Publications by authors named "Patrizia Morbini"

87 Publications

Neuropathological findings from COVID-19 patients with neurological symptoms argue against a direct brain invasion of SARS-CoV-2: A critical systematic review.

Eur J Neurol 2021 Aug 2. Epub 2021 Aug 2.

IRCCS Mondino Foundation, Pavia, Italy.

Background And Purpose: Neuropathological studies can elucidate the mechanisms of nervous system damage associated with SARS-CoV-2 infection. Despite literature on this topic is rapidly expanding, correlations between neurological symptoms and brain pathology findings in COVID-19 patients remain largely unknown.

Methods: We performed a systematic literature review on neuropathological studies in COVID-19, including 438 patients from 45 articles published by April 22, 2021. We retrieved quantitative data regarding demographic, clinical, and neuropathological findings. We carried out a Wilcoxon rank sum test or χ test to compare patients' subgroups based on different clinical and brain pathology features.

Results: Neuropathological findings in COVID-19 patients were microgliosis (52.5%), astrogliosis (45.6%), inflammatory infiltrates (44.0%), hypoxic-ischemic lesions (40.8%), edema (25.3%), and hemorrhagic lesions (20.5%). SARS-CoV-2 RNA and proteins were identified in brain specimens of 41.9% and 28.3% of subjects, respectively. Detailed clinical information was available from 245 patients (55.9%), and among them, 96 subjects (39.2%) had presented with neurological symptoms in association with typical COVID-19 manifestations. We found that: (i) the detection rate of SARS-CoV-2 RNA and proteins in brain specimens did not differ between patients with versus those without neurological symptoms; (ii) brain edema, hypoxic-ischemic lesions, and inflammatory infiltrates were more frequent in subjects with neurological impairment; (iii) neurological symptoms were more common among older individuals.

Conclusions: Our systematic revision of clinical correlates in COVID-19 highlights the pathogenic relevance of brain inflammatory reaction and hypoxic-ischemic damage rather than neuronal viral load. This analysis indicates that a more focused study design is needed, especially in the perspective of potential therapeutic trials.
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http://dx.doi.org/10.1111/ene.15045DOI Listing
August 2021

Integrating data from multidisciplinary Management of Malignant Pleural Mesothelioma: a cohort study.

BMC Cancer 2021 Jul 1;21(1):762. Epub 2021 Jul 1.

Department of Medical Sciences and Infective Diseases, Unit of Respiratory Diseases, IRCCS Policlinico San Matteo Foundation and University of Pavia Medical School, 27100, Pavia, Italy.

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy that most commonly affects the pleural layers. MPM has a strong association with asbestos, mainly caused by exposure to its biopersistent fibers in at least 80% of cases. Individuals with a chronic exposure to asbestos might develop disease with a 20-40-year latency with few or no symptoms. Such has been the case in the Italian regions of Piedmont and Lombardy, where industrial production of materials laden with asbestos, mainly cements, has been responsible for the onset of a large epidemic. Since 2018, a multidisciplinary team at San Matteo hospital in Pavia has been collecting data on over 100 patients with MPM. The main goal of this project is to define and describe an integrated profile for each MPM case at diagnosis by using data mining and partition analysis.

Methods: Here we bring together exhaustive epidemiologic, histologic and radiologic data of 88 MPM patients that came to our observation and draw correlations with predictive and prognostic significance.

Results: The median overall survival (OS) was 15.6 months. Most patients presented with pleural effusion, irrespective of disease stage. Quite unexpectedly, no statistically significant association was demonstrated between OS and TNM disease stage at diagnosis. Although average OS is similar in male and female patients, partition analysis of data underlined a significant differential hierarchy of predictor categories based on patient gender. In females with no smoking history, full chemotherapeutic regimens are associated with better outcomes. Moreover, concerning second line treatments, vinorelbine emerged as the most advantageous choice for female patients, whereas in the male subgroup no statistically significant difference resulted between gemcitabine and vinorelbine.

Conclusion: A multidisciplinary approach to MPM is mandatory to define better therapeutic approaches, personalize the management and improve patient outcomes.
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http://dx.doi.org/10.1186/s12885-021-08532-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252222PMC
July 2021

Acute-onset diplopia from intracranial hypertension due to torcular herophili obstruction by an hemorrhagic intradiploic epidermoid cyst.

Surg Neurol Int 2021 17;12:100. Epub 2021 Mar 17.

Department of Neurosurgery, Maria Cecilia Hospital, Cotignola, Province of Ravenna, Italy.

Background: Epidermoid cysts are benign slow-growing congenital lesions, constituting approximately 1% of all cranial tumors. Most of these lesions are located intradurally, while about 10-25% of them are located within the diploic spaces. Intradiploic epidermoid cysts are usually discovered incidentally and may remain asymptomatic for many years, but in rare instances, they may grow intracranially and produce brain compression. Sometimes, intradiploic epidermoid cysts may occlude the main cranial venous sinuses causing intracranial hypertension.

