IDH mutations in G2-3 conventional central bone chondrosarcoma: a mono institutional experience.

BACKGROUND: Heterozygous isocitrate dehydrogenase (IDH) mutations occur in about half of conventional central bone chondrosarcomas (CCBC). Aim of this study was to assess the frequency and prognostic impact of IDH mutations in high grade CCBC patients. METHODS: 64 patients with G2 and G3 CCBC were included. DNA extraction, PCR amplification of IDH1/2 exon 4s, and sequencing analysis with Sanger were performed. RESULTS: IDH mutations were detected in 24/54 patients (44%): IDH1 in 18, IDH2 in 4, and both IDH1/2 in 2 patients. The frequency of mutations was 37% in G2 vs. 69% in G3 (p = 0.039), and 100% in three Ollier disease associated chondrosarcoma. 5-year overall survival (OS) at 124 months (range 1-166) was 51%, with no significant difference based on the IDH mutational status: 61% in IDHmut vs. 44% in IDH wild type (IDHwt). The 5-year relapse free survival (RFS) was 33% (95% CI:10-57) for IDHmut vs. 57% (95%CI: 30-77) for IDHwt. Progression free survival (PFS) was 25% (95%CI:1-65) IDHmut vs. 16% (95%CI: 0.7-52) IDHwt. 55% (5/9) of IDHmut G2 became higher grade at the recurrence, as compared with 25% (3/12) of G2 IDHwt. CONCLUSIONS: This study shows a higher frequency of IDH mutations in G3 CCBC as compared with G2. No significant differences in OS, RFS, and PFS by mutational status were detected. After relapse, a higher rate of G3 for IDH mutated CCBC was observed.

Prevalence and clinical impact of incidental findings on the unenhanced CT images of PET/CT scan in patients with multiple myeloma: the value of radiological reporting in the multimodal hybrid imaging.

OBJECTIVE: In the hybrid Positron Emission Tomography/Computed Tomography (PET/CT) method, the functional evaluation is integrated with the morphological information provided by co-registered CT, still performed for attenuation correction and lesion localization. However, co-registered CT images could provide additional diagnostic information that PET alone could underestimate. To optimize the diagnostic potential of this hybrid examination, we evaluated the prevalence and the clinical significance of incidental findings detected on co-registered CT images in a cohort of multiple myeloma (MM) patients. PATIENTS AND METHODS: We evaluated 112 MM patients (mean age 65.8 y), who underwent [18F]FDG-PET/CT during their regular workup. All co-registered CT images were retrospectively reviewed by two expert radiologists and each non-myelomatous incidental finding (nM-IF) was collected and clinically graded according to a nM-IF Reporting and Data System (nM-RADS). In addition, nM-IFs were classified according to anatomic localization (skull, lung, mediastinum, abdomen, breast, gastrointestinal, genitourinary and cardiovascular system and muscle/soft tissue). RESULTS: 163 nM-IFs were detected in 94/112 patients (83.9%) (mean value: 1.5 IFs per patient). The most interested anatomic districts were the lung (n=33; 20.2%), genitourinary (n=33; 20.2%) and gastrointestinal (n=30; 18.4%) systems. Focusing on the clinically significant findings (nM3+nM4), 92/163 (56.4%) IFs could have been required further investigations, of which 38/163 (23.3%) were potentially important and detected in 33/112 (29.5%) patients. CONCLUSIONS: The high percentage of potentially clinically significant IFs detected in MM patients emphasizes that co-registered CT images hold precious information often missed. Giving more relevance to co-registered CT with tailored acquisition and reconstruction protocols and dedicated reporting could optimize the potentiality of this multimodality imaging method with impact on clinical management.

Psychopharmacological treatment in borderline personality disorder: A pilot observational study in a real-world setting.

Psychotherapy is the cornerstone of treatment for borderline personality disorder (BPD) while pharmacotherapy should be considered only as an adjunctive intervention. In clinical practice, however, most of BPD patients only receive medication. The aim of the study is to first describe pharmacological treatment in BPD patients in Italy and secondly to evaluate if comorbidity or illness severity are associated with the prescription of different class compounds. Data on pharmacological treatment and clinical evaluation of 75 BPD patients were collected in 5 clinical settings. The association between comorbidity and medication was assessed. Moreover, we evaluated the association between pharmacotherapy and severity, defined by a cluster analysis aimed at detecting different groups of patients. Most of the participants (82.7%) were characterized by polypharmacy, with a mean of 2.4 medications per person. Interestingly, the prescription didn't seem to depend on/be based on the severity of the disorder and was only partially determined by the presence of comorbidity. In conclusion, our findings are similar to what described in other clinical studies, supporting the idea that medication management for BPD is only partially coherent with international guidelines. This pilot study confirms the need for more rigorous studies to gain greater understanding of this topic and diminish the gap between guidelines and the real clinical world.

