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Dysplastic nevi represent one of the least agreed-upon entities in dermatopathology despite the existence of established criteria. This study explores preferentially expressed antigen in melanoma (PRAME) in dysplastic nevi, an uncharted area. We examined 22 common melanocytic nevi (CMN), 20 cutaneous melanomas (CM), 48 low-grade dysplastic nevi (LG-DN), and 40 high-grade dysplastic nevi (HG-DN). PRAME was immunohistochemically assessed using a five-tiered system (0 to 4 +). Among CMN, 59% scored 0, 32% scored 1 + , and 9% scored 2 + . CM had score 2 + and 4 + in 11% and 89% of cases, respectively. Among LG-DN, 38% presented score 0, 31% score 1 + , 17% score 2 + , 8% score 3 + , and 6% score 4 + . Thirty per cent of HG-DN demonstrated a score 0, 30% with score 1 + , 15% score 2 + , 10% score 3 + , and 15% score 4 + . Compared to CMN and CM, LG-DN and HG-DN showed heterogeneous expression profiles of PRAME. PRAME positivity effectively distinguished HG-DN from CM with 85% specificity and 80% sensitivity (p < 0.0001). Predictive values were 87% (negative) and 76% (positive). Furthermore, a trend of increased PRAME expression from LG-DN to HG-DN was observed. However, the applicability of PRAME in the differential diagnosis of dysplastic lesions remains unclear as can yield conflicting results with morphology, which remains the primary diagnostic tool for melanocytic lesions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Teleoperation allows workers to safely control powerful construction machines; however, its primary reliance on visual feedback limits the operator's efficiency in situations with stiff contact or poor visibility, hindering its use for assembly of pre-fabricated building components. Reliable, economical, and easy-to-implement haptic feedback could fill this perception gap and facilitate the broader use of robots in construction and other application areas. Thus, we adapted widely available commercial audio equipment to create AiroTouch, a naturalistic haptic feedback system that measures the vibration experienced by each robot tool and enables the operator to feel a scaled version of this vibration in real time. Accurate haptic transmission was achieved by optimizing the positions of the system's off-the-shelf accelerometers and voice-coil actuators. A study was conducted to evaluate how adding this naturalistic type of vibrotactile feedback affects the operator during telerobotic assembly. Thirty participants used a bimanual dexterous teleoperation system (Intuitive da Vinci Si) to build a small rigid structure under three randomly ordered haptic feedback conditions: no vibrations, one-axis vibrations, and summed three-axis vibrations. The results show that users took advantage of both tested versions of the naturalistic haptic feedback after gaining some experience with the task, causing significantly lower vibrations and forces in the second trial. Subjective responses indicate that haptic feedback increased the realism of the interaction and reduced the perceived task duration, task difficulty, and fatigue. As hypothesized, higher haptic feedback gains were chosen by users with larger hands and for the smaller sensed vibrations in the one-axis condition. These results elucidate important details for effective implementation of naturalistic vibrotactile feedback and demonstrate that our accessible audio-based approach could enhance user performance and experience during telerobotic assembly in construction and other application domains., Competing Interests: KK is a co-inventor of a patented older version of the described technology for haptic feedback. The patent is titled “Systems and methods for providing vibration feedback in robotic systems” and was filed in the United States, Europe, and South Korea in 2011 and 2012. These patents have not been licensed to any company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2024 Gong, Mat Husin, Erol, Ortenzi and Kuchenbecker.)

