IntroductionRadionecrosis is a consequence of SRS (stereotactic radiosurgery) for brain metastases in 34% of cases, and if symptomatic (8%–16%), it requires therapy with corticosteroids and bevacizumab and, less frequently, surgery. Oncological indications are increasing and appropriate stereotactic adapted LINACs (linear accelerators) are becoming more widely available worldwide. Efforts are being made to treat brain radionecrosis in order to relieve symptoms and spare the use of active therapies.Case presentationHerein, we describe a 65-year-old female patient presenting with brain radionecrosis 6 months after stereotactic radiotherapy for two brain metastatic lesions. Being symptomatic with headache and slow cognitive-motor function, the patient received corticosteroids. Because of later lung progression, the patient took cabozantinib. An impressive reduction of the two brain radionecrosis areas was seen at the brain MRI 2 months after the initiation of the angiogenic drug.DiscussionThe high incidence of radionecrosis (2/2 treated lesions) can be interpreted by the combination of SRS and previous ipilimumab that is associated with increased risk of radionecrosis. The molecular mechanisms of brain radionecrosis, and its exact duration in time, are poorly understood. We hypothesize that the antiangiogenic effect of cabozantinib may have had a strong effect in reducing brain radionecrosis areas.ConclusionIn this clinical case, cabozantinib is associated with a fast and significant volume reduction of brain radionecrosis appearing after SRS and concomitant immunotherapy. This drug seems to show, like bevacizumab, clinical implications not only for its efficacy in systemic disease control but also in reducing brain radionecrosis. More research is needed to evaluate all molecular mechanisms of brain radionecrosis and their interaction with systemic therapies like third-generation TKIs.

Aim: Gliomatosis cerebri (GC) is defined as a rare pattern of growth of diffuse gliomas involving three or more cerebral lobes. Given its rarity, it is difficult to define prognostic factors and standard of treatment. We retrospectively analyzed patients (PT) with GC from a single institution with the aim of identifying the main prognostic factors and to assess optimal management. Methods: Medical records were reviewed of patients >= 18 years with a histological and/or radiological diagnosis of GC (with no contrast enhancement) occurring between 2006 and 2017. Median progression free survival ( PFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Results: We analyzed 33 PT, 22 males and 11 females; Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-1 in 21 of the patients. Twenty-two PT underwent biopsy: 16 were astrocytomas and 6 oligodendrogliomas. O6-methylguanin-DNA-methyltransferase (MGMT) was detected in 14 cases, and it was methylated in eight cases. Isocitrate dehydrogenase 1 (IDH1) was analyzed in 16 PT, and it had mutated in 10 of them. Nine PT (27%) were treated with radiation therapy (RT) plus concurrent temozolomide (TMZ), 22 PT (67%) received TMZ alone, and 2 PT (6%) underwent RT alone. We reported "complete response" in 1 patient (3%), partial response in 9 PT (27%), and stable disease in 15 PT (45%), while 8 PT (25%) had a progressive disease. For all PT, PFS and OS were 19.1 and 30.7 months, respectively. For ECOG PS 0-1 and = 2, PFS was 34.6 months vs. 3.4 months (P < 0.0001) and OS was 42 months vs. 8.9 months (P < 0.0001), respectively. Methylated MGMT was associated with longer PFS (41.6 months vs. 8.9 months, P = 0.05) and OS (52.7 months vs. 14.6 months, P = 0.009); PFS for IDH1 mutation and IDH wild-type was 52.7 months vs. 8.9 months (P = 0.006) and OS was 52.7 months vs. 41.7 months ( P = 0.02), respectively. No significant difference was detected as regards treatments. With regard to histological subtype, OS was 42.0 months vs. 52.7 months (P = 0.8) and PFS was 41.6 months vs. 28.6 months (P = 0.7) for astrocytoma vs. oligodendroglioma, respectively. PT with treatment response showed a longer OS. PT receiving second-line treatment had a longer OS of 30.7 months vs. 6.5 months (P = 0.04). Conclusion: ECOG PS, MGMT methylation, and IDH1 mutational status seem to have an important prognostic significance, while the type of treatment does not seem to affect survival. Treatment response could be a surrogate marker for survival.

