"Vanishing" glioblastoma: A case report and review of the literature.

Contrast enhancement resolution induced by corticosteroids is a phenomenon primarily associated with primary central nervous system lymphoma, while malignant brain gliomas usually maintain a consistent radiological appearance during systemic steroid treatment. Although rare, a few primary and metastatic intracranial lesions have shown similar radiographic changes following corticosteroid therapy. In the case of glioblastomas, corticosteroid therapy is commonly used to alleviate pressure effects from peritumoral edema, but its impact on contrast enhancement is not well-established. A few reported cases in the literature describe reduced contrast enhancement in glioblastomas after corticosteroid treatment. We present a case of corticosteroid-induced regression on imaging of glioblastoma evaluated at our institutionwith the intention to explore the pathogenesis of this response and discuss the therapeutic and prognostic implications of this discovery.

TRF2 as novel marker of tumor response to taxane-based therapy: from mechanistic insight to clinical implication.

BACKGROUND: Breast Cancer (BC) can be classified, due to its heterogeneity, into multiple subtypes that differ for prognosis and clinical management. Notably, triple negative breast cancer (TNBC) - the most aggressive BC form - is refractory to endocrine and most of the target therapies. In this view, taxane-based therapy still represents the elective strategy for the treatment of this tumor. However, due variability in patients' response, management of TNBC still represents an unmet medical need. Telomeric Binding Factor 2 (TRF2), a key regulator of telomere integrity that is over-expressed in several tumors, including TNBC, has been recently found to plays a role in regulating autophagy, a degradative process that is involved in drug detoxification. Based on these considerations, we pointed, here, at investigating if TRF2, regulating autophagy, can affect tumor sensitivity to therapy. METHODS: Human TNBC cell lines, over-expressing or not TRF2, were subjected to treatment with different taxanes and drug efficacy was tested in terms of autophagic response and cell proliferation. Autophagy was evaluated first biochemically, by measuring the levels of LC3, and then by immunofluorescence analysis of LC3-puncta positive cells. Concerning the proliferation, cells were subjected to colony formation assays associated with western blot and FACS analyses. The obtained results were then confirmed also in mouse models. Finally, the clinical relevance of our findings was established by retrospective analysis on a cohort of TNBC patients subjected to taxane-based neoadjuvant chemotherapy. RESULTS: This study demonstrated that TRF2, inhibiting autophagy, is able to increase the sensitivity of TNBC cells to taxanes. The data, first obtained in in vitro models, were then recapitulated in preclinical mouse models and in a cohort of TNBC patients, definitively demonstrating that TRF2 over-expression enhances the efficacy of taxane-based neoadjuvant therapy in reducing tumor growth and its recurrence upon surgical intervention. CONCLUSIONS: Based on our finding it is possible to conclude that TRF2, already known for its role in promoting tumor formation and progression, might represents an Achilles' heel for cancer. In this view, TRF2 might be exploited as a putative biomarker to predict the response of TNBC patients to taxane-based neoadjuvant chemotherapy.

Drug repositioning strategy for the identification of novel telomere-damaging agents: A role for NAMPT inhibitors.

Drug repositioning strategy represents a valid tool to accelerate the pharmacological development through the identification of new applications for already existing compounds. In this view, we aimed at discovering molecules able to trigger telomere-localized DNA damage and tumor cell death. By applying an automated high-content spinning-disk microscopy, we performed a screening aimed at identifying, on a library of 527 drugs, molecules able to negatively affect the expression of TRF2, a key protein in telomere maintenance. FK866, resulting from the screening as the best candidate hit, was then validated at biochemical and molecular levels and the mechanism underlying its activity in telomere deprotection was elucidated both in vitro and in vivo. The results of this study allow us to discover a novel role of FK866 in promoting, through the production of reactive oxygen species, telomere loss and deprotection, two events leading to an accumulation of DNA damage and tumor cell death. The ability of FK866 to induce telomere damage and apoptosis was also demonstrated in advanced preclinical models evidencing the antitumoral activity of FK866 in triple-negative breast cancer-a particularly aggressive breast cancer subtype still orphan of targeted therapies and characterized by high expression levels of both NAMPT and TRF2. Overall, our findings pave the way to the development of novel anticancer strategies to counteract triple-negative breast cancer, based on the use of telomere deprotecting agents, including NAMPT inhibitors, that would rapidly progress from bench to bedside.