Background: Circulating cell-free DNA (cfDNA, liquid biopsy) is a powerful tool to detect molecular alterations. However, depending on tumor characteristics, biology and anatomic localization, cfDNA detection and analysis may be challenging. Gliomas are enclosed into an anatomic sanctuary, which obstacles the release of cfDNA into the peripheral blood. Therefore, the advantages of using liquid biopsy for brain tumors is still to be confirmed. The present study evaluates the ability of liquid biopsy to detect IDH1 mutations and its correlation with survival and clinical characteristics of glioma patients., Methods: Blood samples obtained from glioma patients were collected after surgery prior to the adjuvant therapy. cfDNA was extracted from plasma and IDH1 p.R132H mutation analysis was performed on a digital droplet PCR. χ2-test and Cohen k were used to assess the correlation between plasma and tissue IDH1 status, while Kaplan Meier curve and Cox regression analysis were applied to survival analysis. Statistical calculations were performed by MedCalc and GraphPad Prism software., Results: A total of 67 samples were collected. A concordance between IDH1 status in tissue and in plasma was found (p = 0.0024), and the presence of the IDH1 mutation both in tissue (138.8 months vs 24.4, p < 0.0001) and cfDNA (116.3 months vs 35.8, p = 0.016) was associated with longer median OS. A significant association between IDH1 mutation both in tissue and cfDNA, age, tumor grade and OS was demonstrated by univariate Cox regression analysis. No statistically significant association between IDH1 mutation and tumor grade was found (p = 0.10)., Conclusions: The present study demonstrates that liquid biopsy may be used in brain tumors to detect IDH1 mutation which represents an important prognostic biomarker in patients with different types of gliomas, being associated to OS., (© 2024. The Author(s).)

Competing Interests: There are no conflicts of interest.

Despite the adoption of novel therapeutical approaches, the outcomes for glioblastoma (GBM) patients remain poor. In the present study, we investigated the prognostic impact of several clinico-pathological and molecular features as well as the role of the cellular immune response in a series of 59 GBM. CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) were digitally assessed on tissue microarray cores and their prognostic role was investigated. Moreover, the impact of other clinico-pathological features was evaluated. The number of CD4+ and CD8+ is higher in GBM tissue compared to normal brain tissue ( p < 0.0001 and p = 0.0005 respectively). A positive correlation between CD4+ and CD8+ in GBM is present ( r s = 0.417- p = 0.001). CD4+ TILs are inversely related to overall survival (OS) (HR = 1.79, 95% CI 1.1-3.1, p = 0.035). The presence of low CD4+ TILs combined with low CD8+ TILs is an independent predictor of longer OS (HR 0.38, 95% CI 0.18-0.79, p = 0.014). Female sex is independently related to longer OS (HR 0.42, 95% CI 0.22-0.77, p = 0.006). Adjuvant treatment, methylguanine methyltransferase ( MGMT ) promoter methylation, and age remain important prognostic factors but are influenced by other features. Adaptive cell-mediated immunity can affect the outcomes of GBM patients. Further studies are needed to elucidate the commitment of the CD4+ cells and the effects of different TILs subpopulations in GBM.