Anaplastic Astrocytoma(AA) is a malignant, diffusely infiltrating, primary brain tumor. According to the WHO 2016 classification of central-nervous-system tumors, AA has been described as a glial tumor with no co-deletion of 1p/19q, and is divided into IDH mutated tumor, characterized by better prognosis, and IDH wild-type form, with worse prognosis. The standard of care is maximal safe resection followed by radiotherapy and chemotherapy with temozolomide. Several efforts have been made to evaluate, according to molecular selection, which is the best post-surgical treatment. At recurrence, the treatment remains challenging and some trials are ongoing to evaluate new potential drugs, alone or in combination with chemotherapy. We performed a description of the status of the art on diagnosis, molecular characteristics and treatment of AA. In particular, we focused our details on new drugs; indeed, a deeper knowledge of the molecular characteristics of gliomas could lead to to development of active personalized treatments according with precision medicine.

A previous article sought to signpost papers that were considered helpful when starting on the journey of practicing evidence-based medicine (EBM).1 The lead author was invited to run a workshop at the Eighth Conference of the International Society for Evidence-Based Health Care run in collaboration with the Gruppo Italiano per la Medicina Basata sulle Evidenze from 6 November to 9 November 2019. The aim of the workshop was to challenge a group of teachers and educators to consider useful papers for the teaching of EBM/evidence-based healthcare (EBHC). The second aim was to start a database of such studies. The third aim was to share learning and foster discussion from the workshop through journal publication. EBM and EBHC are used interchangeable throughout this article. Working in eight small groups (three to five people), teachers and researchers of EBM/EBHC (n=29) first listed any articles that they considered useful for new teachers starting out their teaching journey. So that the challenge also acted as learning for the participants, they were deliberately not briefed on the full nature of the workshop (eg, the consideration and selection of specific articles). After 15 min, each group spent another 10 min selecting their top three articles from their original list (if this list had more than three papers). This was followed by another 5 min selecting their final article to put forward for this paper consensus and any disagreements resolved via discussion. Groups had to provide the following information for each paper: authors; year of publication; title; reason(s) for inclusion; link to paper/reference. Learning from previous experiences, the workshop lead (DN) instructed that a group could not select an article for which a group member was an author thus avoiding one possible source of conflict. As a group we felt that this specific rule of the article selection process …

BackgroundRecently we defined a user-friendly tool (FADOI-COMPLIMED scores-FCS) to assess complexity of patients hospitalized in medical wards. FCS-1 is an average between the Barthel Index and the Exton-Smith score, while FCS-2 is obtained by using the Charlson score. The aim of this paper is to assess the ability of the FCS to predict mortality in-hospital and after 1-3-6-12-months. In this perspective, we performed comparisons with the validated Multidimensional Prognostic Index (MPI).MethodsIt is a multicenter, prospective observational study, enrolling patients aged over 40, suffering from at least two chronic diseases and consecutively admitted to Internal Medicine departments. For each patient, data from 13 questionnaires were collected. Survival follow-up was conducted at 1-3-6-12 months after discharge. The relationships between cumulative incidences of death with FCS were investigated with logistic regression analyses. ROC curve analyses were performed in order to compare the predictiveness of the logistic models based on FCS with respect to those with MPI taken as reference.ResultsA cohort of 541 patients was evaluated. A 10-point higher value for FCS-1 and FCS-2 leads to an increased risk of 1-year death equal to 25.0% and 27.1%, respectively. In case of in-hospital mortality, the relevant percentages were 63.1% and 15.3%. The logistic model based on FCS is significantly more predictive than the model based on MPI (which requires an almost doubled number of items) for all the time-points considered.ConclusionsAssessment of prognosis of patients has the potential to guide clinical decision-making and lead to better care. We propose a new, efficient and easy-to-use instrument based on FCS, which demonstrated a good predictive power for mortality in patients hospitalized in medical wards. This tool may be of interest for clinical practice, since it well balances feasibility (requiring the compilation of 34 items, taking around 10 minutes) and performance.

