Publications by authors named "Sofia Asioli"

118 Publications

Machine learning in neuro-oncology: toward novel development fields.

J Neurooncol 2022 Jun 28. Epub 2022 Jun 28.

Nervous System Medical Oncology Department, IRCCS Istituto delle Scienze Neurologiche di Bologna, Via Altura 3, Bologna, Italy.

Purpose: Artificial Intelligence (AI) involves several and different techniques able to elaborate a large amount of data responding to a specific planned outcome. There are several possible applications of this technology in neuro-oncology.

Methods: We reviewed, according to PRISMA guidelines, available studies adopting AI in different fields of neuro-oncology including neuro-radiology, pathology, surgery, radiation therapy, and systemic treatments.

Results: Neuro-radiology presented the major number of studies assessing AI. However, this technology is being successfully tested also in other operative settings including surgery and radiation therapy. In this context, AI shows to significantly reduce resources and costs maintaining an elevated qualitative standard. Pathological diagnosis and development of novel systemic treatments are other two fields in which AI showed promising preliminary data.

Conclusion: It is likely that AI will be quickly included in some aspects of daily clinical practice. Possible applications of these techniques are impressive and cover all aspects of neuro-oncology.
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http://dx.doi.org/10.1007/s11060-022-04068-7DOI Listing
June 2022

Neuroplasticity Mechanisms in Frontal Brain Gliomas: A Preliminary Study.

Front Neurol 2022 3;13:867048. Epub 2022 Jun 3.

Functional and Molecular Neuroimaging Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.

Background: Pathological brain processes may induce adaptive cortical reorganization, however, the mechanisms underlying neuroplasticity that occurs in the presence of lesions in eloquent areas are not fully explained. The aim of this study was to evaluate functional compensatory cortical activations in patients with frontal brain gliomas during a phonemic fluency task and to explore correlations with cognitive performance, white matter tracts microstructural alterations, and tumor histopathological and molecular characterization.

Methods: Fifteen patients with frontal glioma were preoperatively investigated with an MRI study on a 3T scanner and a subgroup underwent an extensive neuropsychological assessment. The hemispheric laterality index (LI) was calculated through phonemic fluency task functional MRI (fMRI) activations in the frontal, parietal, and temporal lobe parcellations. Diffusion-weighted images were acquired for all patients and for a group of 24 matched healthy volunteers. Arcuate Fasciculus (AF) and Frontal Aslant Tract (FAT) tractography was performed using constrained spherical deconvolution diffusivity modeling and probabilistic fiber tracking. All patients were operated on with a resective aim and underwent adjuvant therapies, depending on the final diagnosis.

Results: All patients during the phonemic fluency task fMRI showed left hemispheric dominance in temporal and parietal regions. Regarding frontal regions (i.e., frontal operculum) we found right hemispheric dominance that increases when considering only those patients with tumors located on the left side. These latter activations positively correlate with verbal and visuo-spatial short-term memory, and executive functions. No correlations were found between the left frontal operculum and cognitive performance. Furthermore, patients with mutation and without mutation, showed higher rightward frontal operculum fMRI activations and better cognitive performance in tests measuring general cognitive abilities, semantic fluency, verbal short-term memory, and executive functions. As for white matter tracts, we found left and right AF and FAT microstructural alterations in patients with, respectively, left-sided and right-side glioma compared to controls.

Conclusions: Compensatory cortical activation of the corresponding region in the non-dominant hemisphere and its association with better cognitive performance and more favorable histopathological and molecular tumor characteristics shed light on the neuroplasticity mechanisms that occur in the presence of a tumor, helping to predict the rate of post-operative deficit, with the final goal of improving patients'quality of life.
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http://dx.doi.org/10.3389/fneur.2022.867048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204970PMC
June 2022

Periosteal chondrosarcoma: A case series in a referral center with survivorship analysis.

Eur J Surg Oncol 2022 Jun 3. Epub 2022 Jun 3.

Department of Pathology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy. Electronic address:

Background: Periosteal chondrosarcomas are among the rarest types of chondrosarcomas dealt with in few small series of cases. In this study, we aimed to present our experience with this chondrosarcoma, seek for prognostic factors for OS and DFS and survey the status of IDH1 and IDH2.

Results: 55 periosteal chondrosarcomas were retrospectively identified. Median age was 37 years, there was a male predominance (62%). The great majority of cases involved the metaphysis of long bones of the extremities. The median size of the tumors was 7.5 cm. Thirty patients underwent to subtotal surgical resection, 22 to tangential resection and the remaining 3 to amputation. The margins, reported in 54 cases, were wide/radical in 38 patients (70.4%), marginal in 9 (16.7%) and intralesional in 7 (12.9%). Histologically, 23 (42%) were grade 1; 27 (49%), grade 2; 3 (5%), grade 3 and 2 (4%) were dedifferentiated. A third of cases in which mutational analysis was feasible harbored heterozygous mutations in codon 132 of IDH1. Fifty-four cases were included for follow-up (median, 137 months). Four patients had local recurrences and six patients developed metastasis to the lungs. All patients that developed metastasis died of disease, two died of unrelated causes and 46 were alive without disease. OS and DFS was not found to be statistically associated with clinical and pathological parameters considered.

Conclusions: periosteal chondrosarcomas exhibit a low-grade behavior that can be adequately treated with marginal excisions. Clinical and morphologic parameters do not seem to predict their outcome.
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http://dx.doi.org/10.1016/j.ejso.2022.05.024DOI Listing
June 2022

Infra-Temporal and Pterygo-Palatine Fossae Tumors: A Frontier in Endoscopic Endonasal Surgery-Description of the Surgical Anatomy of the Approach and Report of Illustrative Cases.

Int J Environ Res Public Health 2022 05 25;19(11). Epub 2022 May 25.

Programma Neurochirurgia Ipofisi-Pituitary Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy.

Infratemporal and pterygopalatine fossae (ITF and PPF) represent two complex paramedian skull base areas, which can be defined as jewelry boxes, containing a large number of neurovascular and osteomuscular structures of primary importance. They are in close communication with many craniofacial areas, such as nasal/paranasal sinuses, orbit, middle cranial fossa, and oral cavities. Therefore, they can be involved by tumoral, infective or inflammatory lesions spreading from these spaces. Moreover, they can be the primary site of the development of some primitive tumors. For the deep-seated location of ITF and PPF lesions and their close relationship with the surrounding functional neuro-vascular structures, their surgery represents a challenge. In the last decades, the introduction of the endoscope in skull base surgery has favored the development of an innovative anterior endonasal approach for ITF and PPF tumors: the transmaxillary-pterygoid, which gives a direct and straightforward route for these areas. It has demonstrated that it is effective and safe for the treatment of a large number of benign and malignant neoplasms, located in these fossae, avoiding extensive bone drilling, soft tissue demolition, possibly unaesthetic scars, and reducing the risk of neurological deficits. However, some limits, especially for vascular tumors or lesions with lateral extension, are still present. Based on the experience of our multidisciplinary team, we present our operative technique, surgical indications, and pre- and post-operative management protocol for patients with ITF and PPF tumors.
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http://dx.doi.org/10.3390/ijerph19116413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9180479PMC
May 2022

Clinical-Pathological Evaluation and Prognostic Analysis of 228 Merkel Cell Carcinomas Focusing on Tumor-Infiltrating Lymphocytes, MCPYV Infection and ALK Expression.