Impact of pre-treatment variables on the completion of 223radium-dichloride therapy in mCRPC patients with bone metastases.

INTRODUCTION: Radium-223 dichloride (223Ra) is an alpha-particle-emitter radiopharmaceutical, approved for metastatic castration-resistant prostate cancer (mCRPC) patients with symptomatic bone metastases and no visceral involvement. Its administration is based on a schedule of intravenous injection (55kBq/kg) every four weeks for up to six cycles. Because the biological effectiveness of 223Ra-therapy is dose-dependent, the main goal is to complete the entire treatment to achieve a better patient outcome. This study aims to identify potential pre-treatment variables that could impact on 223Ra-treatment completion and then be used to improve the clinical and supportive management of mCRPC patients. MATERIALS AND METHODS: 30 consecutive mCRPC patients (mean age 77 years old), who were admitted for Ra223-therapy at our Department from February 2016 to October 2018, were enrolled for the analysis. The population was grouped as patients who completed 223Ra-therapy (group Ra223-C) and patients who do not (group 223Ra-U). For each group, we analyzed the effects of potential pre-treatment variables (age, Gleason Score, tumor burden, "Time From Diagnosis To 223Ra therapy", type and number of previous treatments, hemoglobin level, Alkaline Phosphatase, Prostate Specific Antigen and pain) on the Ra223-therapy completion. Statistical analysis was performed to evaluate the association between the completion of 223Ra therapy and the variables examined. RESULTS: 16/30 (53%) patients were 223Ra-C, conversely 14/30 (47%) patients were 223Ra-U because of an early interrupted treatment. A statistically significant association was found only with tumor burden: 68.7% of patients who completed 223-therapy had less than 20 bone metastases (χ2=4.821, p=0.028). CONCLUSION: Our preliminary analysis demonstrates that the high tumor burden represents the most important pre-treatment factor that could affect treatment completion and that needs to be considered before starting 223Ra-therapy to achieve a better outcome in mCRPC patients.

A radio ridge connecting two galaxy clusters in a filament of the cosmic web.

Galaxy clusters are the most massive gravitationally bound structures in the Universe. They grow by accreting smaller structures in a merging process that produces shocks and turbulence in the intracluster gas. We observed a ridge of radio emission connecting the merging galaxy clusters Abell 0399 and Abell 0401 with the Low-Frequency Array (LOFAR) telescope network at 140 megahertz. This emission requires a population of relativistic electrons and a magnetic field located in a filament between the two galaxy clusters. We performed simulations to show that a volume-filling distribution of weak shocks may reaccelerate a preexisting population of relativistic particles, producing emission at radio wavelengths that illuminates the magnetic ridge.

Predictive value of 18F-FDG PET/CT on survival in locally advanced rectal cancer after neoadjuvant chemoradiation.

OBJECTIVE: To evaluate the prognostic value of 18F-FDG PET/CT in terms of survival in patients with locally advanced rectal cancer (LARC) who had undergone surgery preceded by neoadjuvant chemoradiotherapy (nCRT). Moreover, the existence of correlation between Overall Survival (OS) and Disease Free Survival (DFS) with pathological staging ((y)pTNM and TRG) was evaluated. PATIENTS AND METHODS: A total of 58 patients with biopsy-proven of LARC were included. All patients underwent conventional diagnostic/staging procedures to characterize the rectal lesion. The first whole-body 18F-FDG PET/CT was performed 1 week before the beginning of nCRT (baseline scan). The second 18F-FDG PET/CT was scheduled at 5-6 weeks from nCRT completion (post-nCRT scan). Survival was evaluated in 3 different restaging classification systems, based on focusing only on primary lesion (TRG), loco-regional evaluation (ypTNM) and whole-body 18F-FDG PET/CT evaluation (VRA). RESULTS: Among the 58 patients at the end of the observation, 46/58 patients (79.3%) were alive and 12/58 (20.7%) were dead. This work demonstrated a higher percentage of patients with TRG complete response (39.7%) compared to literature (24.6%), with longer Overall Survival (OS) and Disease Free Survival (DFS) in responders even if without statistically significant differences. CONCLUSIONS: The present study highlights the predictive and prognostic potential role of 18F-FDG PET/CT in assisting physicians on personalized decision in the selective risk-adapted treatment strategy, and to schedule the correct follow-up approach.