PURPOSE:To assess the contribution of Italian radiation oncologists in the current management of recurrent high-grade gliomas (HGG), focusing on a reirradiation (reRT) approach.METHODS:In 2015, the Reirradiation and the Central Nervous System Study Groups on behalf of the Italian Association of Radiation Oncology (AIRO) proposed a survey. All Italian radiation oncologists were individually invited to complete an online questionnaire regarding their clinical management of recurrent HGG, focusing on a reRT approach.RESULTS:A total of 37 of 210 questionnaires were returned (18% of all centers): 16 (43%) from nonacademic hospitals, 14 (38%) from academic hospitals, 5 (13%) from private institutions, and 2 (6%) from hadron therapy centers. The majority of responding centers (59%) treated ≤5 cases per year. Performance status at the time of recurrence, along with a target diameter <5 cm and an interval from primary radiation ≥6 months, were the prevalent predictive factors considered for reRT. Sixty percent of reirradiated patients had already received a salvage therapy, either chemotherapy (40%) or reoperation (20%). The most common approach for reRT was fractionated stereotactic radiotherapy to a mean (photon) dose of 41.6 Gy.CONCLUSIONS:Although there were wide variations in the clinical practice of reRT across the 37 centers, the core activities were reasonably consistent. These findings provide a basis for encouraging a national collaborative study to develop, implement, and monitor the use of reRT in this challenging clinical setting.

GC is defined as a rare pattern of growth of gliomas, involving three or more cerebral lobes. Considering its rarity, it’s still difficult to define prognostic factors and standard of treatment. Retrospectively, we analyzed patients (PT) with GC from two neuro-oncology centers to identify main prognostic factors and the optimal management. Medical records of patients ≥ 18years, with histological and/or radiological diagnosis of GC occurred between 2006 and 2017 were reviewed. Median progression free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier method. We analyzed 33PT, 22males and 11female; ECOG performance status (PS) was 0–1 in 21PT and ≥ 2 in 12PT. 22PT underwent biopsy: 16 were astrocytomas, 6oligodendrogliomas. MGMT was detected in 14PT: it was metilated in 8cases. IDH1 was analyzed in 16PT: it was mutated in 10PT. 15 of 33PT showed localized enhancing lesions at diagnosis. 9PT(27%) were treated with radiation therapy (RT) plus concurrent temozolomide (TMZ), 22PT(67%) received only TMZ, and 2PT(6%) underwent RT alone. Best response was complete response (CR) in 3PT(3%), partial response (PR) in 9PT(27%) and stable desease (SD) for 15PT(45%); only 8PT(25%) had a progression desease (PD). For all PT, PFS and OS were 19.1 and 30.7 months (ms) respectively. For PS 0–1 and ≥2, PFS was 34.6 vs 3.4ms (p<0.0001) and OS was 42 vs 8.9ms (p<0.0001) respectively. Metilated MGMT was associated with longer PFS (41.6 vs 8.9ms, p=0.05) and OS (52.7 vs 14.6ms, p=0.009); for IDH1 mutated and IDH wt, PFS was 52.7 vs 8.9ms (p=0.006) and OS was 57.7 vs 41ms (p=0.02) respectively. No significantly difference was detected about treatments: PFS was 11.1 vs 19.1ms and OS was 40.4 vs 41.7ms for RT+TMZ and TMZ/RT alone, respectively. No significantly difference was found beetween enhancing and non-enhancing lesions: PFS was 11.1 vs 23.1ms (p=0.2), OS was 14.6 vs 41.7ms (p=0.1). Regarding histological subtype, OS was 42.0 vs 52.7ms and PFS was 41.6 vs 28.6ms for astrocytoma vs oligodendroglioma respectively. PT having PR or CR reported a longer OS versus PT with SD and PD as best response: 4.0ms for PD, 30.7ms for SD and 38.5ms for PR+CR (p<0.0001). 13 of 22PT underwent second-line treatment after relapsing: 1PT did RT+TMZ, 10PT chemotherapy alone (fotemustina, PCV/PC, TMZ), and 2PT RT alone; PTS receiving a second-line treatment had a longer OS: 30.7 vs 6.5ms (p=0.04). PS, MGMT and IDH1 seems to have an important prognostic significance, whereas, type of treatment doesn’t seem to affect survival. Best response could be a good surrogate of OS.