Endocr Pathol 2022 Jun 12;33(2):289-303. Epub 2022 May 12.

Pathology Unit, Department of Oncology, Città Della Salute e Della Scienza of Turin, University of Turin, Via Santena 7, 10126, Turin, Italy.

Merkel cell carcinoma is a rare and aggressive primary neuroendocrine carcinoma of the skin, whose pathogenesis can be traced back to UV radiation damage or Merkel cell polyomavirus (MCPyV) infection. Despite some improvements on the characterization of the disease partly due to its increased incidence, crucial pathogenetic and prognostic factors still need to be refined. A consecutive series of 228 MCC from three hospitals in Turin was collected with the aim of both analyzing the apparent increase in MCC incidence in our area and investigating the distribution and prognostic role of clinical-pathological parameters, with a focus on MCPyV status, ALK tumor expression and tumor infiltrating lymphocytes (TILs). Review of morphology and conventional immunohistochemical staining was possible in 191 cases. In 50 cases, the expression of the novel neuroendocrine marker INSM1 was additionally assessed. Fourteen cases of MCC of unknown primary skin lesion were identified and separately analyzed. While confirming an exponential trend in MCC incidence in the last decades and providing a description of histological and cytological features of a large series of MCC, the present study concludes that 1) INSM1 is a highly sensitive marker in both skin and lymph node primary MCC; 2) positive MCPyV status, brisk TILs and lower tumor size and thickness are independent positive prognostic parameters, and the combination of the former two may provide a novel tool for prognostic stratification; 3) ALK is expressed 87% of MCC and associated with positive viral status, and could represent a prognostic biomarker, if validated in larger series.
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http://dx.doi.org/10.1007/s12022-022-09716-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9135831PMC
June 2022

Bilateral antererior circulation stroke: A rare but threatening consequence of pituitary apoplexy. Case report and systematic literature review.

Neuroradiol J 2022 Mar 27:19714009221083146. Epub 2022 Mar 27.

Programma Neurochirurgia Ipofisi- Pituitary Unit, 419170IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy.

Background: Brain stroke is a rare, life-threatening condition associated with pituitary apoplexy (PA), resulting from direct arterial occlusion due to mechanical compression secondary to the sudden enlargement of the pituitary adenoma, or to vessel vasospasm, induced by tumor hemorrhage.

Case Report: We report the case of a 64-year-old woman with PA complicated by bilateral anterior circulation stroke due to critical stenosis of both anterior cerebral arteries (ACA). Despite the quick surgical decompression and consequent blood flow restoration, the neurological conditions of the patient did not improve and she died 18 days later. Ten other cases of anterior circulation stroke due to PA were retrieved in a systematic review of literature. Clinical and neuroradiological features of these patients and treatment outcome were assessed to suggest the most proper management.

Conclusion: The onset of neurological symptoms suggestive for brain stroke in patients with PA requires performing an emergency Magnetic Resonance Imaging (MRI), including Diffusion-weighted and angiographic MR-sequences. The role of surgery in these cases is debated, however, transsphenoidal adenomectomy would permit us to decompress the ACA and restore blood flow in their territories. Although the prognosis of PA-induced anterior circulation stroke is generally poor, a timely diagnosis and treatment would be paramount for improving patient outcome.
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http://dx.doi.org/10.1177/19714009221083146DOI Listing
March 2022

Knowledge and attitudes of neurologists toward epilepsy surgery: an Italian survey.

Neurol Sci 2022 Jul 21;43(7):4453-4461. Epub 2022 Mar 21.

Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children Hospital, Rome, Italy.

The current study, conceived with the contribution of the Commission for Epilepsy Surgery of the Italian League Against Epilepsy (LICE) and the Epilepsy Study Group of the Italian Neurological Society (SIN), aimed to assess potential physician-related barriers to refer subjects for epilepsy surgery. All the members of SIN and LICE were invited by email to complete a 28-item online questionnaire. The survey items included: (1) individual and medical practice characteristics, (2) knowledge of current indications to select candidates for epilepsy surgery, (3) factors potentially affecting the attitude toward epilepsy surgery. Overall, 210 physicians completed the survey. More than half (63.3%) of the participants showed proper knowledge of the ILAE drug-resistance. Definition and almost two-thirds of them (71.9%) considered themselves adequately informed about indications, risks, and benefits of epilepsy surgery. Surgery was regarded as a valid option to be used as early as possible by 84.8% of the interviewees, and 71% of them estimated its complication rate to be low. However, more than half (63%) of the respondents reportedly referred patients for surgery only after the failure of 3-5 antiseizure medications. Overestimation of risks/complications of surgery and inadequate healthcare resources were identified as the main factor contrasting the patient referral for surgery by 43% and 40.5% of the participants, respectively. In conclusion, this survey confirms the existence of knowledge gap within both physicians and the healthcare system, as well as an educational need regarding epilepsy surgery. Further researches are warranted to define learning outcomes and optimize educational tools.
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http://dx.doi.org/10.1007/s10072-022-06025-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8935880PMC
July 2022

Impact of phospholipase C β1 in glioblastoma: a study on the main mechanisms of tumor aggressiveness.

Cell Mol Life Sci 2022 Mar 18;79(4):195. Epub 2022 Mar 18.

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, 40126, Bologna, Italy.

Glioblastoma represents the most lethal brain tumor in adults. Several studies have shown the key role of phospholipase C β1 (PLCβ1) in the regulation of many mechanisms within the central nervous system suggesting PLCβ1 as a novel signature gene in the molecular classification of high-grade gliomas. This study aims to determine the pathological impact of PLCβ1 in glioblastoma, confirming that PLCβ1 gene expression correlates with glioma's grade, and it is lower in 50 glioblastoma samples compared to 20 healthy individuals. PLCβ1 silencing in cell lines and primary astrocytes, leads to increased cell migration and invasion, with the increment of mesenchymal transcription factors and markers, as Slug and N-Cadherin and metalloproteinases. Cell proliferation, through increased Ki-67 expression, and the main survival pathways, as β-catenin, ERK1/2 and Stat3 pathways, are also affected by PLCβ1 silencing. These data suggest a potential role of PLCβ1 in maintaining a normal or less aggressive glioma phenotype.
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http://dx.doi.org/10.1007/s00018-022-04198-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8933313PMC
March 2022

Secondary peripheral chondrosarcoma arising in solitary osteochondroma: variables influencing prognosis and survival.

