Giovanni Rubino

The prognostic role of Beclin 1 protein expression in high-grade gliomas.

High Grade Gliomas (HGG) have a poor outcome, however, prognostic sub-groups of patients may be individuated by some clinico-biological parameters. It was recently demonstrated that the main response of HGG to therapy is autophagic death. Autophagy is involved in tumor suppression, and is defective in HGG, in which we previously found an underexpression of beclin 1 autophagic gene protein product. Underexpression of Beclin 1 protein has been correlated to poor patient outcome in other tumor types. In this paper, the prognostic role of beclin 1 expression in HGG patients was investigated. We firstly evaluated the tumor cell cytoplasmic expression of Beclin 1 protein (BPCE), in a sample of 76 HGG by immunohistochemistry, and compared it with cell proliferation and apoptosis. We found high BPCE score positively correlated with apoptosis, and negatively with cell proliferation (p < 0,05). We then correlated BPCE score with survival and other prognostic parameters (histological grading , MGMT gene methylation status, age, patient performance status according to the Karnofski classification (KPS), extent of surgery, radiation therapy (RT) modality, temozolomide chemotherapy (TMZ CHT), and optimal/suboptimal post-surgical treatment). Forty-seven (61.8%) and twenty-nine (38.2%) patients showed high and low BPCE scores, respectively. BPCE showed statistically significant correlations with survival both at the univariate (p = 0.03) and multivariate analysis (p = 0.037). High BPCE was also positively correlated with high KPS values (p = 0.023), and with the accomplishment of an optimal post-operative therapy (p = 0.037). Furthermore, among patients showing a MGMT methylated gene, survival was significantly higher in cases with a higher BPCE score. BPCE score might be added to pathological evaluation of HGG for prognostic purposes.

Patterns of care and survival in a retrospective analysis of 1059 patients with glioblastoma multiforme treated between 2002 and 2007: a multicenter study by the Central Nervous System Study Group of Airo (italian Association of Radiation Oncology).

OBJECTIVETo investigate the pattern of care and outcomes for newly diagnosed glioblastoma in Italy and compare our results with the previous Italian Patterns of Care study to determine whether significant changes occurred in clinical practice during the past 10 years. METHODSClinical, pathological, therapeutic, and survival data regarding 1059 patients treated in 18 radiotherapy centers between 2002 and 2007 were collected and retrospectively reviewed. RESULTSMost patients underwent both computed tomography and magnetic resonance imaging either preoperatively (62.7%) or postoperatively (35.5%). Only 123 patients (11.6%) underwent a biopsy. Radiochemotherapy with temozolomide was the most frequent adjuvant treatment (70.7%). Most patients (88.2%) received 3-dimensional conformal radiotherapy. Median survival was 9.5 months. Two- and 5-year survival rates were 24.8% and 3.9%, respectively. Multivariate analysis showed the statistical significance of age, postoperative Karnofsky Performance Status scale score, surgical extent, use of 3-dimensional conformal radiotherapy, and use of chemotherapy. Use of a more aggressive approach was associated with longer survival in elderly patients. Comparing our results with those of the subgroup of patients included in our previous study who were treated between 1997 and 2001, relevant differences were found: more frequent use of magnetic resonance imaging, surgical removal more common than biopsy, and widespread use of 3-dimensional conformal radiotherapy + temozolomide. Furthermore, a significant improvement in terms of survival was noted (P < .001). CONCLUSIONChanges in the care of glioblastoma over the past few years are documented. Prognosis of glioblastoma patients has slightly but significantly improved with a small but noteworthy number of relatively long-term survivors.

Radiotherapy and temozolomide in anaplastic astrocytoma: a retrospective multicenter study by the Central Nervous System Study Group of AIRO (Italian Association of Radiation Oncology).

