Glioblastoma: from volumetric analysis to molecular predictors.

BACKGROUND: Decades of therapeutic and molecular refinements, the prognosis of patients with glioblastoma (GBM) still remains unfavorable. Integrative clinical studies allow a better understanding of the natural evolution of GBM. To assess independent predictors of overall survival (OS) and progression free survival (PFS) clinical, surgical, molecular and radiological variables were evaluated. A novel preoperative volumetric magnetic resonance imaging (MRI) Index for tumor prognosis in GBM patients was investigated. METHODS: A cohort of 195 cases of patients operated for newly GBM were analyzed. Extent of tumoral resection (EOR), tumor growth pattern, expressed by preoperative volumetric ΔT1-T2 MRI Index, molecular markers such as O6-methylguanine-DNA methyltransferase (MGMT) methylation and isocitrate dehydrogenase 1/2 (IDH1/2) mutation, were analyzed. Analysis of survival was done using Cox-proportional hazard models. RESULTS: The 1-, 2- years estimated OS and PFS rate for the whole population were 61% and 27%, 38% and 17%, respectively. A better survival rate, both in terms of survival and tumor progression, was observed in patient with higher EOR (P=0.000), younger age (P=0.000), MGMT methylation status (P=0.001) and lower preoperative ΔT1-T2 MRI Index (P=0.004). Regarding the tumor growth pattern a cut-off value of 0.75 was found to discriminate patient with different prognosis. Patients with a preoperative ΔT1-T2 MRI Index <0.75 had a 1-year estimated OS of 67%, otherwise patients with a preoperative ΔT1-T2 MRI Index >0.75 had a 1-year estimated OS of 34%. CONCLUSIONS: In this investigation longer survival is associated with younger age, EOR, promoter methylation of MGMT and preoperative tumor volumetric features expressed by ΔT1-T2 MRI Index The preoperative ΔT1-T2 MRI Index could be a promising prognostic factor potentially useful in GBM management. Future investigations based on multiparametric MRI data and next generation sequences analysis, may better clarify this result.

A New Epigenetic Model to Stratify Glioma Patients According to Their Immunosuppressive State.

Gliomas are the most common primary neoplasm of the central nervous system. A promising frontier in the definition of glioma prognosis and treatment is represented by epigenetics. Furthermore, in this study, we developed a machine learning classification model based on epigenetic data (CpG probes) to separate patients according to their state of immunosuppression. We considered 573 cases of low-grade glioma (LGG) and glioblastoma (GBM) from The Cancer Genome Atlas (TCGA). First, from gene expression data, we derived a novel binary indicator to flag patients with a favorable immune state. Then, based on previous studies, we selected the genes related to the immune state of tumor microenvironment. After, we improved the selection with a data-driven procedure, based on Boruta. Finally, we tuned, trained, and evaluated both random forest and neural network classifiers on the resulting dataset. We found that a multi-layer perceptron network fed by the 338 probes selected by applying both expert choice and Boruta results in the best performance, achieving an out-of-sample accuracy of 82.8%, a Matthews correlation coefficient of 0.657, and an area under the ROC curve of 0.9. Based on the proposed model, we provided a method to stratify glioma patients according to their epigenomic state.

Partial prostate re-irradiation for the treatment of isolated local recurrence of prostate cancer in patients previously treated with primary external beam radiotherapy: short-term results of a monocentric study.