Orphanet J Rare Dis 2022 02 22;17(1):74. Epub 2022 Feb 22.

Department of Rare Skeletal Disorders, IRCCS Istituto Ortopedico Rizzoli, Via Pupilli 1, 40136, Bologna, Italy.

Background: Secondary peripheral chondrosarcomas arising in solitary osteochondromas is an unusual complication, reported in small series. In this study, we aimed to present our experience with this rare variant of chondrosarcoma and compare results with already published data in order to determine prognostic factors for overall and disease-free survival.

Methods: The case study includes retrospective data from patients diagnosed at a single institution from 1943 to 2019. Clinical data were collected reviewing all available medical records from first to last follow-up visits. To exclude the presence of the Multiple Osteochondroma Hereditary Syndrome, few patients, with a suspect of a familial form of the disease, were evaluated for the presence of germline heterozygous variants in EXT1 and EXT2 genes. Results were summarized using descriptive statistics and statistical analysis were performed to reveal associations between variables.

Results: Two hundred and fourteen secondary peripheral chondrosarcomas that arose exclusively from solitary osteochondromas diagnosed in a multidisciplinary setting at the IRCCS Istituto Ortopedico Rizzoli were retrospectively identified, 66.4% males and 33.6% females with a median age at diagnosis of 38 years. The local recurrence rate was 17.3%, while the metastases one was 5.1%. Besides age, a high histologic grade is the only factor associated with worse 5-year and 10-year overall survival (log-rank p = 0.0005, HR = 3.74; 95% CI 1.69-8.26). Moreover, high histological grade (HR = 3.75; 95% CI = 1.69-8.34; p = 0.001) and surgical debulking (HR = 3.71; 95% CI = 1.57-8.79; p = 0.003) were associated with a significantly worse disease-free survival.

Conclusions: Our study confirm the low-grade behavior of secondary peripheral chondrosarcomas and demonstrate that the best choice of treatment for those arising in solitary osteochondromas is the wide surgical excision, when possible. Location per se is not a factor that affects prognosis, while the accurate histological grade assessment is correlated with the tumor aggressiveness and a long term follow up is necessary for this rare variant of chondrosarcoma.
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http://dx.doi.org/10.1186/s13023-022-02210-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8864784PMC
February 2022

Validation of a Cleanroom Compliant Sonication-Based Decellularization Technique: A New Concept in Nerve Allograft Production.

Int J Mol Sci 2022 Jan 28;23(3). Epub 2022 Jan 28.

Oral and Maxillofacial Surgery Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.

Defects of the peripheral nervous system are extremely frequent in trauma and surgeries and have high socioeconomic costs. If the direct suture of a lesion is not possible, i.e., nerve gap > 2 cm, it is necessary to use grafts. While the gold standard is the autograft, it has disadvantages related to its harvesting, with an inevitable functional deficit and further morbidity. An alternative to autografting is represented by the acellular nerve allograft (ANA), which avoids disadvantages of autograft harvesting and fresh allograft rejection. In this research, the authors intend to transfer to human nerves a novel technique, previously implemented in animal models, to decellularize nerves. The new method is based on soaking the nerve tissues in decellularizing solutions while associating ultrasounds and freeze-thaw cycles. It is performed without interrupting the sterility chain, so that the new graft may not require post-production γ-ray irradiation, which is suspected to affect the structural and functional quality of tissues. The new method is rapid, safe, and inexpensive if compared with available commercial ANAs. Histology and immunohistochemistry have been adopted to evaluate the new decellularized nerves. The study shows that the new method can be applied to human nerve samples, obtaining similar, and, sometimes better, results compared with the chosen control method, the Hudson technique.
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http://dx.doi.org/10.3390/ijms23031530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836166PMC
January 2022

Hemorrhagic Schwannoma of the Cauda Equina: Case Report and Review of the Literature.

NMC Case Rep J 2021 9;8(1):377-385. Epub 2021 Jul 9.

IRCCS/Institute of Neurological Science of Bologna, Department of Neurologic Surgery, Bellaria Hospital, Bologna, Italy.

Spinal intradural hemorrhage is a rare event; the most common causes of spinal bleeding are traumas, medical therapy with anticoagulants and thrombolytics, vascular malformations, and congenital defects of coagulation. Rarely, spinal cord tumors may cause hemorrhage. Herein, we report the case of a patient with acute and quickly worsening lumbar pain: the neurological examination revealed a flaccid paraplegia caused by an intradural lesion extending on the right side of the spinal cord from T1 to L2 vertebral level. Pathological examination revealed an hemorrhagic schwannoma. Acute spinal subdural hemorrhage caused by spinal schwannomas is a very rare occurrence (29 cases only have been previously reported). Review of the literature with clinico-diagnostic features is presented, surgical treatment is explained, and pathological findings with possible etiopathogenesis of hemorrhage are described.
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http://dx.doi.org/10.2176/nmccrj.cr.2020-0186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769457PMC
July 2021

Primary synovial sarcoma of bone: a retrospective analysis of 25 patients.

Histopathology 2022 Mar 18;80(4):686-697. Epub 2022 Jan 18.

Department of Medicine, University of Padua School of Medicine, Padova, Italy.

Aims: To evaluate the diagnostic accuracy of SSX and SSX::SS18 antibodies in decalcified surgical specimens and outcome of synovial sarcomas (SS) of bone.

Methods And Results: Twenty-five cases were classified as bone SS (prevalence 0.32% among malignant primary bone sarcoma). Median age was 34 years (range = 9-79). Twenty-four of 25 patients presented with non-metastatic tumours, one with lung metastases. The majority of tumours involved the long bones of extremities with metaphyseal origin. Mean size of the tumour was 7.1 cm. Twenty cases (80%) were monophasic and five (20%) were biphasic. SS18::SSX fusion-specific antibody had 92% sensitivity and 99% specificity for primary bone SS, whereas SSX C-terminus antibody had 100% sensitivity and 94% specificity. Fluorescence in-situ hybridisation (FISH) analysis was feasible in nine (36%) cases and detected SS18 rearrangement in all nine cases. All patients underwent surgical removal of their primary tumour, with adequate margins in 18 (72%) patients. Chemotherapy with metothrexate, cisplatin, doxorubicin and ifosfamide was used in the seven patients. Two patients with inadequate surgical margins received radiotherapy. With a median follow-up of 80 months (range = 6-428), 5- and 10-year overall survival (OS) was 66.6% and 47.9%, respectively, and 5 and 10 years' disease-free survival (DFS) was 36.8% [95% confidence interval (CI) = 18.0-55.7%] and 32.2% (95% CI = 14.6-51.2%), respectively. A significant improvement in 10 years' DFS in patients undergoing chemotherapy compared with patients who did not was observed (P = 0.039).