Implication of the glutamate-cystine antiporter xCT in schizophrenia cases linked to impaired GSH synthesis.

xCT is the specific chain of the cystine/glutamate antiporter, which is widely reported to support anti-oxidant defenses in vivo. xCT is therefore at the crossroads between two processes that are involved in schizophrenia: oxidative stress and glutamatergic neurotransmission. But data from human studies implicating xCT in the illness and clarifying the upstream mechanisms of xCT imbalance are still scarce. Low glutathione (GSH) levels and genetic risk in GCLC (Glutamate-Cysteine Ligase Catalytic subunit), the gene of limiting synthesizing enzyme for GSH, are both associated with schizophrenia. In the present study, we aimed at determining if xCT regulation by the redox system is involved in schizophrenia pathophysiology. We assessed whether modulating GCLC expression impact on xCT expression and activity (i) in fibroblasts from patients and controls with different GCLC genotypes which are known to affect GCLC regulation and GSH levels; (ii) in rat brain glial cells, i.e., astrocytes and oligodendrocytes, with a knock-down of GCLC. Our results highlight that decreased GCLC expression leads to an upregulation of xCT levels in patients' fibroblasts as well as in astrocytes. These results support the implication of xCT dysregulation in illness pathophysiology and further indicate that it can result from redox changes. Additionally, we showed that these anomalies may already take place at early stages of psychosis and be more prominent in a subgroup of patients with GCLC high-risk genotypes. These data add to the existing evidence identifying the inflammatory/redox systems as important targets to treat schizophrenia already at early stages. SCHIZOPHRENIA: ANTIOXIDANT DEFICIT INCREASES A KEY NEUROTRANSMITTER TRANSPORTER: Deficit of antioxidant synthesis in schizophrenia leads to oxidative stress and changes in neurotransmitter transporter. Led by Kim Do, a team of researchers from Lausanne University in Switzerland investigated the role of the cell-surface transport protein xCT in schizophrenia. They found that an enzyme responsible for antioxidant production is disturbed in patients. This leads to decreased antioxidant levels and consequently to oxidative stress-i.e. the accumulation of reactive oxygen molecules, damaging the cells component and impairing cell functioning-which in turn affects the functioning of the antioxidant pathway, including xCT. xCT, which exports the neurotransmitter glutamate, is thus overproduced in schizophrenia. The resulting increase of neurotransmitter activity, alongside the increase in oxidative stress, is thought to play a major role in the pathophysiology of schizophrenia, including at early stages of the disease.

On-target sorafenib toxicity predicts improved survival in hepatocellular carcinoma: a multi-centre, prospective study.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and has high mortality despite treatment. While sorafenib has a survival benefit for patients with advanced HCC, clinical response is highly variable. AIM: To determine whether development of sorafenib toxicity is a prognostic marker of survival in HCC. METHODS: In this prospective multicentre cohort study, patients with advanced-stage HCC receiving sorafenib were recruited from five international specialist centres. Demographic and clinical data including development and grade of sorafenib toxicity during treatment, radiological response to sorafenib and survival time (months) were recorded prospectively. RESULTS: A total of 634 patients with advanced-stage HCC receiving sorafenib were recruited to the study, with a median follow-up of 6692.3 person-months at risk. The majority of patients were male (81%) with Child-Pugh A stage liver disease (74%) and Barcelona Clinic Liver Cancer stage C HCC (64%). Median survival time was 8.1 months (IQR 3.8-18.6 months). 94% experienced at least one sorafenib-related toxicity: 34% diarrhoea, 16% hypertension and 37% hand-foot syndrome (HFS). Twenty-one per cent ceased sorafenib due to toxicity and 59% ceased treatment due to progressive disease or death. On multivariate analysis, sorafenib-related diarrhoea (HR 0.76, 95% CI 0.61-0.95, P = 0.017), hypertension (HR 0.531, 95% CI 0.37-0.76, P < 0.0001) and HFS (HR 0.65, 95% CI 0.51-0.81, P < 0.0001) were all significant independent predictors of overall survival after adjusting for age, severity of liver disease, tumour stage and sorafenib dose. CONCLUSION: Development of sorafenib-related toxicity including diarrhoea, hypertension and hand-foot syndrome is associated with prolonged overall survival in patients with advanced-stage HCC on sorafenib.