This study reports the results of a monocentric prospective analysis conducted with the aim of evaluating the impact of XRCC1 rs25487, XRCC3 rs861539, XRCC3 rs1799794, RAD51 rs1801320 and GSTP-1 rs1695 single nucleotide polymorphisms (SNP) on patients with high-grade glioma treated with concomitant radio-chemotherapy. From October 2010 to August 2019, a total of 75 patients aged ≥18 years, with histological diagnosis of high-grade glioma, isocitrate dehydrogenase (IDH) 1/2 wild type and treated with radio-chemotherapy and sequential chemotherapy with temozolomide (TMZ) were prospectively recruited. The local ethic committee approved this study (Comitato Etico di Area Vasta Nord Ovest [CEAVNO]; protocol 3304/2011). After a median follow up of 25 months (range: 7-98 months), median progression-free survival (PFS) and overall survival (OS) were 11 months (CI95%: 8-14 months) and 18 months (CI95%: 15-21 months), respectively. In univariate and multivariate Cox regression analysis, a statistically significant association with PFS and OS was found with XRCC3 rs1799794 SNP. The study suggests that XRCC3 rs1799794 SNP can be associated with different PFS and OS in glioblastoma patients treated with radio-chemotherapy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Objective: Despite recent advances in diagnosis and treatment of the disease, the prognosis of patients with glioblastoma multiforme (GBM) remains poor. While the value of molecular pattern profiles at first diagnosis has been demonstrated, only few studies have examined these biomarkers at the time of recurrence. The aim of this study was to explore the impact of extent of resection at repeated craniotomy on overall survival (OS) of patients with recurrent GBM. In addition, we investigated the molecular pattern profiles at first and second surgery to evaluate possible temporal evolution of these patterns and to assess the effect of these modifications on OS., Methods: We conducted a retrospective cohort study of 63 patients (mean age 59.2 years) surgically treated at least two times for recurrent GBM between 2006 and 2020., Results: Median OS and progression-free survival (PFS) were 22 months (range 2-168 months) and 10 months (range 1-96 months), respectively. The OS following gross-total resection (GTR) at recurrence for patients with initial GTR (GTR/GTR) was significantly increased (42.6 months) compared with sub-total resection (STR) at reoperation after initial GTR (GTR/STR) (19 months) and with GTR at reoperation after initial STR (STR/GTR) (17 months) (p = 0.0004). Overall surgical morbidity resulted 12.7% and 11.1% at first and at second surgery, respectively. Changes in genetic profiles between first and second surgery of 1p/19q co-deletion, MGMT promoter methylation and p53 mutations occurred in 5.6%, 1.9% and 9.3% of cases, respectively. MGMT promoter methylation appeared to affect OS in univariate analysis at first (p = 0.038) and second surgery (p = 0.107), whereas p53 mutation appeared to affect OS only at second surgery (p = 0.01). In a multivariate analysis female sex (HR = 0.322, 95% CI 0.147-0.705; p = 0.005), PFS (HR = 0.959, 95% CI 0.934-0.986; p = 0.003), GTR at first and second surgery (HR = 0.195, 95% CI 0.091-0.419; p < 0.0001) and adjuvant chemotherapy at recurrence (HR = 0.407, 95% CI 0.206-0.809; p = 0.01) were associated with longer OS., Conclusions: This study confirmed the role of extent of resection (EOR) at first and at recurrence as a significant predictor of outcome in patients with recurrent GBM. In addition, this study highlighted the concept of a dynamic evolution of GBM genome after initial surgical resection, supporting the need of further studies to investigate the clinical and therapeutic implications of the changes in genetic profiles after initial surgery., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Glioblastoma is one of the most common and lethal primary neoplasms of the brain. Patient survival has not improved significantly over the past three decades and the patient median survival is just over one year. Tumor heterogeneity is thought to be a major determinant of therapeutic failure and a major reason for poor overall survival. This work aims to comprehensively define intra- and inter-tumor heterogeneity by mapping the genomic and mutational landscape of multiple areas of three primary IDH wild-type (IDH-WT) glioblastomas. Using whole exome sequencing, we explored how copy number variation, chromosomal and single loci amplifications/deletions, and mutational burden are spatially distributed across nine different tumor regions. The results show that all tumors exhibit a different signature despite the same diagnosis. Above all, a high inter-tumor heterogeneity emerges. The evolutionary dynamics of all identified mutations within each region underline the questionable value of a single biopsy and thus the therapeutic approach for the patient. Multiregional collection and subsequent sequencing are essential to try to address the clinical challenge of precision medicine. Especially in glioblastoma, this approach could provide powerful support to pathologists and oncologists in evaluating the diagnosis and defining the best treatment option.

Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Despite the combination of novel therapeutical approaches, it remains a deadly malignancy with an abysmal prognosis. GBM is a polymorphic tumour from both molecular and histological points of view. It consists of different malignant cells and various stromal cells, contributing to tumour initiation, progression, and treatment response. GBM's microenvironment is multifaceted and is made up of soluble factors, extracellular matrix components, tissue-resident cell types (e.g., neurons, astrocytes, endothelial cells, pericytes, and fibroblasts) together with resident (e.g., microglia) or recruited (e.g., bone marrow-derived macrophages) immune cells. These latter constitute the so-called immune microenvironment, accounting for a substantial GBM's tumour volume. Despite the abundance of immune cells, an intense state of tumour immunosuppression is promoted and developed; this represents the significant challenge for cancer cells' immune-mediated destruction. Though literature data suggest that distinct GBM's subtypes harbour differences in their microenvironment, its role in treatment response remains obscure. However, an in-depth investigation of GBM's microenvironment may lead to novel therapeutic opportunities to improve patients' outcomes. This review will elucidate the GBM's microenvironment composition, highlighting the current state of the art in immunotherapy approaches. We will focus on novel strategies of active and passive immunotherapies, including vaccination, gene therapy, checkpoint blockade, and adoptive T-cell therapies.

Recent evidence suggests that a loss of expression of caveolin in the stromal compartment (sCav-1) of human invasive breast carcinoma (IBC) may be a predictor of disease recurrence, metastasis and poor outcome. At present, there is little knowledge regarding the expression of sCav-1 at the metastatic sites. We therefore studied sCav-1 expression in IBCs and in their axillary lymph nodes to seek a correlation with cancer metastasis. 189 consecutive invasive IBCs (53 with axillary lymph node metastases and 136 without) were studied by immunohistochemistry, using a rabbit polyclonal anti-Cav-1 antibody. In IBCs sCav-1 was evaluated in fibroblasts scattered in the tumor stroma whereas in lymph nodes sCav-1 was assessed in fibroblast-like stromal cells. For the first time, we observed a statistically significant progressive loss of sCav-1 from normal/reactive axillary lymph nodes of tumors limited to the breast to metastatic axillary lymph nodes, through normal/reactive axillary lymph nodes of tumors with axillary metastatic spread. These data indicate that Cav-1 expressed by the stromal compartment of lymph nodes, somehow, may possibly contribute to metastatic spread in IBC.

Task-aware robotic grasping is critical if robots are to successfully cooperate with humans. The choice of a grasp is multi-faceted; however, the task to perform primes this choice in terms of hand shaping and placement on the object. This grasping strategy is particularly important for a robot companion, as it can potentially hinder the success of the collaboration with humans. In this work, we investigate how different grasping strategies of a robot passer influence the performance and the perceptions of the interaction of a human receiver. Our findings suggest that a grasping strategy that accounts for the subsequent task of the receiver improves substantially the performance of the human receiver in executing the subsequent task. The time to complete the task is reduced by eliminating the need of a post-handover re-adjustment of the object. Furthermore, the human perceptions of the interaction improve when a task-oriented grasping strategy is adopted. The influence of the robotic grasp strategy increases as the constraints induced by the object's affordances become more restrictive. The results of this work can benefit the wider robotics community, with application ranging from industrial to household human-robot interaction for cooperative and collaborative object manipulation., (Copyright © 2020 Ortenzi, Cini, Pardi, Marturi, Stolkin, Corke and Controzzi.)