Conclusions: Our series highlights the utility of SS18::SSX fusion-specific and SSX C-terminus antibodies to support the diagnosis of SS. Adjustment chemotherapy was associated with improved prognosis in this series.
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http://dx.doi.org/10.1111/his.14602DOI Listing
March 2022

Role of PLCγ1 in the modulation of cell migration and cell invasion in glioblastoma.

Adv Biol Regul 2022 01 19;83:100838. Epub 2021 Nov 19.

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy. Electronic address:

Phosphoinositide-specific phospholipases C (PLCs) are a class of enzymes involved in several cell activities, such as cell cycle regulation, proliferation, differentiation and cytoskeletal dynamics. Among these enzymes, PLCγ1 is one of the most expressed PLCs in the brain, contributing to a complex network in the developing nervous system. Several studies have shown that PLCγ1 signaling imbalance is linked to several brain disorders, including glioblastoma, the most aggressive brain tumor in adults. Indeed, it has been demonstrated a link between PLCγ1 inhibition and the arrest of glioma cell motility of fetal rat brain aggregates and the impairment of cell invasion abilities following its down-regulation. This study aims to determine the pathological influence of PLCγ1 in glioblastoma, through a translational study which combines in silico data, data from glioblastoma patients' samples and data on engineered cell lines. We found out that PLCγ1 gene expression correlates with the pathological grade of gliomas, and it is higher in fifty patients' glioblastoma tissue samples compared to twenty healthy controls. Moreover, it was demonstrated that PLCγ1 silencing in U87-MG leads to a reduction in cell migration and invasion abilities. The opposite trend was observed following PLCγ1 overexpression, suggesting an interesting possible involvement of PLCγ1 in gliomas' aggressiveness.
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http://dx.doi.org/10.1016/j.jbior.2021.100838DOI Listing
January 2022

Is There a Role for Surgical Resection of Multifocal Glioblastoma? A Retrospective Analysis of 100 Patients.

Neurosurgery 2021 11;89(6):1042-1051

Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum University of Bologna, Italy.

Background: Glioblastoma with multiple localizations (mGBMs) can be defined as multifocal, where enhancing lesions present a connection visible on magnetic resonance imaging fluid-attenuated inversion recovery imaging, or multicentric, in the absence of a clear dissemination pathway.

Objective: To evaluate the role of the extent of resection (EOR) in the treatment of mGBMs and its correlation with overall survival (OS) and progression free survival (PFS).

Methods: One hundred patients with mGBMs were treated at our Institution between 2009 and 2019. Clinical, radiological, and follow-up data were collected. EOR of the contrast-enhancing part of lesions was classified as gross total resection (GTR, absence of tumor remnant), subtotal resection (STR, residual tumor < 30% of the initial mass), partial resection (PR, residual tumor > 30% of the initial mass), and needle or open biopsy (residual tumor > 75% of the initial mass).

Results: Approximately 15% of patients underwent GTR, 14% STR, 32% PR, and 39% biopsy. Median OS was 17 mo for GTR, 11 mo for STR, 7 mo for PR, and 5 mo for biopsy. Greater EOR was associated with a significantly longer OS than biopsy. GTR and STR were associated with a longer PFS in Kaplan-Meier survival analyses. After adjusting for age, Karnofsky performance status (KPS), number of lesions, and adjunctive therapy in multivariable Cox regression analyses, GTR, STR, and PR were still associated with OS, but only GTR remained associated with PFS.

Conclusion: Our study suggests that EOR may positively influence survival of patients with mGBM. Surgical resection can be a reasonable option when performance and access to adjuvant treatment can be preserved.
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http://dx.doi.org/10.1093/neuros/nyab345DOI Listing
November 2021

Machine learning-based clinical outcome prediction in surgery for acromegaly.

Endocrine 2022 Feb 12;75(2):508-515. Epub 2021 Oct 12.

Machine Intelligence in Clinical Neuroscience (MICN) Laboratory, Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Purpose: Biochemical remission (BR), gross total resection (GTR), and intraoperative cerebrospinal fluid (CSF) leaks are important metrics in transsphenoidal surgery for acromegaly, and prediction of their likelihood using machine learning would be clinically advantageous. We aim to develop and externally validate clinical prediction models for outcomes after transsphenoidal surgery for acromegaly.

Methods: Using data from two registries, we develop and externally validate machine learning models for GTR, BR, and CSF leaks after endoscopic transsphenoidal surgery in acromegalic patients. For the model development a registry from Bologna, Italy was used. External validation was then performed using data from Zurich, Switzerland. Gender, age, prior surgery, as well as Hardy and Knosp classification were used as input features. Discrimination and calibration metrics were assessed.

Results: The derivation cohort consisted of 307 patients (43.3% male; mean [SD] age, 47.2 [12.7] years). GTR was achieved in 226 (73.6%) and BR in 245 (79.8%) patients. In the external validation cohort with 46 patients, 31 (75.6%) achieved GTR and 31 (77.5%) achieved BR. Area under the curve (AUC) at external validation was 0.75 (95% confidence interval: 0.59-0.88) for GTR, 0.63 (0.40-0.82) for BR, as well as 0.77 (0.62-0.91) for intraoperative CSF leaks. While prior surgery was the most important variable for prediction of GTR, age, and Hardy grading contributed most to the predictions of BR and CSF leaks, respectively.

Conclusions: Gross total resection, biochemical remission, and CSF leaks remain hard to predict, but machine learning offers potential in helping to tailor surgical therapy. We demonstrate the feasibility of developing and externally validating clinical prediction models for these outcomes after surgery for acromegaly and lay the groundwork for development of a multicenter model with more robust generalization.
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http://dx.doi.org/10.1007/s12020-021-02890-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8816764PMC
February 2022

Intron 4-5 hTERT DNA Hypermethylation in Merkel Cell Carcinoma: Frequency, Association with Other Clinico-pathological Features and Prognostic Relevance.

Endocr Pathol 2021 Sep 28;32(3):385-395. Epub 2021 Apr 28.

Department of Biomedical and Neuromotor Sciences (DIBINEM) Surgical Pathology Section- Alma Mater Studiorum , University of Bologna , Bologna, Italy.