Impaired fornix-hippocampus integrity is linked to peripheral glutathione peroxidase in early psychosis.

Several lines of evidence implicate the fornix-hippocampus circuit in schizophrenia. In early-phase psychosis, this circuit has not been extensively investigated and the underlying mechanisms affecting the circuit are unknown. The hippocampus and fornix are vulnerable to oxidative stress at peripuberty in a glutathione (GSH)-deficient animal model. The purposes of the current study were to assess the integrity of the fornix-hippocampus circuit in early-psychosis patients (EP), and to study its relationship with peripheral redox markers. Diffusion spectrum imaging and T1-weighted magnetic resonance imaging (MRI) were used to assess the fornix and hippocampus in 42 EP patients compared with 42 gender- and age-matched healthy controls. Generalized fractional anisotropy (gFA) and volumetric properties were used to measure fornix and hippocampal integrity, respectively. Correlation analysis was used to quantify the relationship of gFA in the fornix and hippocampal volume, with blood GSH levels and glutathione peroxidase (GPx) activity. Patients compared with controls exhibited lower gFA in the fornix as well as smaller volume in the hippocampus. In EP, but not in controls, smaller hippocampal volume was associated with high GPx activity. Disruption of the fornix-hippocampus circuit is already present in the early stages of psychosis. Higher blood GPx activity is associated with smaller hippocampal volume, which may support a role of oxidative stress in disease mechanisms.

Surgical margins do not affect prognosis in high grade myxofibrosarcoma.

INTRODUCTION: Myxofibrosarcoma (MFS) is one of the most common soft tissue sarcomas (STS) in elderly patients and it primarily affects the extremities. The aim of this retrospective analysis is to understand the natural history of MFS and whether adequate treatment influence prognosis. PATIENTS AND METHODS: We reviewed 129 adult patients with primary, localized, FNCLCC grade 3 MFS of the extremities operated at Istituto Ortopedico Rizzoli, Bologna. Sarcoma specific survival (SS), local recurrence (LR) and distant metastasis (DM) were analyzed. RESULTS: Among excised MFS (119), 106 (89.9%) had R0 margins, 13 (10.1%) R1 margins. No significant correlation between margins adequacy and tumor depth, location and size was found. Estimated SS was 73.2% at 5 years and 66.3% at 10 years, with a better SS in superficial MFS (p = 0.011). Local recurred MFS had a worse SS (p = 0.049). Local recurrence-free rate was 74.3% at 5 and 10 years. Even if not significant, a better outcome in term of LR was observed in superficial MFS and R0 margins. Distant metastasis-free survival was 75.6% at 5 years and 72.9% at 10 years, with a better outcome in superficial MFS (p = 0.012). DISCUSSION: Myxofibrosarcoma remain a debated entity with specific behavior features. Myxofibrosarcoma tends to local recur due to its infiltrative grow pattern making difficult to achieve "safe margins". To date, surgical margins as classified for other STS are not predictive of LR and patients' survival. Tumor grade and depth are still the most important prognostic factors.

A large light-mass component of cosmic rays at 10(17)-10(17.5) electronvolts from radio observations.

Cosmic rays are the highest-energy particles found in nature. Measurements of the mass composition of cosmic rays with energies of 10(17)-10(18) electronvolts are essential to understanding whether they have galactic or extragalactic sources. It has also been proposed that the astrophysical neutrino signal comes from accelerators capable of producing cosmic rays of these energies. Cosmic rays initiate air showers--cascades of secondary particles in the atmosphere-and their masses can be inferred from measurements of the atmospheric depth of the shower maximum (Xmax; the depth of the air shower when it contains the most particles) or of the composition of shower particles reaching the ground. Current measurements have either high uncertainty, or a low duty cycle and a high energy threshold. Radio detection of cosmic rays is a rapidly developing technique for determining Xmax (refs 10, 11) with a duty cycle of, in principle, nearly 100 per cent. The radiation is generated by the separation of relativistic electrons and positrons in the geomagnetic field and a negative charge excess in the shower front. Here we report radio measurements of Xmax with a mean uncertainty of 16 grams per square centimetre for air showers initiated by cosmic rays with energies of 10(17)-10(17.5) electronvolts. This high resolution in Xmax enables us to determine the mass spectrum of the cosmic rays: we find a mixed composition, with a light-mass fraction (protons and helium nuclei) of about 80 per cent. Unless, contrary to current expectations, the extragalactic component of cosmic rays contributes substantially to the total flux below 10(17.5) electronvolts, our measurements indicate the existence of an additional galactic component, to account for the light composition that we measured in the 10(17)-10(17.5) electronvolt range.