Dural Tail Sign and Middle Meningeal Artery Hypertrophy in Glioblastoma: A Rarity?

BACKGROUND: Dural tail sign and increased caliber of branches of the external carotid artery (ECA) are common findings in meningioma and they have been rarely reported in intra-axial lesions. Anyway, some cases of glioblastoma (GBM) are reported in the literature, mostly superficially localized, characterized by these 2 findings and therefore, misdiagnosed with meningioma. The aim of this study is to verify the prevalence of dural tail sign and hypertrophy of middle meningeal artery (MMA) in a large cohort of GBMs. METHODS: 180 GBM patients were retrospectively evaluated. Deep or superficial localization of GBM was established and the presence of dural tail sign and hypertrophy of the ipsilateral MMA were assessed. The rate of tumor necrosis and the incidence of dural metastases during the radiological follow-up were also evaluated. Inter-rater reliability was calculated using Cohen's K-test. RESULTS: Dural tail sign and enlarged MMA were evident in 30% and 19% of 96 superficial GBM, respectively. Deep GBM did not present those signs. Only one patient developed dural metastasis at follow-up and no differences in terms of tumor necrosis and hypoxic biomarkers expression were evident among GBMs with and without dural and vessel signs. CONCLUSIONS: Dural tail sign and hypertrophy of the MMA in superficial GBM are more common than expected. They probably represent reactive rather than a neoplastic infiltration. Knowing these radiological signs may be important in terms of neurosurgery planning and avoiding excessive bleeding. Anyway, this hypothesis should be confirmed by a prospective neurosurgery studio.

MiR-182-3p targets TRF2 and impairs tumor growth of triple-negative breast cancer.

The telomeric repeat-binding factor 2 (TRF2) is a telomere-capping protein that plays a key role in the maintenance of telomere structure and function. It is highly expressed in different cancer types, and it contributes to cancer progression. To date, anti-cancer strategies to target TRF2 remain a challenge. Here, we developed a miRNA-based approach to reduce TRF2 expression. By performing a high-throughput luciferase screening of 54 candidate miRNAs, we identified miR-182-3p as a specific and efficient post-transcriptional regulator of TRF2. Ectopic expression of miR-182-3p drastically reduced TRF2 protein levels in a panel of telomerase- or alternative lengthening of telomeres (ALT)-positive cancer cell lines. Moreover, miR-182-3p induced DNA damage at telomeric and pericentromeric sites, eventually leading to strong apoptosis activation. We also observed that treatment with lipid nanoparticles (LNPs) containing miR-182-3p impaired tumor growth in triple-negative breast cancer (TNBC) models, including patient-derived tumor xenografts (PDTXs), without affecting mouse survival or tissue function. Finally, LNPs-miR-182-3p were able to cross the blood-brain barrier and reduce intracranial tumors representing a possible therapeutic option for metastatic brain lesions.

Role of yUbp8 in Mitochondria and Hypoxia Entangles the Finding of Human Ortholog Usp22 in the Glioblastoma Pseudo-Palisade Microlayer.

KAT Gcn5 and DUB Ubp8 are required for respiration and mitochondria functions in budding yeast, and in this study we show that loss of respiratory activity is acquired over time. Interestingly, we show that absence of Ubp8 allows cells to grow in hypoxic conditions with altered mitophagy. Comparatively, the aggressive glioblastoma (GBM) multiforme tumor shows survival mechanisms able to overcome hypoxia in the brain. Starting from yeast and our findings on the role of Ubp8 in hypoxia, we extended our analysis to the human ortholog and signature cancer gene Usp22 in glioblastoma tumor specimens. Here we demonstrate that Usp22 is localized and overexpressed in the pseudo-palisade tissue around the necrotic area of the tumor. In addition, Usp22 colocalizes with the mitophagy marker Parkin, indicating a link with mitochondria function in GBM. Collectively, this evidence suggests that altered expression of Usp22 might provide a way for tumor cells to survive in hypoxic conditions, allowing the escape of cells from the necrotic area toward vascularized tissues. Collectively, our experimental data suggest a model for a possible mechanism of uncontrolled proliferation and invasion in glioblastoma.