Merkel cell carcinoma (MCC) is an aggressive skin tumor with neuroendocrine differentiation, mainly affecting elderly population or immunocompromised individuals. As methylation of the human telomerase reverse transcriptase (mhTERT) has been shown to be a prognostic factor in different tumors, we investigated its role in MCC, in particular in intron 4-5 where rs10069690 has been mapped and recognized as a cancer susceptibility locus. DNA methylation analysis of hTERT gene was assessed retrospectively in a cohort of 69 MCC patients from the University of Bologna, University of Turin and University of Insubria. Overall mortality was evaluated with Kaplan-Meier curves and multivariable Royston-Parmar models. High levels of mhTERT (mhTERT) (HR = 2.500, p = 0.015) and p63 (HR = 2.659, p = 0.016) were the only two clinico-pathological features significantly associated with a higher overall mortality at the multivariate analysis. We did not find different levels of mhTERT between MCPyV (+) and (-) cases (21 vs 14, p = 0.554); furthermore, mhTERT was strongly associated with older age (80.5 vs 72 years, p = 0.026), no angioinvasion (40.7% vs 71.0%, p = 0.015), lower Ki67 (50 vs 70%, p = 0.005), and PD-L1 expressions in both tumor (0 vs 3%, p = 0.021) and immune cells (0 vs 10%, p = 0.002). mhTERT is a frequently involved epigenetic mechanism and a relevant prognostic factor in MCC. In addition, it belongs to the shared oncogenic pathways of MCC (MCPyV and UV-radiations) and it could be crucial, together with other epigenetic and genetic mechanisms as gene amplification, in determining the final levels of hTERT mRNA and telomerase activity in these patients.
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http://dx.doi.org/10.1007/s12022-021-09669-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370894PMC
September 2021

The surgical treatment of epilepsy.

Neurol Sci 2021 Jun 2;42(6):2249-2260. Epub 2021 Apr 2.

Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children Hospital, Rome, Italy.

In 2009, the Commission for Epilepsy Surgery of the Italian League Against Epilepsy (LICE) conducted an overview about the techniques used for the pre-surgical evaluation and the surgical treatment of epilepsies. The recognition that, in selected cases, surgery can be considered the first-line approach, suggested that the experience gained by the main Italian referral centers should be pooled in order to provide a handy source of reference. In light of the progress made over these past years, some parts of that first report have accordingly been updated. The present revision aims to harmonize the general principles regulating the patient selection and the pre-surgical work-up, as well as to expand the use of epilepsy surgery, that still represents an underutilized resource, regrettably. The objective of this contribution is drawing up a methodological framework within which to integrate the experiences of each group in this complex and dynamic sector of the neurosciences.
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http://dx.doi.org/10.1007/s10072-021-05198-yDOI Listing
June 2021

From Neurosurgical Planning to Histopathological Brain Tumor Characterization: Potentialities of Arcuate Fasciculus Along-Tract Diffusion Tensor Imaging Tractography Measures.

Front Neurol 2021 26;12:633209. Epub 2021 Feb 26.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Tractography has been widely adopted to improve brain gliomas' surgical planning and guide their resection. This study aimed to evaluate state-of-the-art of arcuate fasciculus (AF) tractography for surgical planning and explore the role of along-tract analyses for characterizing tumor histopathology. High angular resolution diffusion imaging (HARDI) images were acquired for nine patients with tumors located in or near language areas (age: 41 ± 14 years, mean ± standard deviation; five males) and 32 healthy volunteers (age: 39 ± 16 years; 16 males). Phonemic fluency task fMRI was acquired preoperatively for patients. AF tractography was performed using constrained spherical deconvolution diffusivity modeling and probabilistic fiber tracking. Along-tract analyses were performed, dividing the AF into 15 segments along the length of the tract defined using the Laplacian operator. For each AF segment, diffusion tensor imaging (DTI) measures were compared with those obtained in healthy controls (HCs). The hemispheric laterality index (LI) was calculated from language task fMRI activations in the frontal, parietal, and temporal lobe parcellations. Tumors were grouped into low/high grade (LG/HG). Four tumors were LG gliomas (one dysembryoplastic neuroepithelial tumor and three glioma grade II) and five HG gliomas (two grade III and three grade IV). For LG tumors, gross total removal was achieved in all but one case, for HG in two patients. Tractography identified the AF trajectory in all cases. Four along-tract DTI measures potentially discriminated LG and HG tumor patients (false discovery rate < 0.1): the number of abnormal MD and RD segments, median AD, and MD measures. Both a higher number of abnormal AF segments and a higher AD and MD measures were associated with HG tumor patients. Moreover, correlations (unadjusted < 0.05) were found between the parietal lobe LI and the DTI measures, which discriminated between LG and HG tumor patients. In particular, a more rightward parietal lobe activation (LI < 0) correlated with a higher number of abnormal MD segments ( = -0.732) and RD segments ( = -0.724). AF tractography allows to detect the course of the tract, favoring the safer-as-possible tumor resection. Our preliminary study shows that along-tract DTI metrics can provide useful information for differentiating LG and HG tumors during pre-surgical tumor characterization.
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http://dx.doi.org/10.3389/fneur.2021.633209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952864PMC
February 2021

Early stability and late random tumor progression of a HER2-positive primary breast cancer patient-derived xenograft.

Sci Rep 2021 01 15;11(1):1563. Epub 2021 Jan 15.

Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, 40126, Bologna, Italy.

We established patient-derived xenografts (PDX) from human primary breast cancers and studied whether stability or progressive events occurred during long-term in vivo passages (up to 4 years) in severely immunodeficient mice. While most PDX showed stable biomarker expression and growth phenotype, a HER2-positive PDX (PDX-BRB4) originated a subline (out of 6 studied in parallel) that progressively acquired a significantly increased tumor growth rate, resistance to cell senescence of in vitro cultures, increased stem cell marker expression and high lung metastatic ability, along with a strong decrease of BCL2 expression. RNAseq analysis of the progressed subline showed that BCL2 was connected to three main hub genes also down-regulated (CDKN2A, STAT5A and WT1). Gene expression of progressed subline suggested a partial epithelial-to-mesenchymal transition. PDX-BRB4 with its progressed subline is a preclinical model mirroring the clinical paradox of high level-BCL2 as a good prognostic factor in breast cancer. Sequential in vivo passages of PDX-BRB4 chronically treated with trastuzumab developed progressive loss of sensitivity to trastuzumab while HER2 expression and sensitivity to the pan-HER tyrosine kinase inhibitor neratinib were maintained. Long-term PDX studies, even though demanding, can originate new preclinical models, suitable to investigate the mechanisms of breast cancer progression and new therapeutic approaches.
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http://dx.doi.org/10.1038/s41598-021-81085-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810859PMC
January 2021

Location-dependent role of phospholipase C signaling in the brain: Physiology and pathology.

Adv Biol Regul 2021 01 28;79:100771. Epub 2020 Nov 28.