Although the evidence for the benefit of adding temozolomide (TMZ) to radiotherapy (RT) is limited to glioblastoma patients, there is currently a trend toward treating anaplastic astrocytomas (AAs) with combined RT + TMZ. The aim of the present study was to describe the patterns of care of patients affected by AA and, particularly, to compare the outcome of patients treated exclusively with RT with those treated with RT + TMZ. Data of 295 newly diagnosed AAs treated with postoperative RT ± TMZ in the period from 2002 to 2007 were reviewed. More than 75% of patients underwent a surgical removal. All the patients had postoperative RT; 86.1% of them were treated with 3D-conformal RT (3D-CRT). Sixty-seven percent of the entire group received postoperative chemotherapy with TMZ (n = 198). One-hundred sixty-six patients received both concomitant and sequential TMZ. Prescription of postoperative TMZ increased in the most recent period (2005-2007). One- and 4-year survival rates were 70.2% and 28.6%, respectively. No statistically significant improvement in survival was observed with the addition of TMZ to RT (P = .59). Multivariate analysis showed the statistical significance of age, presence of seizures, Recursive Partitioning Analysis classes I-III, extent of surgical removal, and 3D-CRT. Changes in the care of AA over the past years are documented. Currently there is not evidence to justify the addition of TMZ to postoperative RT for patients with newly diagnosed AA outside a clinical trial. Results of prospective and randomized trials are needed.

Three-dimensional conformal radiotherapy, temozolomide chemotherapy, and high-dose fractionated stereotactic boost in a protocol-driven, postoperative treatment schedule for high-grade gliomas

AIMS AND BACKGROUND No available scientific report deals with high-dose (> or = 70 Gy) radiotherapy plus temozolomide chemotherapy (TMZ CHT) in high-grade gliomas. The survival results of a protocol-driven, postoperative treatment schedule are reported here to contribute to the discussion on this issue. METHODS AND STUDY DESIGN Uniform criteria were prospectively adopted for case selection during the period 1993-2006 in the management of 123 patients, and we progressively introduced three-dimensional conformal radiotherapy (3D-CRT, 60 Gy), TMZ CHT and a high-dose (70 Gy) stereotactic boost (HDSRT) in the treatment schedule. Palliative radiotherapy was delivered by whole brain irradiation (WBI, 50 Gy) for bulky tumors, whereas radical irradiation was performed with 3D-CRT throughout the study period. Two periods of accrual are considered: 36 patients were treated before 31 December 1999 (29.25%) and 87 (70.75%) after 1 January 2000. This subdivision was due to the implementation of HDSRT hardware and TMZ CHT from January 2000. RESULTS The median overall survival was 13 months and the 1-, 2- and 3-year survival rates were 53%, 19.5% and 11.6%, respectively. The differences in survival related to the treatment variables were highly significant, both in univariate and multivariate analysis. The median survival and 1-, 2- and 3-year survival rates in the palliative WBI group were 9.75 months and 37%, 2%, and 0%, respectively; in the 3D-CRT group 17.25 months and 64%, 34%, and 15%, respectively; in the TMZ CHT concomitant with radiotherapy group 20 months and 61%, 39%, and 21%, respectively; in the TMZ CHT concomitant with and sequential to radiotherapy group 25.75 months and 84%, 54%, and 26%, respectively, and in the HDSRT group 22 months and 72%, 48%, and 37%, respectively. No symptomatic radiation necrosis occurred in any of the groups. CONCLUSIONS The results reported here are generally better than those reported in the literature. The selection of patients on the basis of favorable prognostic factors and suitability to the currently available, aggressive postoperative treatment resources can be the mainstay for improving therapeutic results. In particular, the new treatment option reported here (HDSRT in association with TMZ CHT) proved to be safe and effective in obtaining a relatively favorable outcome.

3D bone texture analysis as a potential predictor of radiation-induced insufficiency fractures

Background The aim of our work is to assess the potential role of texture analysis (TA), applied to computed tomography (CT) simulation scans, in relation to the development of insufficiency fractures (IFs) in patients undergoing radiation therapy (RT) for pelvic malignancies. Methods We analyzed patients undergoing pelvic RT from Jan-2010 to Dec-2016, 31 of whom had developed IFs of the pelvis. We analyzed CT simulation scans using LifeX Software©, and in particular we selected three regions of interest (ROI): L5 body, the sacrum and both the femoral heads. The ROI were automatically contoured using the treatment planning software Raystation©. TA parameters included parameters from the gray-level histogram, indices from sphericity and from the matrix of GLCM (gray level co-occurrence matrix). The IFs patients were matched (1:1 ratio) with control patients who had not developed IFs, and were matched for age, sex, type of tumor, menopausal status, RT dose and use of chemotherapy. Univariate and multivariate analyses (logistic regression) were used for statistical analysis. Results Significant TA parameters on univariate analysis included both parameters from the histogram distribution, as well from the matrix of GLCM. On logistic regression analysis the significant parameters were L5-energy [P=0.033, odds ratio (OR): 1.997, 95% CI: 1.059-3.767] and FH-Skewness (P=0.014, OR: 2.338, 95% CI: 1.191-4.591), with a R2: 0.268. A ROC curve was generated from the binary logistic regression, and the AUC was 0.741 (95% CI: 0.627-0.855, P=0.001, S.E.: 0.058). Conclusions In our experience, 3D-bone CT TA can be used to stratify the risk of the patients to develop radiation-induced IFs. A prospective study will be conducted to validate these findings.