There are many feasible tools for the assessment of clinical practice, but there is a wide consensus on the fact that the simultaneous use of several different methods could be strategic for a comprehensive overall judgment of clinical competence. Multiple-choice questions (MCQs) are a well-established reliable method of assessing knowledge. Constructing effective MCQ tests and items requires scrupulous care in the design, review and validation stages. Creating high-quality multiple-choice questions requires a very deep experience, knowledge and large amount of time. Hereby, after reviewing their construction, strengths and limitations, we debate their completeness for the assessment of professional competence.

Internal medicine patients are mostly elderly with multiple comorbidities, usually chronic. The high prevalence of comorbidity and multimorbidity has a significant impact on both positive responses to treatment and the occurrence of adverse events. Clustering is the process of nosography grouping into meaningful associations with some index disease, so that the objects within a cluster have high similarity in comparison with one another. In the decision-making process it is imperative that, in addition to understanding the immediate clinical problems, we are able to explicit all the contextual factors that have to be taken into account for the best outcome of care. Cluster analysis could be leveraged in developing better interventions targeted to improve health outcomes in subgroups of patients.

Glioblastoma is the most common and aggressive primitive brain tumor in adults. Temozolomide (TMZ) administered daily with radiation therapy, followed by adjuvant TMZ has become the standard treatment. Although TMZ treatment has been considered to have a low toxicity profile, studies have noted the development of a severe myelosuppression, especially during the concomitant treatment; this toxicity may in some cases be prolonged and consequently treatment must be definitively discontinued. We analyzed two cases treated at our oncological center who developed severe and prolonged hematological toxicity during concomitant chemoradiotherapy treatment with TMZ. Hypothesizing that radiation therapy and daily TMZ could be the major causes of severe hematological toxicity during the concomitant phase, we decided to treat both patients with maintenance TMZ at the time of recovery of hematological values. Patients showed good tolerability without important myelosuppression. In conclusion, we suggest that glioblastoma patients with severe myelotoxicity during daily TMZ and radiation therapy be treated with maintenance TMZ at the time of blood value recovery.

Acute pyelonephritis (aPN) is defined as a severe form of urinary tract infection. Despite its severity and the high incidence in the community setting, there is no consensus on the optimal duration of treatment. The aim was to compare effectiveness and tolerability of short- versus long-course treatment with the same antibiotic agent in patients with aPN. We searched MEDLINE (PubMed), EMBASE and CENTRAL up to June 2016 for randomized controlled trials (RCTs). Three pairs of authors independently extracted data and appraised risk of bias. We included 4 RCTs (439 participants). Short antibiotic treatment lasted from 4 to 14 days and long treatment from 7 to 42 days but was at least 2 days longer than the corresponding short-course. At the end of treatment, we did not find any significant differences in clinical success [risk ratio (RR) 1.01; 95% confidence interval (CI), 0.96-1.07, moderate quality evidence] as well as in microbiological success (RR 0.99; 95% CI, 0.92-1.07, very low-quality evidence). At 4-6 weeks after the end of treatment there were no significant differences in clinical relapses (RR 1.20, 95% CI 0.43-3.30, very low-quality evidence) and re-infection of other germs (RR 2.40; 95% CI, 0.68-8.49, very low-quality evidence), even if short-term therapy seemed to have more risk of recurrences (RR 2.39, 95% CI 1.19-4.83, very low quality of evidence). The incidence of any adverse effect seemed to be lower with the short-term therapy, though the results are not statistically significant (RR 0.63, 95% CI 0.39-1.02, low quality evidence). Short-term treatment for aPN seems to be equivalent to long-term treatment in terms of clinical and microbiological success at the end of treatment or tolerability. The only relevant difference is the frequency of recurrence of the same biological germ up to 4-6 weeks after the end of treatment, which is significantly higher with the short-term therapy.

