Phospho-mTOR expression in human glioblastoma microglia-macrophage cells

The glioblastoma (GBM) immune microenvironment is highly heterogeneous, and microglia may represent 30–70% of the entire tumor. However, the role of microglia and other specific immune populations is poorly characterized. Activation of mTOR signaling occurs in numerous human cancers and has roles in microglia-glioma cell interactions. We now show in human tumor specimens (42 patients), that 39% of tumor-associated microglial (TAM) cells express mTOR phosphorylated at Ser-2448; and similar mTOR activation is observed using a human microglia-glioma interaction paradigm. In addition, we confirm previous studies that microglia express urea and ARG1 (taken as M2 marker) in the presence of glioma cells, and this phenotype is down-regulated in the presence of a mTOR inhibitor. These results suggest that mTOR suppression in GBM patients might induce a reduction of the M2 phenotype expression in up to 40% of all TAMs. Since the M2 profile of microglial activation is believed to be associated with tumor progression, reductions in that phenotype may represent an additional anti-tumor mechanism of action of mTOR inhibitors, along with direct anti-proliferative activities

Acute subdural hematoma in the elderly. outcome analysis in a retrospective multicentric series of 213 patients

OBJECTIVE: The objective of this study was to analyze the risk factors associated with the outcome of acute subdural hematoma (ASDH) in elderly patients treated either surgically or nonsurgically. METHODS: The authors performed a retrospective multicentric analysis of clinical and radiological data on patients aged ≥ 70 years who had been consecutively admitted to the neurosurgical department of 5 Italian hospitals for the management of posttraumatic ASDH in a 3-year period. Outcome was measured according to the Glasgow Outcome Scale (GOS) at discharge and at 6 months' follow-up. A GOS score of 1-3 was defined as a poor outcome and a GOS score of 4-5 as a good outcome. Univariate and multivariate statistics were used to determine outcome predictors in the entire study population and in the surgical group. RESULTS: Overall, 213 patients were admitted during the 3-year study period. Outcome was poor in 135 (63%) patients, as 65 (31%) died during their admission, 33 (15%) were in a vegetative state, and 37 (17%) had severe disability at discharge. Surgical patients had worse clinical and radiological findings on arrival or during their admission than the patients undergoing conservative treatment. Surgery was performed in 147 (69%) patients, and 114 (78%) of them had a poor outcome. In stratifying patients by their Glasgow Coma Scale (GCS) score, the authors found that surgery reduced mortality but not the frequency of a poor outcome in the patients with a moderate to severe GCS score. The GCS score and midline shift were the most significant predictors of outcome. Antiplatelet drugs were associated with better outcomes; however, patients taking such medications had a better GCS score and better radiological findings, which could have influenced the former finding. Patients with fixed pupils never had a good outcome. Age and Charlson Comorbidity Index were not associated with outcome. CONCLUSIONS: Traumatic ASDH in the elderly is a severe condition, with the GCS score and midline shift the stronger outcome predictors, while age per se and comorbidities were not associated with outcome. Antithrombotic drugs do not seem to negatively influence pretreatment status or posttreatment outcome. Surgery was performed in patients with a worse clinical and radiological status, reducing the rate of death but not the frequency of a poor outcome

Glioblastoma stem cells express non-canonical proteins and exclusive mesenchymal-like or non-mesenchymal-like protein signatures

Glioblastoma (GBM) cancer stem cells (GSCs) contribute to GBM's origin, recurrence, and resistance to treatment. However, the understanding of how mRNA expression patterns of GBM subtypes are reflected at global proteome level in GSCs is limited. To characterize protein expression in GSCs, we performed in-depth proteogenomic analysis of patient-derived GSCs by RNA-sequencing and mass-spectrometry. We quantified > 10 000 proteins in two independent GSC panels and propose a GSC-associated proteomic signature characterizing two distinct phenotypic conditions; one defined by proteins upregulated in proneural and classical GSCs (GPC-like), and another by proteins upregulated in mesenchymal GSCs (GM-like). The GM-like protein set in GBM tissue was associated with necrosis, recurrence, and worse overall survival. Through proteogenomics, we discovered 252 non-canonical peptides in the GSCs, i.e., protein sequences that are variant or derive from genome regions previously considered non-protein-coding, including variants of the heterogeneous ribonucleoproteins implicated in RNA splicing. In summary, GSCs express two protein sets that have an inverse association with clinical outcomes in GBM. The discovery of non-canonical protein sequences questions existing gene models and pinpoints new protein targets for research in GBM

Preliminary experience with 4K ultra-high definition endoscope: analysis of pros and cons in skull base surgery