Light Chain Cast Nephropathy in Multiple Myeloma: Prevalence, Impact and Management Challenges.

"Cast nephropathy" (CN) is a pathological feature of myeloma kidney, also seen to a lesser extent in the context of severe nephrotic syndrome from non-haematological diseases. The name relates to obstruction of distal tubules by "casts" of luminal proteins concentrated by intensive water reabsorption resulting from dehydration or high-dose diuretics. Filtered proteins form complexes with endogenous tubular Tamm-Horsfall glycoprotein. The resulting gel further slows or stops luminal flow upon complete obstruction of distal convoluted tubules and collecting ducts. Thus, a tubular obstructive form of acute kidney injury (AKI) is a common consequence of CN. The pathogenesis of CN will be reviewed in light of recent advances in the understanding of monoclonal disorders of B lymphocytes, leading to the release of immunoglobulin components (free light chains, FLC) into the bloodstream and their filtration across the glomerular basement membrane. Treatment aiming at reduction of the circulating burden of FLC may help recovery of renal function in a fraction of these patients, besides filling the void between the onset of AKI, histopathological diagnosis, and full response to pharmacologic treatment.

Dermoid Cysts of the Asterion: An Unusual Location for Unusual Dermoids, Radiological Findings and Neurosurgical Implications.

Asterion is an uncommon site for lesions, especially dermoid cysts. We report a case series of three asterional intracranial dermoid cysts, which, to the best of our knowledge, have never been described before. Patients presented with non-specific symptoms and underwent surgical excision of the lesions. It is crucial to correctly diagnose intracranial masses and to identify their relationships with surrounding anatomical structures, especially if the location is unusual as the asterion, to plan surgery. The challenge of this tumor location is to preserve the venous drainage system during surgical procedures, because of the contiguity between the asterion and the transverse-sigmoid junction. Rupturing or damaging of the venous drainage system have been proven to be catastrophic because they lengthen surgical time and present dire consequences for patients. In conclusion, it is crucial to familiarize with atypical dermoid presentation to ensure proper diagnoses and to perform adequate imaging for optimal surgical planning.

Visual Aura Secondary to Supratentorial Lipomatous Meningioma: A Rare Case Report.

BACKGROUND/AIM: Lipomatous meningioma is a rare type of meningioma that is formed as the result of an accumulation of lipids inside the cell due to metabolic activity dysregulation. It differs from other types of meningiomas in its radiological and immunohistochemical characteristics. We report a rare case of a patient treated in our department for this particular type of meningioma who developed a type of migraine with the aura component as the first clinical symptom. CASE REPORT: A 55-year-old woman presented with a migraine and reported having phosphenes in recent years. Head Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) scans were performed; these showed an extensive hypodense and hypointense formation located in the left parieto-occipital region. This formation was implanted in the tentorium region, with a prevailingly adipose-type signal intensity. The patient underwent an occipital craniotomy with the total removal of the lesion. The histological examination indicated a lipomatous metaplastic meningioma. CONCLUSION: We reported the first case of a lipomatous meningioma presenting with a migraine with a visual aura. Seizures and headaches can be included as possible symptoms. According to the current literature, lipomatous meningiomas affect women more commonly than men. The patient of our reported case presented visual disturbances in the form of a visual aura, which occurred 10 years before finding the meningioma, and surgery dramatically improved the symptoms and quality of life.

Treatment of kidney clear cell carcinoma, lung adenocarcinoma and glioblastoma cell lines with hydrogels made of DNA nanostars.

Overcoming the systemic administration of chemotherapy to reduce drug toxicity and the application of personalised medicine are two of the major challenges in the treatment of cancer. To this aim, efforts are focused on finding novel nanomaterials for the targeted administration of drugs and bioactive molecules in the tumor sites. DNA-based hydrogels are promising candidates for these applications. However, while such materials are fairly known from a structural and physical standpoint, their effects on cell cultures are far less investigated. Here, we studied the biological response of three different cell lines (clear cell renal cell carcinoma 786-O, lung adenocarcinoma H1975 and glioblastoma U87MG) to the treatment with DNA-GEL - a DNA-based hydrogel composed of interacting DNA nanostars. Additionally, we investigated the structural modification of DNA-GELs under cell culture conditions. The results we collected show a cell type specificity of the response, with interesting implications for future applications.