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. Electronic address:

Phosphoinositide-specific phospholipases C (PI-PLCs) are a class of enzymes involved in the phosphatidylinositol metabolism, which is implicated in the activation of several signaling pathways and which controls several cellular processes. The scientific community has long accepted the existence of a nuclear phosphoinositide (PI) metabolism, independent from the cytoplasmic one, critical in nuclear function control. Indeed, nuclear PIs are involved in many activities, such as cell cycle regulation, cell proliferation, cell differentiation, membrane transport, gene expression and cytoskeletal dynamics. There are several types of PIs and enzymes implicated in brain activities and among these enzymes, PI-PLCs contribute to a specific and complex network in the developing nervous system. Moreover, considering the abundant presence of PI-PLCβ1, PI-PLCγ1 and PI-PLCβ4 in the brain, a specific role for each PLC subtype has been suggested in the control of neuronal activity, which is important for synapse function, development and other mechanisms. The focus of this review is to describe the latest research about the involvement of PI-PLC signaling in the nervous system, both physiologically and in pathological conditions. Indeed, PI-PLC signaling imbalance seems to be also linked to several brain disorders including epilepsy, movement and behavior disorders, neurodegenerative diseases and, in addition, some PI-PLC subtypes could become potential novel signature genes for high-grade gliomas.
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http://dx.doi.org/10.1016/j.jbior.2020.100771DOI Listing
January 2021

Temporal lobe epilepsy surgery in children and adults: A multicenter study.

Epilepsia 2021 01 1;62(1):128-142. Epub 2020 Dec 1.

Department of Neuroscience, Imaging and Clinical Sciences, "G. D'Annunzio" University, Chieti, Italy.

Objective: To assess seizure and cognitive outcomes and their predictors in children (<16 years at surgery) and adults undergoing temporal lobe epilepsy (TLE) surgery in eight Italian centers.

Methods: This is a retrospective multicenter study. We performed a descriptive analysis and subsequently carried out multivariable mixed-effect models corrected for multiple comparisons.

Results: We analyzed data from 511 patients (114 children) and observed significant differences in several clinical features between adults and children. The possibility of achieving Engel class IA outcome and discontinuing antiepileptic drugs (AEDs) at last follow-up (FU) was significantly higher in children (P = .006 and < .0001). However, percentages of children and adults in Engel class I at last FU (mean ± SD, 45.9 ± 17 months in children; 45.9 ± 20.6 months in adults) did not differ significantly. We identified different predictors of seizure outcome in children vs adults and at short- vs long-term FU. The only variables consistently associated with class I outcome over time were postoperative electroencephalography (EEG) in adults (abnormal, improved,odds ratio [OR] = 0.414, P = .023, Q = 0.046 vs normal, at 2-year FU and abnormal, improved, OR = 0.301, P = .001, Q = 0.002 vs normal, at last FU) and the completeness of resection of temporal magnetic resonance (MR) abnormalities other than hippocampal sclerosis in children (OR = 7.93, P = .001, Q = 0.003, at 2-year FU and OR = 45.03, P < .0001, Q < 0.0001, at last FU). Cognitive outcome was best predicted by preoperative performances in either age group.

Significance: Clinical differences between adult and pediatric patients undergoing TLE surgery are reflected in differences in long-term outcomes and predictors of failures. Children are more likely to achieve sustained seizure freedom and withdraw AEDs after TLE surgery. Earlier referral should be encouraged as it can improve surgical outcome.
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http://dx.doi.org/10.1111/epi.16772DOI Listing
January 2021

Management of sellar and parasellar tumors becoming symptomatic during pregnancy: a practical algorithm based on multi-center experience and systematic literature review.

Pituitary 2021 Apr 17;24(2):269-283. Epub 2020 Nov 17.

Pituitary Unit, IRCCS Istituto Delle Scienze Neurologiche di Bologna, Via Altura, 3, 40139, Bologna, Italy.

Introduction: Sellar/parasellar tumors (SPTs) very rarely become symptomatic during pregnancy. No specific guidelines exist for their management, that is extremely challenging as mother and fetus health can be jeopardized.

Materials And Methods: Data of patients with SPTs becoming symptomatic during pregnancy treated at two Italian referral Centers were retrospectively collected. Systematic literature review was also performed.

Results: Our series consisted of 6 cases, 3 meningiomas, 1 ACTH-secreting adenoma, 1 pituicytoma and 1 craniopharyngioma. Mean age at presentation was 33.6 ± 6.0 years. Five patients complained of visual disturbances, associated with headache in one case, that occurred between gestation week (GW) 22 and 34. In 5 cases, pregnancy was uneventful with the delivery of a healthy baby between GW 33 and 35, followed by endoscopic surgical tumor exeresis (n = 4) or proton bean therapy (n = 1). Another patient presented with stigmata typical of Cushing's syndrome and rapidly worsening pre-eclampsia, that required pregnancy interruption and adenomectomy. Based on personal and literature cases, a practical algorithm was proposed to help clinicians dealing with these patients.

Conclusions: SPTs becoming symptomatic in pregnancy deserve careful monitoring and multidisciplinary management. Overall, wait-and-see approach is suggested, reserving surgery to patients with rapidly progressive/life-threatening situations, significant risk of permanent neurological impairment or malignant lesions.
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http://dx.doi.org/10.1007/s11102-020-01107-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966198PMC
April 2021

Pre-Operative Evaluation of DNA Methylation Profile in Oral Squamous Cell Carcinoma Can Predict Tumor Aggressive Potential.

Int J Mol Sci 2020 Sep 14;21(18). Epub 2020 Sep 14.

Section of Oral Science, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40159 Bologna, Italy.

Background: Prognosis of oral squamous cell carcinoma (OSCC) is difficult to exactly assess on pre-operative biopsies. Since OSCC DNA methylation profile has proved to be a useful pre-operative diagnostic tool, the aim of the present study was to evaluate the prognostic impact of DNA methylation profile to discriminate OSCC with high and low aggressive potential.

Methods: 36 OSCC cases underwent neoplastic cells collection by gentle brushing of the lesion, before performing a pre-operative biopsy. The CpG islands methylation status of 13 gene (, , , , , , , , , , , , ) was studied by bisulfite Next Generation Sequencing (NGS). A Cox proportional hazards model via likelihood-based component-wise boosting was used to evaluate the prognostic power of the CpG sites.

Results: The boosting estimation identified five CpGs with prognostic significance: , , , and . The combination of significant provided promising results for adverse events prediction (Brier score = 0.080, C-index = 0.802 and AUC = 0.850). had a strong prognostic power in patients with early OSCC.