Negli ultimi venti anni la chirurgia endoscopica del basicranio ha osservato continui sviluppi tecnici e tecnologici. Lendoscopia 3D e l alta definizione (HD) 4K hanno fornito grandi vantaggi in termini di visualizzazione e di risoluzione spaziale. L ultra HD 4K, recentemente introdotta nella pratica clinica, determinerà i prossimi passi soprattutto nella chirurgica endoscopica del basicranio. I pazienti sono stati operati attraverso un approccio transnasale transfenoidale endoscopico, utilizzando un endoscopio Olympus NBI 4K UHD con ottica 4 mm 0 ° Ultra Telescope, lampada allo xeno 300 W (CLV-S400) predisposto per la tecnologia narrow band imaging (NBI) collegato con una videocamera ad un alta qualità unità di controllo (OTV-S400 - VISERA 4K UHD) (Olympus, Tokyo, Giappone). Due schermi, un 31 Monitor - (LMD-X310S) e quello principale ultra-HD 55 a pollici ottimizzati per la riproduzione immagini UHD (LMD-X550S). In casi selezionati abbiamo usato un sistema di navigazione (Stealthstation S7, Medtronic, Minneapolis, MN, Stati Uniti). Abbiamo valutato 22 adenomi ipofisari (86,3% macroadenomi; 13,7% microadenomi). Il 50% non erano secernenti (NS), 22,8% GH, 18,2% ACTH, 9% PRLsecernenti. 3/22 erano recidive. Nel 91% dei casi abbiamo raggiunto la rimozione totale, mentre nel 9% la resezione subtotale. Un followup medio di 187 giorni, durata media del ricovero era 3,09 ± 0,61 giorni. Tempo chirurgico 128,18 ± 30,74 minuti. Abbiamo avuto solo 1 caso di fistola intraoperatoria a basso flusso senza ulteriori complicazioni nel follow up. Il 100% dei casi non ha richiesto emotrasfusione. La visualizzazione e lalta risoluzione del campo operatorio hanno fornito una vista dettagliata di tutte le strutture anatomiche e patologie e permesso il miglioramento della sicurezza e lefficacia della procedura chirurgica. Il tempo operatorio è stato simile a quello dellendoscopio HD standard 2D e 3D, come la fatica fisica era paragonabile ad altri in termini di ergonomicità e peso

Frataxin participates to the hypoxia-induced response in tumors

Defective expression of frataxin is responsible for the degenerative disease Friedreich's ataxia. Frataxin is a protein required for cell survival since complete knockout is lethal. Frataxin protects tumor cells against oxidative stress and apoptosis but also acts as a tumor suppressor. The molecular bases of this apparent paradox are missing. We therefore sought to investigate the pathways through which frataxin enhances stress resistance in tumor cells. We found that frataxin expression is upregulated in several tumor cell lines in response to hypoxic stress, a condition often associated with tumor progression. Moreover, frataxin upregulation in response to hypoxia is dependent on hypoxia-inducible factors expression and modulates the activation of the tumor-suppressor p53. Importantly, we show for the first time that frataxin is in fact increased in human tumors in vivo. These results show that frataxin participates to the hypoxia-induced stress response in tumors, thus implying that modulation of its expression could have a critical role in tumor cell survival and/or progression

Androgen deprivation therapy promotes an obesity-like microenvironment in periprostatic fat

Prostate cancer is a leading cause of morbidity and cancer-related death worldwide. Androgen deprivation therapy (ADT) is the cornerstone of management for advanced disease. The use of these therapies is associated with multiple side effects, including metabolic syndrome and truncal obesity. At the same time, obesity has been associated with both prostate cancer development and disease progression, linked to its effects on chronic inflammation at a tissue level. The connection between ADT, obesity, inflammation and prostate cancer progression is well established in clinical settings; however, an understanding of the changes in adipose tissue at the molecular level induced by castration therapies is missing. Here, we investigated the transcriptional changes in periprostatic fat tissue induced by profound ADT in a group of patients with high-risk tumours compared to a matching untreated cohort. We find that the deprivation of androgen is associated with a pro-inflammatory and obesity-like adipose tissue microenvironment. This study suggests that the beneficial effect of therapies based on androgen deprivation may be partially counteracted by metabolic and inflammatory side effects in the adipose tissue surrounding the prostate

Immunologic risk stratification of pediatric heart transplant patients by combining HLA-EMMA and PIRCHE-II