Solitary fibrous tumors (SFTs) are uncommon mesenchymal lesions originally described as pleura-based neoplasms. Intradural juxtamedullary SFTs are rare, hard, and scarcely vascularized and generally present a conspicuous extramedullary exophytic component without dural attachment and nerve root involvement. Gross-total resection is the mainstay of treatment, although the absence of an arachnoidal plane and the firm adherence to the spinal cord make resection challenging.  We describe the case of a 74-yr-old female patient presenting with a history of progressive spastic tetraparesis due to a cervical juxtamedullary SFT. The patient was not able to walk and magnetic resonance imaging (MRI) of the cervical spine demonstrated a possible intramedullary lesion at C2-C3 with homogeneous enhancement after gadolinium injection. Given the progressive nature of symptoms, the patient elected to have surgical resection of the tumor. The patient underwent C2-C3 laminoplasty and tumor resection under neurophysiologic monitoring. The tumor presented extremely hard without dural attachment or nerve root involvement and was progressively debulked using microsurgical techniques and ultrasonic aspirator. The identification of a plane between the mass and the spinal cord white matter allowed for a gross total resection. Permanent pathological analysis eventually demonstrated SFT. The patient's neurological condition was unchanged postoperatively. MRI performed 2 mo after the operation demonstrated gross total resection of the lesion. At the 6-mo follow-up visit, the patient was able to walk with assistance.  The patient signed the Institutional Consent Form to undergo the surgical procedure and to allow the use of her images and videos for any type of medical publications., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Laser capture microdissection (LCM) coupled with RNA-seq is a powerful tool to identify genes that are differentially expressed in specific histological tumor subtypes. To better understand the role of single tumor cell populations in the complex heterogeneity of glioblastoma, we paired microdissection and NGS technology to study intra-tumoral differences into specific histological regions and cells of human GBM FFPE tumors. We here isolated astrocytes, neurons and endothelial cells in 6 different histological contexts: tumor core astrocytes, pseudopalisading astrocytes, perineuronal astrocytes in satellitosis, neurons with satellitosis, tumor blood vessels, and normal blood vessels. A customized protocol was developed for RNA amplification, library construction, and whole transcriptome analysis of each single portion. We first validated our protocol comparing the obtained RNA expression pattern with the gene expression levels of RNA-seq raw data experiments from the BioProject NCBI database, using Spearman's correlation coefficients calculation. We found a good concordance for pseudopalisading and tumor core astrocytes compartments (0.5 Spearman correlation) and a high concordance for perineuronal astrocytes, neurons, normal, and tumor endothelial cells compartments (0.7 Spearman correlation). Then, Principal Component Analysis and differential expression analysis were employed to find differences between tumor compartments and control tissue and between same cell types into distinct tumor contexts. Data consistent with the literature emerged, in which multiple therapeutic targets significant for glioblastoma (such as Integrins, Extracellular Matrix, transmembrane transport, and metabolic processes) play a fundamental role in the disease progression. Moreover, specific cellular processes have been associated with certain cellular subtypes within the tumor. Our results are promising and suggest a compelling method for studying glioblastoma heterogeneity in FFPE samples and its application in both prospective and retrospective studies.

Background: Bladder cancer (BC) is the 9th most common cancer diagnosis worldwide. Low grade (LG) represents 70% of all BCs, characterized by recurrence and rare ability (10-15%) to progress to high grade (HG) and invade. The remaining 30% is high grade (HG), fast invasive BC, which is resistant to therapy. Identifying biomarkers for predicting those tumors able to progress is a key goal for patient outcome improvement. This study focuses on the most promising prognostic markers., Materials and Methods: TP53 and FGFR3 mutational status, Survivin, CK19, CK20, E-cadherin and CD44 gene expression analysis were performed on 66 BCs., Results: Survivin was found associated to tumor grade (p<0.05). Moreover, Survivin correlated with CD44 in TP53 wild type (p = 0.0242) and FGFR3 wild type (p = 0.0036) tumors. In particular the Survivin-CD44 correlation was associated to HG FGFR3 wild type BCs (p = 0.0045). Unsupervised hierarchical clustering based on gene expression data identified four distinct molecular groups reflecting the patient histology (p = 0.038)., Conclusion: We suggest Survivin, both as a biomarker associated to G3 BCs but negatively related to TP53 mutational status, and as a potential novel therapeutic target., Competing Interests: The authors have declared that no competing interests exist.

Glioblastoma is a devastating disease that despite all the information gathered so far, its optimal management remains elusive due to the absence of validated targets from clinical studies. A better clarification of the molecular mechanisms is needed. In this study, having access to IDH1 wild-type glioblastoma of patients with exceptionally long recurrence free survival (RFS), we decided to compare their mutational and gene expression profile to groups of IDH1 wild-type glioblastoma of patients with shorter RFS, by using NGS technology. The exome analysis revealed that Long-RFS tumors have a lower mutational rate compared to the other groups. A total of 158 genes were found differentially expressed among the groups, 112 of which distinguished the two RFS extreme groups. Overall, the exome data suggests that shorter RFS tumors could be, chronologically, in a more advanced state in the muli-step tumor process of sequential accumulation of mutations. New players in this kind of cancer emerge from the analysis, confirmed at the RNA/DNA level, identifying, therefore, possible oncodrivers or tumor suppressor genes., Competing Interests: CONFLICTS OF INTEREST There is no conflicts of interest in this study.