Many different therapeutic options are available for locally recurrent prostate cancer (PCa). However, standard treatment has not yet been established. We conducted a partial prostate re-irradiation (PPR) program for the treatment of isolated and limited-size intraprostatic recurrences, in patients who previously underwent external beam radiation therapy (EBRT) as primary treatment for prostatic cancer (PCa). The analysis of this experience in terms of feasibility, toxicity, and efficacy is reported. The inclusion criteria of this retrospective analysis were: previous definitive EBRT, evidence of biochemical recurrence, radiological detection of isolated local relapse, and PPR as local salvage therapy. Gastrointestinal (GI) and genitourinary (GU) toxicities were registered according to the RTOG/EORTC criteria. Between July 2012 and May 2019, 44 patients were treated with PPR. All patients completed the planned treatment. The median follow-up was 25.4 months. Tumor progression was observed in 18 patients (40.9%). Two-year local control, biochemical failure-, and clinical relapse-free survival rates were 90.1%, 58.3%, and 67.9%, respectively. The occurrence of biochemical failure after PPR is lower for patients with the time interval between the primary EBRT and first biochemical failure >4 years; local control results strongly associated with a biologically effective dose (BED) at first EBRT >177 Gy. No acute grade 3 or greater toxic events were observed. Two late grade 3 GU toxicities were reported. Although retrospective in design, our study indicates that PPR appears as a feasible, well-tolerated, and effective salvage treatment for isolated local PCa recurrence. Long term data are required in order to confirm these results.

A Novel Comprehensive Clinical Stratification Model to Refine Prognosis of Glioblastoma Patients Undergoing Surgical Resection.

Despite recent discoveries in genetics and molecular fields, glioblastoma (GBM) prognosis still remains unfavorable with less than 10% of patients alive 5 years after diagnosis. Numerous studies have focused on the research of biological biomarkers to stratify GBM patients. We addressed this issue in our study by using clinical/molecular and image data, which is generally available to Neurosurgical Departments in order to create a prognostic score that can be useful to stratify GBM patients undergoing surgical resection. By using the random forest approach [CART analysis (classification and regression tree)] on Survival time data of 465 cases, we developed a new prediction score resulting in 10 groups based on extent of resection (EOR), age, tumor volumetric features, intraoperative protocols and tumor molecular classes. The resulting tree was trimmed according to similarities in the relative hazard ratios amongst groups, giving rise to a 5-group classification tree. These 5 groups were different in terms of overall survival (OS) (p < 0.000). The score performance in predicting death was defined by a Harrell's c-index of 0.79 (95% confidence interval [0.76-0.81]). The proposed score could be useful in a clinical setting to refine the prognosis of GBM patients after surgery and prior to postoperative treatment.

Multimodal treatment for high-risk locally-advanced prostate cancer following radical prostatectomy and extended lymphadenectomy.

BACKGROUND: The aim of this study was to prospectively evaluate the safety and oncologic outcomes of multimodal treatment in high risk-locally advanced prostate cancer patients (PCa). METHODS: High-risk-locally advanced prostate cancer patients without distant metastases before radical prostatectomy (RP) were included. Adjuvant high-dose intensity-modulated radiation therapy (IMRT) with concurrent docetaxel and long-term androgen-deprivation therapy (ADT) were started after 3-6 months from RP. ADT was maintained for two years. Acute and late toxicity were evaluated with the Common Terminology Criteria for Adverse Events (v. 3.0). Biochemical and clinical recurrence-free survival were explored by using the Kaplan-Meier method. RESULTS: Overall 42 patients were included. Acute genitourinary toxicity was observed with Grade I, II, and III in four (9.5%), two (4.8%), and one (2.3%) patients, respectively. Acute gastrointestinal toxicity was reported to be of Grade I and II in 12 (29.3%) and three (7.2%) patients, respectively. In these patients, concomitant genito-urinary and gastrointestinal toxicity occurred in three (7.2%) cases. A residual GU Grade I toxicity was present only in one patient. Toxicity due to CHT was found in four (9.5%) patients. Complete continence after RP and IMRT was achieved in 32 patients (76.2%). After a median follow-up of 3.4 years, BCR and clinical recurrence were observed in 16.7% and 9.5% of patients, respectively. A 5-year biochemical and clinical recurrence-free survival rate were 70.7% and 84.0%, respectively. Five-year overall survival was 93.6%. None of the patients died for prostate cancer during follow-up. CONCLUSIONS: This novel multimodal treatment paradigm for high-risk locally advanced prostate cancer has an acceptable level of toxicity and good oncological outcomes observed after a long follow-up.