The purpose of the study was to evaluate the clinical outcome of the association of BCNU wafers implantation and 5-aminolevulinic acid (5-ALA) fluorescence in the treatment of patients with newly diagnosed glioblastoma (ndGBM). Clinical and surgical data from patients who underwent 5-ALA surgery followed by BCNU wafers implantation were retrospectively evaluated (20 patients, Group I) and compared with data of patients undergoing surgery with BCNU wafers alone (42 patients, Group II) and 5-ALA alone (59 patients, Group III). Patients undergoing 5-ALA assisted resection followed by BCNU wafers implantation (Group I) resulted long survivors (>3 years) in 15 % of cases and showed a median PFS and MS of 11 and 22 months, respectively. Patients treated with BCNU wafers presented a significantly higher survival when tumor was removed with the assistance of 5-ALA (22 months with vs 18 months without 5-ALA, p < 0.0001); these data could be partially explained by the significantly higher CRET achieved in patients operated with 5-ALA assistance (80 % with vs 47 %% without 5-ALA). Moreover, patients of Group I showed a significant increased survival compared with Group III (5-ALA without BCNU) (22 months with vs 21 months without BCNU wafers, p = 0.0025) even with a comparable CRET (80 % vs 76 %, respectively). The occurrence of adverse events related to wafers did not significantly increase with 5-ALA (20 % with and 19 % without 5-ALA) and did not impact in survival outcome. In conclusion, our experience shows that on selected ndGBM patients 5-ALA technology and BCNU wafers implantation show a synergic action on patients’ outcome without increasing adverse events occurrence.

Background: MGMT gene promoter methylation status is acknowledged as a prognostic factor and predictive marker for temozolomide (TMZ) treatment. Although MGMT status determined by pyrosequencing was showed to correlate with progression free survival (PFS) and overall survival (OS), it is still unclear a cut-off value that discriminates between methylated and unmethylated patient (pts) and its correlation with the patient clinical outcome. Matherials and Methods: We analyzed the tissue samples from 128 PTS diagnosed with GBM from November 2009 to December 2015. All PTS underwent treatment with RT + TMZ and had an ECOG-PS 0-2. Methylation percentage for each sample was obtained by calculating the average methylation of all 10CpG sites (75-84) of MGMT promoter by pyrosequencing analysis. PTS with 0-6% of methylation were classified as unmethylated (UM), PTS with 7-24% as low methylated (LM) and PTS with ≥ 25% as high methylated (HM). 25% was the median value of methylation of our PTS having >6% of methylation. Results: Median age was 60 yrs (range 25-84), 60.9% were male, 74.2% had an ECOG PS 0-1, 50.8% underwent radical surgery, 85 PTS were dead at the time of analysis. 75 PTS were UM, 26 PTS were LM and 27 PTS were HM. On univariate analysis HM, LM and UM showed a PFS of 15.8, 10 and 9.1 ms, respectively (p=0.1). OS was 38.7, 21 and 18.8ms (p= 0.06). On multivariate analysis UM and LM PTS had a statistically lower PFS vs HM PTS (HR=2.57; p=0.001; HR= 2.5; p=0.007, respectively) and statistically lower OS (HR=3.47; p<0.001; HR=2.63; p=0.016; respectively). No significant difference was showed between UM and LM PTS in terms of PFS and OS, both on univariate and multivariate analyses. Conclusions: MGMT promoter methylation status determined by pyrosequencing analysis may correlate to PFS and OS. We found a cut-off of 25% of methylation which determined two sub-groups of PTS having different clinical outcome; in particular, HM PTS had a significant longer PFS and OS.