Glioblastoma (GBM) is the most frequent malignant primary brain tumor in adults and, despite recent advances, the prognosis for this cancer remains dismal. The aims of this study were to test the influence of XRCC1 rs25487, XRCC3 rs861539, XRCC3 rs1799794, RAD51 rs1801320 and GSTP-1 rs1695 single nucleotide polymorphisms on progression free survival (PFS) and overall survival (OS) in GBM patients treated with radiotherapy (RT) and temozolomide (TMZ). Fifty GBM patients treated with upfront radio-chemotherapy (RT 60 Gy/30 sessions; TMZ 75 mg/m 2 during RT and 200 mg/m 2  days 1 → 5 every 28 days) were enrolled. Survival curves were calculated using the Kaplan-Meier method, and the log-rank test was used to evaluate differences between curves. A trend to a statistically significant association with PFS in univariate and multivariate COX regression analysis was found with GSTP-1 rs1695 polymorphism (p = 0.087 and p = 0.097 on univariate and multivariate analyses, respectively). Conversely, the same GSTP-1 rs1695 SNP revealed a statistically significant association with OS (p = 0.007 and p = 0.042 on univariate and multivariate analysis, respectively). Our pharmacogenetic prospective study suggests that GSTP-1 rs1695 genotypes can be associated with different OS in GBM patients treated with RT and TMZ.

Resistance to antiangiogenic therapy in glioblastoma (GBM) patients may involve hypoxia-induced expression of C-X-C motif chemokine receptor 4 (CXCR4) on invading tumor cells, macrophage/microglial cells (MGCs), and glioma stem cells (GSCs). We determined whether antagonizing CXCR4 with POL5551 disrupts anti-vascular endothelial growth factor (VEGF) therapy-induced glioma growth and dissemination. Mice bearing orthotopic CT-2A or GL261 gliomas received POL5551 and/or anti-VEGF antibody B20-4.1.1. Brain tissue was analyzed for tumor volume, invasiveness, hypoxia, vascular density, proliferation, apoptosis, GSCs, and MGCs. Glioma cells were evaluated for CXCR4 expression and polymorphism and POL5551's effects on CXCR4 ligand binding, cell viability, and migration. No CXCR4 mutations were identified. POL5551 inhibited CXCR4 binding to its ligand, stromal cell-derived factor-1α, and reduced hypoxia- and stromal cell-derived factor-1α-mediated migration dose-dependently but minimally affected cell viability. In vivo, B20-4.1.1 increased hypoxic foci and invasiveness, as seen in GBM patients receiving anti-VEGF therapy. Combination of POL5551 and B20-4.1.1 reduced both glioma invasiveness by 16% to 39% and vascular density compared to B20-4.1.1 alone in both glioma models. Reduced populations of GSCs and MGCs were also seen in CT-2A tumors. POL5551 concentrations, evaluated by mass spectrometry, were higher in tumors than in neighboring brain tissues, likely accounting for the results. Inhibition of CXCR4-regulated tumoral, stem cell, and immune mechanisms by adjunctive CXCR4 antagonists may help overcome antiangiogenic therapy resistance, benefiting GBM patients., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Optic gliomas are brain tumors characterized by slow growth, progressive loss of vision, and limited therapeutic options. Optic gliomas contain various amounts of myxoid matrix, which can represent most of the tumor mass. We sought to investigate biological function and protein structure of the myxoid matrix in optic gliomas to identify novel therapeutic targets. We reviewed histological features and clinical imaging properties, analyzed vasculature by immunohistochemistry and electron microscopy, and performed liquid chromatography-mass spectrometry on optic gliomas, which varied in the amount of myxoid matrix. We found that although subtypes of optic gliomas are indistinguishable on imaging, the microvascular network of pilomyxoid astrocytoma, a subtype of optic glioma with abundant myxoid matrix, is characterized by the presence of endothelium-free channels in the myxoid matrix. These tumors show normal perfusion by clinical imaging and lack histological evidence of hemorrhage organization or thrombosis. The myxoid matrix is composed predominantly of the proteoglycan versican and its linking protein, a vertebrate hyaluronan and proteoglycan link protein 1. We propose that pediatric optic gliomas can maintain blood supply without endothelial cells by using invertebrate-like channels, which we termed primitive myxoid vascularization. Enzymatic targeting of the proteoglycan versican/hyaluronan and proteoglycan link protein 1 rich myxoid matrix, which is in direct contact with circulating blood, can provide novel therapeutic avenues for optic gliomas of childhood., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Glioblastoma (GBM) stem cells (GSCs) reside in both hypoxic and vascular microenvironments within tumors. The molecular mechanisms that allow GSCs to occupy such contrasting niches are not understood. We used patient-derived GBM cultures to identify GSC subtypes with differential activation of Notch signaling, which co-exist in tumors but occupy distinct niches and match their metabolism accordingly. Multipotent GSCs with Notch pathway activation reside in perivascular niches, and are unable to entrain anaerobic glycolysis during hypoxia. In contrast, most CD133-expressing GSCs do not depend on canonical Notch signaling, populate tumors regardless of local vascularity and selectively utilize anaerobic glycolysis to expand in hypoxia. Ectopic activation of Notch signaling in CD133-expressing GSCs is sufficient to suppress anaerobic glycolysis and resistance to hypoxia. These findings demonstrate a novel role for Notch signaling in regulating GSC metabolism and suggest intratumoral GSC heterogeneity ensures metabolic adaptations to support tumor growth in diverse tumor microenvironments., Competing Interests: CONFLICTS OF INTEREST None