Conclusions: These data confirm that the study of methylation profile provides new insights into the molecular mechanisms of OSCC and can allow a better OSCC prognostic stratification even before surgery.
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http://dx.doi.org/10.3390/ijms21186691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555204PMC
September 2020

Association of Clinicopathological Features With Outcome in Chondrosarcomas of the Head and Neck.

Otolaryngol Head Neck Surg 2021 04 15;164(4):807-814. Epub 2020 Sep 15.

Service of Anatomic Pathology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

Objective: The aim of this study is to assess the association between clinical and radiological features as well as of isocitrate dehydrogenase 1 and 2 ( 1,2) mutations with outcome in head and neck chondrosarcomas.

Study Design: Retrospective study.

Setting: Tertiary referral center.

Methods: Clinical, histological, and molecular data of patients with head and neck chondrosarcomas treated by surgery were collected.

Results: Forty-six patients were included. The mean age at diagnosis was 56 years (range, 17-78). The tumor originated from the skull base (52.2%), facial bones (28.2%), or laryngotracheal area (19.6%). At last follow-up (median 52.5 months), 38 patients were alive, 30 of which were disease free, whereas 8 had died, 4 of disease progression and 4 of other causes. Fourteen (30.4%) had local recurrence and 2 (4.3%) had lung metastasis. All cases were negative for cytokeratin AE1/AE3, brachyury, and IDH1 at immunohistochemistry, while Sanger sequencing identified IDH1/2 point mutations, typically IDH1 R132C, in 9 (37.5%) tumors arising from the skull base. Margin infiltration on the surgical specimen negatively affected the outcome, whereas no correlation was identified with mutation status.

Conclusions: An adequate margin positively affects survival. mutation status does not affect patient outcome.
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http://dx.doi.org/10.1177/0194599820957271DOI Listing
April 2021

Focal Cortical Dysplasia IIIa in Hippocampal Sclerosis-Associated Epilepsy: Anatomo-Electro-Clinical Profile and Surgical Results From a Multicentric Retrospective Study.

Neurosurgery 2021 01;88(2):384-393

Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children Hospital, Rome, Italy.

Background: Hippocampal sclerosis (HS) may be associated with focal cortical dysplasia IIIa (FCD IIIa) in patients undergoing surgery for temporal lobe epilepsy (TLE).

Objective: To investigate whether the anatomo-electro-clinical profile and surgical outcome in patients with HS-related TLE are affected by coexisting FCD IIIa.

Methods: A total of 220 patients, operated in 5 centers, with at least 24 mo follow-up (FU), were retrospectively studied. Preliminary univariate and subsequent multivariate analyses were performed to investigate possible associations between several potential presurgical, surgical, and postsurgical predictors and different variables (Engel's class I and Engel's class Ia, co-occurrence of FCD IIIa).

Results: At last available postoperative control (FU: range 24-95 mo, median 47 mo), 182 (82.7%) patients were classified as Engel's class I and 142 (64.5%) as Engel's class Ia. At multivariate analysis, extension of neocortical resection and postoperative electroencephalogram were significantly associated with Engel's class I, whereas length of FU had a significant impact on class Ia in the whole cohort and in isolated HS (iHS) patients, but not in the FCD IIIa group. No differences emerged in the anatomo-electro-clinical profile and surgical results between patients with FCD IIIa and with iHS.

Conclusion: Coexistence of FCD IIIa did not confer a distinct anatomo-electro-clinical profile to patients with HS-related epilepsy. Postoperative seizure outcome was similar in FCD IIIa and iHS cases. These findings indicate limited clinical relevance of FCD IIIa in HS-related epilepsy and might be useful for refining future FCD classifications. Further studies are needed to clarify the correlation of class Ia outcome with the duration of FU.
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http://dx.doi.org/10.1093/neuros/nyaa369DOI Listing
January 2021

Health Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant Epilepsy.

Int J Environ Res Public Health 2020 08 24;17(17). Epub 2020 Aug 24.

Pediatric Neurology Unit, Salesi Children Hospital, 60123 Ancona, Italy.

: Vagus nerve stimulation (VNS) is a palliative treatment for medical intractable epileptic syndromes not eligible for resective surgery. Health technology assessment (HTA) represents a modern approach to the analysis of technologies used for healthcare. The purpose of this study is to assess the clinical, organizational, financial, and economic impact of VNS therapy in drug-resistant epilepsies and to establish the congruity between costs incurred and health service reimbursement. : The present study used an HTA approach. It is based on an extensive detailed bibliographic search on databases (Medline, Pubmed, Embase and Cochrane, sites of scientific societies and institutional sites). The HTA study includes the following issues: (a) social impact and costs of the disease; (b) VNS eligibility and clinical results; (c) quality of life (QoL) after VNS therapy; (d) economic impact and productivity regained after VNS; and (e) costs of VNS. Results: Literature data indicate VNS as an effective treatment with a potential positive impact on social aspects and on quality of life. The diagnosis-related group (DRG) financing, both on national and regional levels, does not cover the cost of the medical device. There was an evident insufficient coverage of the DRG compared to the full cost of implanting the device. : VNS is a palliative treatment for reducing seizure frequency and intensity. Despite its economic cost, VNS should improve patients' quality of life and reduce care needs.
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http://dx.doi.org/10.3390/ijerph17176150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504285PMC
August 2020

DNA Methylation of Steroidogenic Enzymes in Benign Adrenocortical Tumors: New Insights in Aldosterone-Producing Adenomas.

J Clin Endocrinol Metab 2020 12;105(12)

Clinica Medica 3, Department of Medicine, University of Padova, Italy.

Context: DNA methylation has been identified among putative regulatory mechanisms for CYP11B2 expression in primary aldosteronism.

Objective: The objective of this work is to investigate DNA methylation and expression of genes encoding steroidogenic enzymes in benign adrenocortical tumors.

Design And Setting: This cross-sectional study took place at university hospitals.

Patients: We collected fresh-frozen tissues from patients with benign adrenocortical adenomas (n = 48) (nonfunctioning n = 9, autonomous cortisol secretion n = 9, Cushing syndrome n = 17, aldosterone-producing [APA] n = 13) and adrenal cortex adjacent to APA (n = 12). We collected formalin-fixed, paraffin-embedded (FFPE) specimens of paired APA and concurrent aldosterone-producing cell clusters (APCCs) (n = 6).

Intervention: DNA methylation levels were evaluated by quantitative bisulfite next-generation sequencing in fresh-frozen tissues (CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP21A2, HSD3B1, HSD3B2, NR5A1, STAR, and TSPO) and FFPE APA/APCC paired samples (CYP11B2). CYP11B1, CYP11B2, CYP17, CYP21, and STAR gene expressions were examined by quantitative real-time polymerase chain reaction.

Main Outcome Measure: The main outcome measure was DNA methylation.