Brain metastases are a serious relatively common complication of breast cancer. We evaluated prognostic factors for survival after diagnosis of brain metastases from breast cancer in a contemporary cohort of patients. Patients diagnosed with breast cancer brain metastases at our institution between 1999 and March 2016 were evaluated. Overall survival was defined as time from brain metastasis diagnosis to death or last follow-up. Patients were classified according to the Breast cancer-specific Graded Prognostic Assessment (BS-GPA), based on age, Karnofsky performance score and breast cancer phenotype. 181 patients were identified. Tumor phenotype distribution was as follows: triple negative (TN, 18.8%), hormone receptor (HR)−HER2+ (16.6%), HR+HER2+ (23.2%) and HR+HER2− (30.9%), not available (10.5%). Median overall survival from brain metastasis diagnosis was 7.7 mos (95% CI 5.4–10.0 mos). Although TN patients experienced the worse outcome, no significant difference was observed across tumor phenotypes (median 5.1, 7.7, 11.0 and 8.6 months in TN, HR−HER2+, HR+HER2+, HR+HER2−, p = 0.081). The BS-GPA index was significantly associated with overall survival (median 18.8, 8.8, 6.2 and 3.6 months, respectively, for BS-GPA categories 3.5–4, 2.5–3, 1.5–2 and 0–1, p = 0.014). Increased number of local treatments for brain metastasis (radiotherapy or neurosurgery) or the administration of systemic therapy after brain metastasis diagnosis were also significant predictors of better overall survival (p < 0.001) and, when evaluated in multivariate analysis with BS-GPA, both added independent prognostication beyond BS-GPA. Patient-related features, tumor phenotype and multimodal treatments all independently contribute to modulate prognosis of patients diagnosed with breast cancer brain metastases.

Background: various prospective clinical trials on high-grade gliomas were performed in the last years but patient (PTS) characteristics and outcome may be different in real clinical practice. We performed a retrospective analysis to evaluate the real-life experience in Padua Neuro-Oncology center. Matherials and Methods: retrospectively, we reviewed the medical records of PTS admitted to our observation from June 2010 to June 2015 with a diagnosis of AA or GBM. We analyzed clinical outcome with prognostic factors. Results: we analyzed 592 PTS with a diagnosis of CNS primary tumor. Among these, we enrolled 395 PTS: 33 (8.4%) with a histological diagnosis of AA, 293 (74%) with a histological diagnosis of GBM and 69 (17.4%) with a radiological diagnosis of GBM. At diagnosis, median age was 63.2 (range 24-88), 61.8% were male; 80% of PTS had an ECOG PS 0-2. Among PTS who underwent surgery, 48% had a radical surgery; 279 PTS (70.6%) performed RT in association to chemotherapy. 17% of PTS performed a second surgery at relapse and 45% a second-line treatment. MGMT was analyzed in all PTS who underwent surgery: it was methylated in 38.7% of PTS, IDH1 was mutated in 6%. GBM PTS with ECOG PS 0-2 and >2 had a median OS of 21.1 and 7.2 ms, respectively. GBM PTS with met and unmet MGMT had a mOS of 22.7 and 13.7 ms (p=0.005). AA PTS with met and unmet MGMT had a mOS of 29.5 and 16.6 ms (p=0.03). Considering all high-grade gliomas, PTS with met MGMT + mutIDH1 reported a mOS of 23.1ms, PTS with metMGMT + wtIDH1 had a mOS of 20.9 ms and PTS with unmetMGMT + wtIDH1 showed a mOS of 12.6ms (p<0.001). On multivariate analysis, ECOG PS 0-2 (HR=0.6), radical surgery (HR=0.7), methylated MGMT (HR=0.5) and PTS receiving a second-line chemoterapy (HR=0.7) were positive prognostic factors in terms of OS. Conclusions: in our real-life experience most PTS underwent surgery, performed a radiation therapy in association to chemotherapy and nearly half of PTS performed a second-line chemotherapy, although a subset of PTS had a poor performance status. However, we reported a good clinical outcome demonstrating the importance of molecular characterization in these PTS. Type of surgery, ECOG PS, MGMT methylation and lines of chemotherapy were independent prognostic factors.