Impact of DNA repair gene polymorphisms on the risk of biochemical recurrence after radiotherapy and overall survival in prostate cancer.

The identification of biomarkers of biochemical recurrence (BCR) in prostate cancer (PCa) patients undergoing radiotherapy (RT) represents an unanswered clinical issue. The primary aim of this study was the definition of new genetic prognostic biomarkers in DNA repair genes (DRGs), considering both BCR and overall survival (OS) as clinical end-points. The secondary aim was to explore the potential clinical impact of these genetic variants with the decision curve analysis (DCA) and the sensitivity analysis.We analyzed 22 germline polymorphisms in 14 DRGs on 542 Caucasian PCa patients treated with RT as primary therapy. Significant associations were further tested with a bootstrapping technique. According to our analyses, ERCC2-rs1799793 and EXO1-rs4149963 were significantly associated with BCR (p = 0.01 and p = 0.01, respectively). Moreover, MSH6-rs3136228 was associated with a worse OS (p = 0.04). Nonetheless, the DCA and the sensitivity analyses gave no ultimate response about the clinical impact of such variants.This study highlights the potential prognostic role of polymorphisms in DRGs for PCa, paving the way to the introduction of not invasive tools for the personalization of patients management. Nonetheless, other prospective studies are necessary to ultimately clarify the clinical impact of pharmacogenetics in PCa.

Treatment of recurrent high-grade gliomas with GliaSite brachytherapy: a prospective mono-institutional Italian experience.

AIMS AND BACKGROUND: The present study evaluated toxicity, local control, and survival in patients with relapsed high-grade glioma after surgery and external beam radiation therapy and treated with re-operation and GliaSite brachytherapy. METHODS: Between 2006 and 2008, 15 patients with recurrent high-grade glioma underwent re-operation and GliaSite brachytherapy. Ten patients were males and 5 females. Median age was 40 years (range, 20-71). Karnofsky performance status was ≥70. All patients but one received GliaSite irradiation of the surgical cavity wall at the dose of 4500 cGy at a depth of 1 cm. RESULTS: No severe acute side effects were observed during GliaSite brachytherapy. Pathologically documented, symptomatic late radiation necrosis was observed in 3 patients (20%); 2 subsequently died of further complications. Two patients were alive at a median follow-up 13 months (range, 1-30). Median overall survival after GliaSite brachytherapy was 13 months. CONCLUSIONS: Patients with recurrent high-grade glioma can be treated with additional surgery and GliaSite brachytherapy, delivering 4500 cGy at 1 cm depth without significant acute side effects but with a significant rate (20%) of late radiation necrosis, resulting in 13% of treatment-related deaths. Compared with the literature, survival results in our study appear to be satisfactory, but they may be related to patient selection criteria. Re-intervention followed by GliaSite brachytherapy should not be offered as a standard treatment for recurrent high-grade glioma, because of the high rate of late complications, treatment-related deaths, and high treatment costs.

Updating and inhibition processes in working memory: a comparison between Alzheimer's type dementia and frontal lobe focal damage.

A large debate has recently focused on the componential nature of the working-memory system (), as evidenced by functional-imaging studies and by using more sophisticated experimental paradigms. The present work aims at further disentangling the role and effects of central executive (CE) and of phonological loop (PL). It is suggested that maintaining active verbal information mostly relates to an intact PL, while the inhibition of interfering information preponderantly involves the CE. To distinguish these effects, two groups of brain damaged patients were administered with an updating task. Frontal lobe patients showed major difficulties in inhibiting interfering information, an ability requiring an involvement of the CE component. In contrast, Alzheimer's dementia patients evidenced a relative impairment in maintaining relevant information, requiring the intervention of the PL.