Results: CYP11B2 methylation levels were significantly lower in APA than in other adrenal tissues (P < .001). Methylation levels of the remaining genes were comparable among groups. Overall, CYP11B2 expression and DNA methylation were negatively correlated (ρ = -0.379; P = .003). In FFPE-paired APA/APCC samples, CYP11B2 methylation level was significantly lower in APA than in concurrent APCCs (P = .028).

Conclusions: DNA methylation plays a regulatory role for CYP11B2 expression and may contribute to aldosterone hypersecretion in APA. Lower CYP11B2 methylation levels in APA than in APCCs may suggest an APCC-to-APA switch via progressive CYP11B2 demethylation. Conversely, DNA methylation seems not to be relevant in regulating the expression of genes encoding steroidogenic enzymes other than CYP11B2.
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http://dx.doi.org/10.1210/clinem/dgaa585DOI Listing
December 2020

Histopathological grading affects survival in patients with IDH-mutant grade II and grade III diffuse gliomas.

Eur J Cancer 2020 09 26;137:10-17. Epub 2020 Jul 26.

Department of Medical Oncology, AUSL / IRCCS Institute of Neurological Sciences, Bologna, Italy.

Background: Diffuse grade II and grade III gliomas are actually classified in accordance with the presence of isocitrate dehydrogenase mutation (IDH-mut) and the deletion of both 1p and 19q chromosome arms (1p/19q codel). The role of tumour grading as independent prognostic factor in these group of tumours remains matter of debate. The aim of this study was to determine if grade is an independent prognostic factor and not somehow associated to IDH mutation and 1p/19q status of the tumour.

Methods: We analysed 399 consecutive patients with newly diagnosed, histologically proven World Health Organisation (WHO) 2016 grade II or grade III IDH-mut gliomas, assessed by polymerase chain reaction, immunohistochemistry or next-generation sequencing (NGS).

Results: The analysis included 399 patients with grade II (n = 250, 62.7%) or grade III (n = 149, 37.3%) diffuse gliomas. Median follow-up time was 105.3 months. Median survival was 148.1 months. In multivariate analysis, grade II (hazard ratio [HR] = 0.342, 95% confidence interval [CI]: 0.221-0.531; P < 0.001) and 1p/19q codeletion (HR = 0.440, 95% CI: 0.290-0.668; P < 0.001) were independently associated with a lower risk for death. The difference in survival remained significant (p = 0.006 in astrocytomas, p = 0.014 in oligodendrogliomas) when adjusted for histological subtype. Residual disease after surgery (or biopsy) negatively affected survival (HR: 2.151, 95% CI: 1.375-3.367, P = 0.001). Post-surgical treatment with radiotherapy + adjuvant chemotherapy improved survival compared with follow-up and other treatments (HR: 0.316, 95% CI: 0.156-0.641, P = 0.001).

Conclusions: In our study, histopathological grade still affects survival in IDH-mutant WHO grade II and III diffuse gliomas. This effect appears to be independent from molecular features, extension of surgical resection and post-surgical treatments. Therefore, physicians should continue to take into account tumour grade, along their molecular characteristics, for a better clinical and therapeutic management of the patients.
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http://dx.doi.org/10.1016/j.ejca.2020.06.018DOI Listing
September 2020

Exploring the Prognostic Role of Ki67 Proliferative Index in Merkel Cell Carcinoma of the Skin: Clinico-Pathologic Analysis of 84 Cases and Review of the Literature.

Endocr Pathol 2020 Dec 22;31(4):392-400. Epub 2020 Jul 22.

Department of Medicine and Surgery, University of Insubria, Varese, Italy.

The exact prediction of outcome of patients with Merkel cell carcinoma (MCC) of the skin is difficult to determine, although several attempts have been made to identify clinico-pathologic prognostic factors. The Ki67 proliferative index is a well-known marker routinely used to define the prognosis of patients with neuroendocrine neoplasms. However, its prognostic value has been poorly investigated in MCC, and available published results are often contradictory mainly because restricted to small series in the absence of standardized methods for Ki67 evaluation. For this reason, we explored the potential prognostic role of Ki67 proliferative index in a large series of MCCs using the WHO standardized method of counting positive cells in at least 500 tumor cells in hot spot areas on camera-captured printed images. In addition, since MCC may be considered as the cutaneous counterpart of digestive neuroendocrine carcinomas (NECs), we decided to stratify MCCs using the available and efficient Ki67 threshold of 55%, which was found prognostic in digestive NECs. This choice was also supported by the Youden index analysis. In addition, we analyzed the prognostic value of other clinico-pathologic parameters using both univariate and multivariate analysis. Ki67 index appeared significantly associated with prognosis at univariate analysis together with stage IV, lack of MCPyV, and p63 expression, but not at the multivariate analysis, where survival resulted independently influenced by p63 expression and tumor stage, only.
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http://dx.doi.org/10.1007/s12022-020-09640-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666272PMC
December 2020

Rare Primary Central Nervous System Tumors in Adults: An Overview.

Front Oncol 2020 26;10:996. Epub 2020 Jun 26.

Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, France.

Overall, tumors of primary central nervous system (CNS) are quite common in adults with an incidence rate close to 30 new cases/100,000 inhabitants per year. Significant clinical and biological advances have been accomplished in the most common adult primary CNS tumors (i.e., diffuse gliomas). However, most CNS tumor subtypes are rare with an incidence rate below the threshold defining rare disease of 6.0 new cases/100,000 inhabitants per year. Close to 150 entities of primary CNS tumors have now been identified by the novel integrated histomolecular classification published by the World Health Organization (WHO) and its updates by the c-IMPACT NOW consortium (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy). While these entities can be better classified into smaller groups either by their histomolecular features and/or by their location, assessing their treatment by clinical trials and improving the survival of patients remain challenging. Despite these tumors are rare, research, and advances remain slower compared to diffuse gliomas for instance. In some cases (i.e., ependymoma, medulloblastoma) the understanding is high because single or few driver mutations have been defined. The European Union has launched European Reference Networks (ERNs) dedicated to support advances on the clinical side of rare diseases including rare cancers. The ERN for rare solid adult tumors is termed EURACAN. Within EURACAN, Domain 10 brings together the European patient advocacy groups (ePAGs) and physicians dedicated to improving outcomes in rare primary CNS tumors and also aims at supporting research, care and teaching in the field. In this review, we discuss the relevant biological and clinical characteristics, clinical management of patients, and research directions for the following types of rare primary CNS tumors: medulloblastoma, pineal region tumors, glioneuronal and rare glial tumors, ependymal tumors, grade III meningioma and mesenchymal tumors, primary central nervous system lymphoma, germ cell tumors, spinal cord tumors and rare pituitary tumors.
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http://dx.doi.org/10.3389/fonc.2020.00996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333775PMC
June 2020
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