Background: The efficacy of Temozolomide(TMZ) plus radiation therapy(RT) in elderly patients with glioblastoma is unclear. We performed a large multicenter retrospective study to analyze prognostic factors and clinical outcome in these patients. Patients and methods: inclusion criteria for this multicenter retrospective study were age ≥65 years, newly histologically confirmed glioblastoma, ECOG PS 0-2, adjuvant treatment with RT plus TMZ. Generally, brain MRI was performed every 2 or 3 months. Survival curves were performed by Kaplan-Meier methods. Results: we enrolled 237 patients; the average age was 71 and ECOG PS was 0-1 in 196 patients; radical/subtotal surgery was performed in 174 cases. MGMT was analyzed in 151 patients and was methylated in 56%. IDH1 was assessed in 100 patients and was mutated in 6%. Seventy-one patients were treated with RT 40Gy and 166 with RT 60Gy. Progression-free survival (PFS) and overall survival (OS) were 11.3 and 17.3 months, respectively. Overall Survival was 19.4 vs 13.8 months for patients treated with RT 60Gy and 40Gy (p = 0.02); OS was 17.7 vs 16.1 months for patients treated with radical/subtotal surgery vs partial/biopsy surgery (p = 0.02); OS was 21.2 vs 13.6 months for methylated and unmethylated MGMG (p < 0.001). On multivariate analysis, radical/subtotal surgery, RT 60Gy, methylated MGMT and ECOG PS 0-1 were independent predictors of longer survival. Twenty-five patients (10%) had grade 3-4 haematological toxicity during the concomitant treatment. Conclusions: Concomitant treatment is effective and safe in GBM elderly patients, especially in patients with an optimal performance status. In these patients, an aggressive approach with an extensive surgery and standard therapy may be useful. Mutant IDH1 patients showed a trend for better outcome while MGMT methylation status was the most important prognostic factor.

The efficacy of temozolomide (TMZ) plus radiation therapy (RT) in elderly patients with glioblastoma is unclear. We performed a large multicenter retrospective study to analyze prognostic factors and clinical outcome in these patients. Inclusion criteria were age ≥65 years, newly histologically confirmed glioblastoma, ECOG PS 0-2, adjuvant treatment with RT plus TMZ. We enrolled 237 patients; the average age was 71 and ECOG PS was 0-1 in 196 patients; gross total resection was performed in 174 cases. MGMT was analyzed in 151 persons and was methylated in 56 %. IDH1 was assessed in 100 patients and was mutated in 6 %. Seventy-one patients were treated with RT 40 Gy and 166 with RT 60 Gy. Progression-free survival and overall survival (OS) were 11.3 and 17.3 months, respectively. Overall survival was 19.4 vs 13.8 months for patients treated with RT 60 Gy and 40 Gy (p = 0.02); OS was 17.7 versus 16.1 months for patients treated with gross total resection vs partial surgery (p = 0.02); OS was 21.2 versus 13.6 months for methylated and unmethylated MGMT (p < 0.001). On multivariate analysis, gross total resection, RT 60 Gy, methylated MGMT and ECOG PS 0-1 were independent predictors of longer survival. Twenty-five patients (10 %) had grade 3-4 haematological toxicity during the concomitant treatment. We showed that, in elderly patients in good clinical condition treated with concomitant treatment, standard-course irradiation might be more effective than short-course irradiation. Methylated MGMT remains the most important prognostic factor.

