzed. Using interphase fluorescence in situ hybridization, we studied the prognostic impact of the abnormalities detected for 11 different chromosomes, together with other relevant clinicobiological and histopathological characteristics of the disease, on recurrence-free survival (RFS) at 2.5, 5, and 10 years. From the prognostic point of view, losses of chromosomes 9, 10, 14, and 18 and del(1p36) were associated with a shorter RFS at 2.5, 5, and 10 years. Similarly, histologically benign/grade I meningiomas showing coexistence of monosomy 14 and del(1p36) in the ancestral tumor cell clone displayed a higher frequency of early relapses. In fact, coexistence of -14 and del(1p36) in the ancestral tumor cell clone, together with tumor size, represented the best combination of independent prognostic factors for the identification of those patients with a high risk of an early relapse. Our results indicate that patients with large histologically benign/grade I meningiomas carrying monosomy 14 and del(1p36) in their ancestral tumor cell clone have a high probability of relapsing early after diagnostic surgery. These findings suggest the need for closer follow-up in this small group of patients.