Purpose: Is it possible a correlation between some periprosthetic femoral fractures and atypical fractures?, Case: We present a case of a 77-year-old woman with atypical periprosthetic femoral fracture. The patient had a history of long-term bisphosphonate use. We performed an open reduction, a synthesis of the fracture and a histological exam. The patient stopped the bisphosphonate (BF) therapy. Three months later, before starting the teriparatide treatment, the patient had a re-fracture so we did a second osteosynthesis and began a teriparatide therapy. After six months, the radiography showed a bone healing at the fracture site., Result: The histological examination confirmed the diagnosis of atypical femoral fracture., Conclusion: At first, the fracture showed a delayed union which led to a new surgery, as often happens in BF-related atypical fractures. Appropriate treatment (BF suspension and teriparatide beginning) permitted fracture healing. The atypical characteristic of the fracture was confirmed by histological exam.Some periprosthetic femoral fractures in patients treated with BF, especially in long time therapies, should be suspected as atypical fractures and a specific medical treatment should be performed, as well as a correct surgical treatment., Competing Interests: Disclosure The Authors declare no conflict of interest. No financial support was received for this study. Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Glioblastoma (GB) is the most aggressive type of primary brain tumor. Despite the progress in recent years regarding the diagnosis and treatment of GB, the recurrence rate remains high, due to the infiltrative and dispersive nature of the tumor, which typically results in poor patient prognosis. In the present study, 19 formalin-fixed, paraffin-embedded GB samples were selected from patients with GB tumors. The samples were classified into a short or long recurrence-free survival (RFS) group, based on the time of first recurrence of the disease in the patients. The 19 samples were molecularly characterized for mutations in the isocitrate dehydrogenase 1 (IDH1) gene, amplification of the epidermal growth factor receptor (EGFR) gene, presence of the EGFR variant III, and methylation of the promoter region of the O 6 -methylguanine-DNA methyltransferase (MGMT) gene. Then, the expression of 84 genes involved in cell-cell and cell-matrix interactions, and that of 84 microRNAs (miRNAs) associated with brain cancer, was profiled. In addition, a copy number variation analysis of 23 genes reported to undergo frequent genomic alterations in human glioma was also performed. Differences in the expression levels of a number of genes were detected across the short and long RFS groups. Among these genes, 5 in particular were selected, and a 5-genes combination approach was developed, which was able to differentiate between patients with short and long RFS outcome. The high levels of sensitivity and precision displayed by this 5-genes combination approach, which were confirmed with a cross-validation method, provide a strong foundation for further validation of the involvement of the aforementioned genes in GB in a larger patient population. In conclusion, the present study has demonstrated how the expression pattern of miRNAs and mRNAs in patients with GB defines a particular molecular hallmark that may increase or reduce the aggressive behavior of GB tumors, thus influencing the survival rates of patients with GB, their response to therapy and their tendency to suffer a relapse.