Background:Temozolomide (TMZ) administered daily with radiation therapy (RT) for 6 weeks, followed by adjuvant TMZ for 6 cycles, is the standard therapy for newly diagnosed glioblastoma (GBM) patients. Although TMZ is considered to be a safe drug, it has been demonstrated to cause severe myelotoxicity; in particular, some case reports and small series studies have reported severe myelotoxicity developing during TMZ and concomitant RT. We performed a prospective study to analyze the incidence of early severe myelotoxicity and its possible clinical and genetic factors.Patients and Methods:From November 2010 to July 2012, newly diagnosed GBM patients were enrolled. They were eligible for the study if they met the following criteria: pathologically proven GBM, age 18 years and older, an Eastern Cooperative Oncology Group performance status of 0 to 2, adequate renal and hepatic function, and adequate blood cell counts before starting TMZ plus RT. Grading of hematologic toxicity developing during radiation and TMZ was based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Clinical factors from all patients were recorded. The methylation status and polymorphic variants of O-6-methylguanine-DNAmethyl-transferase gene in peripheral blood mononuclear cells, and polymorphic genetic variants of genes involved in the pharmacokinetics and pharmacodynamics of TMZ, were analyzed. For genetic analyses, patients with toxicity were matched (1:2) for age, performance status, anticonvulsants, and proton pump inhibitors with patients without myelotoxicity.Results:We enrolled 87 consecutive GBM patients: 32 women and 55 men; the average age was 60 years. During TMZ and RT, 4 patients (5%) showed grade 3-4 myelotoxicity, and its median duration was 255 days. Predictor factors of severe myelotoxicity were female sex, pretreatment platelet count of 3,00,000/mm(3), methylated O-6-methylguanine-DNA methyltransferase promoter in the hematopoietic cell system, and specific polymorphic variants of the cytochrome P450 oxidoreductase and methionine adenosyltransferase 1A genes.Conclusions:Although we studied a small population, we suggest that both clinical and genetic factors might simultaneously be associated with severe myelosuppression developed during TMZ plus RT. However, our results deserve validation in larger prospective studies and, if the factors associated with severe myelotoxicity are validated, dose adjustments of TMZ for those patients may reduce the risk of severe myelotoxicity during the concomitant treatment.

Aim: Intraoperative radiotherapy (IORT) is now an acceptable option for low risk early stage breast cancers, allowing patients not to undergo a full course of external radiotherapy. It is not clear, however, whether IORT, providing radiations very close to the chest wall, may produce heart damage. In this study we tried to evaluate if acute or chronic heart damage in early stage breast cancer patients treated with breast conservative surgery (BCS) and IORT, can be assessed by ultra-sensitive cardiac Troponine I (TnI) levels or N-terminal proB-type natriuretic peptide (NT-proBNP), respectively. Materials and methods: We enrolled 43 patients who received IORT for breast cancer, as part of a TARGIT-A trial. Twenty-two patients had left and 21 right breast cancer. TnI levels were measured immediately before surgery, and six hours after the end of IORT; both TnI and NT-proBNP levels were measured after 12 months. For the patients with left breast cancer, a little tungsten sheet was placed under the major pectoralis muscle, on the chest projection of the X-ray source, in order to protect the heart. Results: None of the patients showed altered serum levels of TnI before surgery, or after IORT procedure and NT-proBNP during follow-up. No difference in TnI and NTproBNP values was noticed between right-sided and left-sided breast cancers treated with BCS and IORT. Conclusions: IORT for early stage breast cancer treatment does not increase TnI and NT-proBNP levels, suggesting that the procedure does not determine acute or chronic heart damage.