AI and High-Grade Glioma for Diagnosis and Outcome Prediction: Do All Machine Learning Models Perform Equally Well?

Radiomic models outperform clinical data for outcome prediction in high-grade gliomas (HGG). However, lack of parameter standardization limits clinical applications. Many machine learning (ML) radiomic models employ single classifiers rather than ensemble learning, which is known to boost performance, and comparative analyses are lacking in the literature. We aimed to compare ML classifiers to predict clinically relevant tasks for HGG: overall survival (OS), isocitrate dehydrogenase (IDH) mutation, O-6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, epidermal growth factor receptor vIII (EGFR) amplification, and Ki-67 expression, based on radiomic features from conventional and advanced magnetic resonance imaging (MRI). Our objective was to identify the best algorithm for each task. One hundred fifty-six adult patients with pathologic diagnosis of HGG were included. Three tumoral regions were manually segmented: contrast-enhancing tumor, necrosis, and non-enhancing tumor. Radiomic features were extracted with a custom version of Pyradiomics and selected through Boruta algorithm. A Grid Search algorithm was applied when computing ten times K-fold cross-validation (K=10) to get the highest mean and lowest spread of accuracy. Model performance was assessed as AUC-ROC curve mean values with 95% confidence intervals (CI). Extreme Gradient Boosting (xGB) obtained highest accuracy for OS (74,5%), Adaboost (AB) for IDH mutation (87.5%), MGMT methylation (70,8%), Ki-67 expression (86%), and EGFR amplification (81%). Ensemble classifiers showed the best performance across tasks. High-scoring radiomic features shed light on possible correlations between MRI and tumor histology.

Acute Kidney Injury in Monoclonal Gammopathies.

Monoclonal gammopathies (MG) encompass a variety of disorders related to clonal expansion and/or malignant transformation of B lymphocytes. Deposition of free immunoglobulin (Ig) components (light or heavy chains, LC/HC) within the kidney during MG may result over time in multiple types and degrees of injury, including acute kidney injury (AKI). AKI is generally a consequence of tubular obstruction by luminal aggregates of LC, a pattern known as "cast nephropathy". Monoclonal Ig LC can also be found as intracellular crystals in glomerular podocytes or proximal tubular cells. Proliferative glomerulonephritis with monoclonal Ig deposits is another, less frequent form of kidney injury with a sizable impact on renal function. Hypercalcemia (in turn related to bone reabsorption triggered by proliferating plasmacytoid B cells) may lead to AKI via functional mechanisms. Pharmacologic treatment of MG may also result in additional renal injury due to local toxicity or the tumor lysis syndrome. The present review focuses on AKI complicating MG, evaluating predictors, risk factors, mechanisms of damage, prognosis, and options for treatment.

Deep Learning Can Differentiate IDH-Mutant from IDH-Wild GBM.

Isocitrate dehydrogenase (IDH) mutant and wildtype glioblastoma multiforme (GBM) often show overlapping features on magnetic resonance imaging (MRI), representing a diagnostic challenge. Deep learning showed promising results for IDH identification in mixed low/high grade glioma populations; however, a GBM-specific model is still lacking in the literature. Our aim was to develop a GBM-tailored deep-learning model for IDH prediction by applying convoluted neural networks (CNN) on multiparametric MRI. We selected 100 adult patients with pathologically demonstrated WHO grade IV gliomas and IDH testing. MRI sequences included: MPRAGE, T1, T2, FLAIR, rCBV and ADC. The model consisted of a 4-block 2D CNN, applied to each MRI sequence. Probability of IDH mutation was obtained from the last dense layer of a softmax activation function. Model performance was evaluated in the test cohort considering categorical cross-entropy loss (CCEL) and accuracy. Calculated performance was: rCBV (accuracy 83%, CCEL 0.64), T1 (accuracy 77%, CCEL 1.4), FLAIR (accuracy 77%, CCEL 1.98), T2 (accuracy 67%, CCEL 2.41), MPRAGE (accuracy 66%, CCEL 2.55). Lower performance was achieved on ADC maps. We present a GBM-specific deep-learning model for IDH mutation prediction, with a maximal accuracy of 83% on rCBV maps. Highest predictivity achieved on perfusion images possibly reflects the known link between IDH and neoangiogenesis through the hypoxia inducible factor.