Smoking in Patients with Parkinson's Disease: preliminary striatal DaT-SPECT findings.

OBJECTIVE: To assess whether cigarette smoking interferes with dopaminergic transmission in current- and never-smoking patients with Parkinson's disease. MATERIALS AND METHODS: Striatal [123I]FP-CIT single photon emission computed tomography was performed in 67 patients with Parkinson's disease (35 women and 32 men aging 60.8 ± 10.1 years and staging 1.76 ± 0.5 on the Hoehn and Yahr scale). At study time, there were 13 current-smokers and 54 never-smokers. RESULTS: Current-smokers showed a significantly lower putamen/occipital [123I]FP-CIT ratio and a non-significant trend to a lower caudate/occipital [123I]FP-CIT ratio uptake. Current-smokers were also characterized by a lower off UPDRS-III motor score. A logistic regression analysis adjusted for age, sex, disease duration, Hoehn and Yahr staging, and medication indicated a significant lower [123I]FP-CIT uptake not only in the putamen (odds ratio, 0.1; 95% confidence interval, 0.01 to 0.65; P = 0.02) but also in the caudate (odds ratio, 0.2; 95% confidence interval, 0.04 to 0.71; P = 0.015) as well as a lower UPDRS-III motor score (odds ratio, 0.9; 95% confidence interval, 0.81 to 0.99; P = 0.04) in current-smokers. CONCLUSIONS: The lower [123I]FP-CIT uptake together with the lower UPDRS-III motor score observed in our current-smokers patients with Parkinson's disease (even taking into account variables that are probably expression of dopaminergic neuron decline and treatment) would support an effect of smoking on dopaminergic synaptic mechanisms.

Comparative study of the radiobiological effects induced on adherent vs suspended cells by BNCT, neutrons and gamma rays treatments.

The present work is part of a preclinical in vitro study to assess the efficacy of BNCT applied to liver or lung coloncarcinoma metastases and to limb osteosarcoma. Adherent growing cell lines can be irradiated as adherent to the culture flasks or as cell suspensions, differences in radio-sensitivity of the two modalities of radiation exposure have been investigated. Dose related cell survival and cell cycle perturbation results evidenced that the radiosensitivity of adherent cells is higher than that of the suspended ones.

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients.

Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.

Predictability and survival in liver replantransplantation: monocentric experience.

Liver retransplantation is the only treatment for patients with hepatic graft failure. Due to the shortage of organs, it is essential to optimize its use. Between 1998-2010, our center performed retransplantations on 48 (12.8%) patients (re-OLT). The data are compared with those for a group of 374 patients who did not receive retransplantations (NO re-OLT). The re-OLT vs NO re-OLT groups did not significantly differ in mean age of recipients (47 vs 51 years), indications for transplantation (hepatitis C virus cirrhosis 54% vs 56%, alcoholic cirrhosis 25% vs 17%, hepatocellular carcinoma 14% vs 22%), mean Model for End-stage Liver Disease (25 vs 20), mean total cold ischemia time (385 vs 379 minutes), or mean age of donors (52 vs 49 years). The main causes of retransplantation were primary graft nonfunction (64%), arterial thrombosis (8%), biliary complications (6%), and hepatitis C virus recurrence (4%). The difference in overall patient survival was not statistically significant. The patient's survival at 1, 3, 5, and 10 years for RE-OLT vs NO-reOLT was 56% vs 63%, 53% vs 60%, 46% vs 57%, and 44% vs 53%, respectively. Multivariate analysis identified Model for End-stage Liver Disease≥23 as a predictor factor of retransplantation (P=.04). Other variables predicting outcome included age of donors (≥65 years vs younger group), age of recipients (≥50 years vs younger group), cold ischemia (≥600 vs <600 minutes), and transplantation indications (hepatitis C virus, hepatitis B virus, alcohol, and others). The retransplantation performed between 8-15 days appeared to have worse results than those in other periods (0-7 days, 16-30 days, 1-6 months, >6 months). The incidence of re-OLT in the series (12.8%) was comparable to that in the literature, and primary graft nonfunction in the study represents the main cause of retransplantation. Our analysis showed that the indication of the first transplant and the age of the donor were not risk factors for re-OLT. Liver retransplantation is a concrete alternative lifesaver for patients with graft failure.