In this paper we report on a successful management of multiple bone metastases from differentiated thyroid cancer. In 2007, a 75-year-old female patient, previously referred for thyroidectomy for multinodular goiter, underwent surgical removal of a lumbar mass with histological findings of metastasis from well differentiated thyroid cancer. After surgery, serum thyroglobulin (sTg) was 204.4 ng/mL. A diagnostic/dosimetric (123)I WBS was performed, following stimulation by rTSH. Serial WBSs were acquired, along with SPECT/CT and bone scan for localization of lesions. sTg raised to 3.810 ng/mL, and (123)I WBS showed thyroid remnants and numerous areas with high iodine-uptake corresponding to skeletal sites, the two largest loading on the skull, with osteolytic pattern. Calculated radiation absorbed dose for skull lesions, determined by mean of MIRD methodology, was 63.5 mGy/MBq. The patient underwent surgical removal of the two major skull lesions. Successively, 100 mCi (131)I was administered after stimulation by rTSH, with stimulated sTg 297 ng/mL. After 8 months, diagnostic WBS was negative both for remnants and metastases and rTSH-stimulated Tg was 0.6 ng/mL. To date, the patient has maintained sTg values <1 ng/mL during L-T4 suppressive therapy and after rTSH stimulations. In this unusual case of extensive bone cancerous involvement with high iodine avidity, a multidisciplinary approach based on surgery and dosimetry-guided radiometabolic therapy allowed to accurately assess the patient, execute a small number of treatments and achieve a complete remission of the disease in a very short time, with no additive morbidity., (Copyright © 2014 Elsevier España, S.L.U. and SEMNIM. All rights reserved.)

High-grade gliomas (glioblastomas) are the most common and deadly brain tumors in adults, currently with no satisfactory treatment available. Apart from de novo glioblastoma, it is currently accepted that these malignancies mainly progress from lower grade glial tumors. However, the molecular entities governing the progression of gliomas are poorly understood. Extracellular and membrane proteins are key biomolecules found at the cell-to-cell communication interface and hence are a promising proteome subpopulation that could help understand the development of glioma. Accordingly, the current study aims at identifying new protein markers of human glioma progression. For this purpose, we used glial tumors generated orthotopically with T98G and U373 human glioma cells in nude mice. This setup allowed also to discriminate the protein origin, namely, human (tumor) or mouse (host). Extracellular and membrane proteins were selectively purified using biotinylation followed by streptavidin affinity chromatography. Isolated proteins were digested and then identified and quantified employing 2D-nano-HPLC-MS/MS analysis. A total of 23 and 27 up-regulated extracellular and membrane proteins were identified in the T98G and U373 models, respectively. Approximately two-thirds of these were predominantly produced by the tumor, whereas the remaining proteins appeared to be mainly overexpressed by the host tissue. Following extensive validation, we have focused our attention on sparc-like protein 1. This protein was further investigated using immunohistochemistry in a large collection of human glioma samples of different grades. The results showed that sparc-like protein 1 expression correlates with glioma grade, suggesting the possible role for this protein in the progression of this malignancy.