Facial Transplantation: Nonimmune-Related Hyperacute Graft Failure-The Role of Perfusion Injury: A Case Report.

BACKGROUND: The aim of this study was to report the first case of acute facial allograft transplantation (facial allograft transplantation) failure with allograft removal and autologous free-flap reconstruction. METHODS: A 49-year-old female patient affected by neurofibromatosis type 1 with a massive neurofibroma infiltrating the whole left hemiface was planned for FAT for the left hemiface including the auricle, all skin and soft tissues from the temporal region, periorbital and nasal region, and up to the perioral area. The maxillary process of the zygomatic bone, left hemimaxilla, and hemimandible from contralateral parasyphysis to the incisura mandibulae were also included. RESULTS: Total surgical time was 26 hours. There were 2 intraoperative arterial thromboses that were solved with new anastomoses and sufficient flap perfusion. On postoperative day 2, the allograft became pale with suspected arterial occlusion and the patient returned to the operative room for exploration no flow into the FAT was found. The allograft was removed and the recipient site reconstructed with a skin-grafted composite left latissimus dorsi-serratus anterior flap. CONCLUSIONS: Hyperacute loss of FAT is a very dramatic event, and the activation of a backup surgical plan is crucial to save patient's life, give a reasonable temporary reconstruction, and return on the waiting-list for a second face transplantation.

A preliminary study of micro-RNAs as minimally invasive biomarkers for the diagnosis of prostate cancer patients.

BACKGROUND: A prostate cancer diagnosis is based on biopsy sampling that is an invasive, expensive procedure, and doesn't accurately represent multifocal disease. METHODS: To establish a model using plasma miRs to distinguish Prostate cancer patients from non-cancer controls, we enrolled 600 patients histologically diagnosed as having or not prostate cancer at biopsy. Two hundred ninety patients were eligible for the analysis. Samples were randomly divided into discovery and validation cohorts. RESULTS: NGS-miR-expression profiling revealed a miRs signature able to distinguish prostate cancer from non-cancer plasma samples. Of 51 miRs selected in the discovery cohort, we successfully validated 5 miRs (4732-3p, 98-5p, let-7a-5p, 26b-5p, and 21-5p) deregulated in prostate cancer samples compared to controls (p ≤ 0.05). Multivariate and ROC analyses show miR-26b-5p as a strong predictor of PCa, with an AUC of 0.89 (CI = 0.83-0.95;p < 0.001). Combining miRs 26b-5p and 98-5p, we developed a model that has the best predictive power in discriminating prostate cancer from non-cancer (AUC = 0.94; CI: 0,835-0,954). To distinguish between low and high-grade prostate cancer, we found that miR-4732-3p levels were significantly higher; instead, miR-26b-5p and miR-98-5p levels were lower in low-grade compared to the high-grade group (p ≤ 0.05). Combining miR-26b-5p and miR-4732-3p we have the highest diagnostic accuracy for high-grade prostate cancer patients, (AUC = 0.80; CI 0,69-0,873). CONCLUSIONS: Noninvasive diagnostic tests may reduce the number of unnecessary prostate biopsies. The 2-miRs-diagnostic model (miR-26b-5p and miR-98-5p) and the 2-miRs-grade model (miR-26b-5p and miR-4732-3p) are promising minimally invasive tools in prostate cancer clinical management.

Novel ACTA1 mutation causes late-presenting nemaline myopathy with unusual dark cores.

ACTA1 gene encodes the skeletal muscle alpha-actin, the core of thin filaments of the sarcomere. ACTA1 mutations are responsible of several muscle disorders including nemaline, cores, actin aggregate myopathies and fiber-type disproportion. We report clinical, muscle imaging, histopatological and genetic data of an Italian family carrying a novel ACTA1 mutation. All affected members showed a late-presenting, diffuse muscle weakness with sternocleidomastoideus and temporalis atrophy. Mild dysmorphic features were also detected. The most affected muscles by muscle MRI were rectus abdominis, gluteus minimus, vastus intermedius and both gastrocnemii. Muscle biopsy showed the presence of nemaline bodies with several unusual dark areas at Gomori Trichrome, corresponding to unstructured cores with abundant electrodense material by electron microscopy. The molecular analysis revealed missense variant c.148G>A; p.(Gly50Ser) in the exon 3 of ACTA1, segregating with affected members in the family. We performed a functional essay of fibre contractility showing a higher pCa50 (a measure of the calcium sensitivity of force) of type 1 fibers compared to control subjects' type 1 muscle fibers. Our findings expand the clinico-pathological spectrum of ACTA1-related congenital myopathies and the genetic spectrum of core-rod myopathies.