Patients Affected by Unmethylated O(6)-Methylguanine-DNA Methyltransferase Glioblastoma Undergoing Radiochemotherapy May Benefit from Moderately Dose-Escalated Radiotherapy

Purpose To compare the therapeutic results of two radiotherapy (RT) dose schedules in combined temozolomide- (TMZ-) RT treatment in newly diagnosed glioblastoma (GB), according to the O(6)-methylguanine-DNA methyltransferase (MGMT) methylation status. Material and Method Patients received either standard (60 Gy) or moderately escalated dose (70 Gy) radiotherapy (RT) with concomitant and adjuvant TMZ between June 2006 and October 2013. We retrospectively evaluated the therapeutic effectiveness of RT schedules in terms of Overall Survival (OS) and Progression-Disease Free Survival (PDFS) analyzing the MGMT methylation status. Results One hundred and seventeen patients were selected for the present analysis. Seventy-two out of the selected cases received the standard RT-TMZ course (SDRT-TMZ) whereas the remaining 45 underwent the escalated schedule (HDRT-TMZ). The analysis according to the MGMT promoter methylation status showed that, in unmethylated-MGMT GB patients, HDRT-TMZ and SDRT-TMZ groups had different median OS (p = 0,01) and PDFS (p = 0,007), that is, 8 months and 5 months for the SDRT-TMZ group and 14 months and 9 months for the HDRT-TMZ group, respectively. No difference in survival outcomes was found in methylated MGMT patients according to the two RT schedules (p = 0,12). Conclusions In our experience, unmethylated-MGMT GB patients benefited from a moderately escalated dose of RT plus TMZ.

Automatic segmentation of glioblastoma for radiation therapy treatment planning

During the radiation therapy (RT) process, the treatment is planned and simulated with a treatment planning system (TPS): the organs at risk (OAR) and the tumor target are identified and contoured, and the RT dose, delivered by the planned photon beams, is obtained for optimization of the resulting plan. The contouring work-up of tumor target identifies the Planning Treatment Volume (PTV), i.e. the physical RT treatment volume. PTV of glioblastomas (GB) includes, after expansion, Gross Tumor Volume (GTV, the tumor) and Clinical Target Volume (CTV, tumor plus edema). Usually, GTV contouring is performed manually. In this work, we used GlioCAD, a Computer-Assisted Detection software for automatic contouring of gliomas in MRI/DTI, to delineate GTV. The dataset included the images of 21 patients undergoing RT for GB. For each patient, we co-registered CT-planning images and diagnostic MRI (16 T1-gad, 6 T2 Flair, 13 Flair Fat Sat), which were used for GlioCAD training and validation. CAD outlined the tumor with good accuracy, after ruling out some false positives in post-processing. We identified GTVs, suitable for RT requirements. An evolution of GlioCAD will take into account edema for outlining CTV. The method seems promising. A further automatic system for the delineation of sites at risk in the brain is under development, which may be helpful for standardization of RT-treatment planning.

A Husband and a Wife with Simultaneous Presentation of Glioblastoma Multiforme: A Case Report

Glioblastoma multiforme (GBM) is the most lethal subtype of glioma, classified as a WHO grade 4 infiltrative glioma. The etiology of GBM remains unknown and risk factors can be identified only in a small minority. We report the synchronous occurrence of GBM in an otherwise unrelated married couple, i.e. a husband and his wife, who developed GBM within an interval of 1 month. No specific causative environmental factors were identified for both patients, and the genetic screens were negative for hereditary syndromes. Family history was negative for tumors, and no other incidence of cancer in either siblings, parents or other children was reported. An analysis of the couples exposure to nonionizing electromagnetic fields and ionizing radiations revealed values within the normal ranges usually found in homes. Overall, conjugal tumors are rarely reported. However, the case reported herein raises important questions about possible etiologic factors.