Human leukocyte antigen (HLA) molecular mismatch is a powerful biomarker of rejection. Few studies have explored its use in assessing rejection risk in heart transplant recipients. We tested the hypothesis that a combination of HLA Epitope Mismatch Algorithm (HLA-EMMA) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) algorithms can improve risk stratification of pediatric heart transplant recipients. Class I and II HLA genotyping were performed by next-generation sequencing on 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC). Using high-resolution genotypes, we performed HLA molecular mismatch analysis with HLA-EMMA and PIRCHE-II, and correlated these findings with clinical outcomes. Patients without pre-formed donor specific antibody (DSA) (n=100) were used for correlations with post-transplant DSA and antibody mediated rejection (ABMR). Risk cut-offs were determined for DSA and ABMR using both algorithms. HLA-EMMA cut-offs alone predict the risk of DSA and ABMR; however, if used in combination with PIRCHE-II, the population could be further stratified into low-, intermediate-, and high-risk groups. The combination of HLA-EMMA and PIRCHE-II enables more granular immunological risk stratification. Intermediate-risk cases, like low-risk cases, are at a lower risk of DSA and ABMR. This new way of risk evaluation may facilitate individualized immunosuppression and surveillance.</p

Immunologic risk stratification of pediatric heart transplant patients by combining HLA-EMMA and PIRCHE-II

Human leukocyte antigen (HLA) molecular mismatch is a powerful biomarker of rejection. Few studies have explored its use in assessing rejection risk in heart transplant recipients. We tested the hypothesis that a combination of HLA Epitope Mismatch Algorithm (HLA-EMMA) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) algorithms can improve risk stratification of pediatric heart transplant recipients. Class I and II HLA genotyping were performed by next-generation sequencing on 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC). Using high-resolution genotypes, we performed HLA molecular mismatch analysis with HLA-EMMA and PIRCHE-II, and correlated these findings with clinical outcomes. Patients without pre-formed donor specific antibody (DSA) (n=100) were used for correlations with post-transplant DSA and antibody mediated rejection (ABMR). Risk cut-offs were determined for DSA and ABMR using both algorithms. HLA-EMMA cut-offs alone predict the risk of DSA and ABMR; however, if used in combination with PIRCHE-II, the population could be further stratified into low-, intermediate-, and high-risk groups. The combination of HLA-EMMA and PIRCHE-II enables more granular immunological risk stratification. Intermediate-risk cases, like low-risk cases, are at a lower risk of DSA and ABMR. This new way of risk evaluation may facilitate individualized immunosuppression and surveillance.</p

Detection of ctDNA in plasma of patients with clinically localised prostate cancer is associated with rapid disease progression.

BACKGROUND DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown. METHODS We performed whole-genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 h and 6 weeks) surgery. In a separate cohort (n = 189), we identified the presence of ctDNA TP53 mutations in preoperative plasma in a retrospective cohort and determined its association with biochemical- and metastasis-free survival. RESULTS Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2-4.8, p = 0.014). CONCLUSIONS CtDNA is uncommonly detected in localised prostate cancer, but its presence portends more rapidly progressive disease

Subgroup Economic Analysis for Glioblastoma in a Health Resource-Limited Setting

BACKGROUND: The aim of this research was to evaluate the economic outcomes of radiotherapy (RT), temozolomide (TMZ) and nitrosourea (NT) strategies for glioblastoma patients with different prognostic factors. METHODOLOGY/PRINCIPAL FINDINGS: A Markov model was developed to track monthly patient transitions. Transition probabilities and utilities were derived primarily from published reports. Costs were estimated from the perspective of the Chinese healthcare system. The survival data with different prognostic factors were simulated using Weibull survival models. Costs over a 5-year period and quality-adjusted life years (QALYs) were estimated. Probabilistic sensitivity and one-way analyses were performed. The baseline analysis in the overall cohort showed that the TMZ strategy increased the cost and QALY relative to the RT strategy by $25,328.4 and 0.29, respectively; and the TMZ strategy increased the cost and QALY relative to the NT strategy by$23,906.5 and 0.25, respectively. Therefore, the incremental cost effectiveness ratio (ICER) per additional QALY of the TMZ strategy, relative to the RT strategy and the NT strategy, amounts to $87,940.6 and$94,968.3, respectively. Subgroups with more favorable prognostic factors achieved more health benefits with improved ICERs. Probabilistic sensitivity analyses confirmed that the TMZ strategy was not cost-effective. In general, the results were most sensitive to the cost of TMZ, which indicates that better outcomes could be achieved by decreasing the cost of TMZ. CONCLUSIONS/SIGNIFICANCE: In health resource-limited settings, TMZ is not a cost-effective option for glioblastoma patients. Selecting patients with more favorable prognostic factors increases the likelihood of cost-effectiveness