DNA-GEL, Novel Nanomaterial for Biomedical Applications and Delivery of Bioactive Molecules.

Novel DNA materials promise unpredictable perspectives for applications in cell biology. The realization of DNA-hydrogels built by a controlled association of DNA nanostars, whose binding can be tuned with minor changes in the nucleotide sequences, has been recently described. DNA hydrogels, with specific gelation properties that can be reassambled in desired culture media supplemented with drugs, RNA, DNA molecules and other bioactive compounds offer the opportunity to develop a novel nanomaterial for the delivery of single or multiple drugs in tumor tissues as an innovative and promising strategy. We provide here a comprehensive description of different, recently realized DNA-gels with the perspective of stimulating their biomedical application. Finally, we discuss the possibility to design sophisticated 3D tissue-like DNA-gels incorporating cell spheroids or single cells for the assembly of a novel kind of cellular matrix as a preclinical investigation for the implementation of tools for in vivo delivery of bioactive molecules.

Monoclonal Gammopathies of Renal Significance: Renal Biopsy and Beyond.

Monoclonal Gammopathies of Renal Significance (MGRS) are a rather heterogeneous group of renal disorders caused by a circulating monoclonal (MC) immunoglobulin (Ig) component, often in the absence of multiple myeloma (MM) or another clinically relevant lymphoproliferative disorder. Nevertheless, substantial kidney damage could occur, despite the "benign" features of the bone-marrow biopsy. One example is renal amyloidosis, often linked to a small clone of plasma cells, without the invasive features of MM. However, patients with amyloidosis may present with a nephrotic syndrome and renal failure, eventually leading to end-stage kidney disease. At the same time, other organs, such as the heart and the liver, may be severely damaged by Ig light chains or amyloid deposits, occasionally resulting in fatal arrhythmias and/or organ failure. Acute kidney injury (AKI) may as well result from massive excretion of MC proteins, with deposition disease in glomeruli or renal tubules, not rarely obstructed by luminal aggregates, or "casts". Proliferative glomerulonephritis with monoclonal Ig deposits is another, less frequent clinical presentation of an MGRS. The present review deals with the implications of MGRS for renal function and prognosis, and the potential of tools, such as the renal biopsy, for assessing clinical risk and guiding therapy of the underlying condition.

[Steroid and cyclosporine therapy in idiopathic membranous nephropathy: monocentric experience and literature review].

INTRODUCTION: Immunosuppressive treatment of patients with idiopathic membranous nephropathy (IMN) is debated due to its possible side effects. The 2012 KDIGO guidelines suggest alkylating agents as first choice therapy. The aim of the study is to retrospectively evaluate the induction and maintenance of clinical remission in patients with histological diagnosis of IMN undergoing steroid and/or cyclosporine therapy at the Nephrology Unit of the Sant'Andrea Hospital in Rome. MATERIALS AND METHODS: Therapy A (conservative) was reserved to low-risk patients. 8 medium and high risk patients were induced by Therapy B (Prednisone 1 mg / kg ≤12-16 weeks plus 8 weeks withdrawal); 6 patients by Therapy C (Prednisone 1 mg /kg ≥20-24 weeks plus 8 week withdrawal) and, finally, 6 steroid-resistent patients by Therapy D (steroid withdrawal + cyclosporine 3-5 mg / kg for 2 years). RESULTS: Complete remission was observed in 37.5% of patients in Therapy B, in 83.3% of patients in Therapy C and in 66.6% of patients in Therapy D. Patients in group B relapsed more frequently than patients in the other groups. Side effects were irrelevant. CONCLUSIONS: In view of the potential cytotoxicity of alkylating agents, steroids are a valid alternative in inducing and maintaining clinical remission over time, when administered with a more aggressive induction scheme. In cases of steroid resistance or rapid relapse, cyclosporine is a valid alternative to alkylating agents.