Case Description: We present the case of a 24-year-old male harboring a paramedian right occipital intradiploic cyst with erosion of both outer and inner bony tables, which occluded the torcular herophili producing a worsening symptomatology with acute-onset diplopia from right sixth cranial nerve palsy; the patient also presented bilateral papilledema, but only reported mild headache and dizziness. Neuroradiological studies evidentiated a lesion compatible with intradiploic epidermoid cyst with intralesional hemorrhagic component, overlying and almost completely occluding the torcular herophili. Considering the fast worsening of symptomatology and the evidence of intracranial hypertension, the patient was operated on immediately after completion of clinical and radiological assessment. The lesion was radically removed with almost immediate reversal of signs and symptoms. Histopathology confirmed the diagnosis of epidermoid cyst with intralesional hemorrhagic components.

Conclusion: Intradiploic epidermoid cysts may cause intracranial hypertension by occlusion of main cranial venous sinuses; intralesional hemorrhage may act as precipitating factor in occlusion of the torcular herophili, producing rapidly worsening intracranial hypertension, which requires prompt surgical treatment to reverse symptomatology. Radical surgical resection is necessary to avoid recurrence.
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http://dx.doi.org/10.25259/SNI_578_2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053460PMC
March 2021

miRNAs Potentially Involved in Post Lung Transplant-Obliterative Bronchiolitis: The Role of miR-21-5p.

Cells 2021 03 20;10(3). Epub 2021 Mar 20.

Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy.

Epigenetic changes, including miRNAs deregulation, have been suggested to play a significant role in development of obliterative bronchiolitis (OB) in transplanted lungs. Many studies have tried to identify ideal candidate miRNAs and the downstream pathways implicated in the bronchiolar fibro-obliterative process. Several candidate miRNAs, previously indicated as possibly being associated with OB, were analyzed by combining the quantitative real time-polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH) of lung tissues of OB affected patients. Disease and OB-lesion-specific expression of miR-21-5p was confirmed and by computational analysis we were able to identify the network of genes most probably associated miR-21-5p in the context of OB fibrogenesis. Among all potentially associated genes, STAT3 had a very high probability score. Immunohistochemistry showed that STAT3/miR-21-5p were co-over expressed in OB lesions, thus, suggesting miR-21-5p could regulate STAT3 expression. However, miR-21-5p inhibition in cultures of bronchiolitis obliterans syndrome (BOS) derived myofibroblasts did not significantly affect STAT3 mRNA and protein expression levels. This study demonstrates the specificity of miR-21-5p over-expression in OB lesions and contributes to existing knowledge on the miR-21-5p downstream pathway. Activation of STAT3 is associated with miR-21-5p upregulation, however, STAT-3 network activation is most likely complex and miR-21-5p is not the sole regulator of STAT3.
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http://dx.doi.org/10.3390/cells10030688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003603PMC
March 2021

PD-L1 Testing and Squamous Cell Carcinoma of the Head and Neck: A Multicenter Study on the Diagnostic Reproducibility of Different Protocols.

Cancers (Basel) 2021 Jan 14;13(2). Epub 2021 Jan 14.

Section of Pathology, Department of Medicine and Surgery, University Milan Bicocca, ASST Monza, 20100 Milan, Italy.

Immune checkpoint inhibitors for blocking the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis are now available for squamous cell carcinoma of the head and neck (HNSCC) in relapsing and/or metastatic settings. In this work, we compared the resulting combined positive score (CPS) of PD-L1 using alternative methods adopted in routine clinical practice and determined the level of diagnostic agreement and inter-observer reliability in this setting. The study applied 5 different protocols on 40 tissue microarrays from HNSCC. The error rate of the individual protocols ranged from a minimum of 7% to a maximum of 21%, the sensitivity from 79% to 96%, and the specificity from 50% to 100%. In the intermediate group (1 ≤ CPS < 20), the majority of errors consisted of an underestimation of PD-L1 expression. In strong expressors, 5 out of 14 samples (36%) were correctly evaluated by all the protocols, but no protocol was able to correctly identify all the "strong expressors". The overall inter-observer agreement in PD-L1 CPS reached 87%. The inter-observer reliability was moderate, with an ICC of 0.774 (95% CI (0.651; 0.871)). In conclusion, our study showed moderate interobserver reliability among different protocols. In order to improve the performances, adequate specific training to evaluate PD-L1 by CPS in the HNSCC setting should be coordinated.
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http://dx.doi.org/10.3390/cancers13020292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830149PMC
January 2021

Recent advancement on PD-L1 expression quantification: the radiologist perspective on CT-guided FNAC.

Diagn Interv Radiol 2021 Mar;27(2):214-218

Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, Unit of Radiology, University of Pavia, Pavia, Italy.

Purpose: We aimed to evaluate the feasibility, accuracy, and safety of Programmed Death-1/ Programmed Death-Ligand 1 (PD-1/ PD-L1) expression quantification in cytology cell-block samples obtained through transthoracic CT-guided fine-needle aspiration cytology (FNAC) from the interventional radiologist's perspective.

Methods: We performed a consecutive unselected series of 361 CT-guided biopsies of pulmonary nodules and masses which came to our observation from June 2017 to October 2018. For each case, exhaustive clinical, morphologic, molecular and tomographic data were available. All the material obtained was fixed in formalin to obtain a cell-block for the pathologist, who performed immunohistochemical analysis to detect PD-L1 expression levels on each sample.

Results: Of all the analyzed samples, 93.6% (338/361) were defined to be diagnostic, including neoplastic (72%, 260/361) and non-neoplastic lesions (21.6%, 78/361); only 6.4% (23/361) of them resulted in nondiagnostic specimens. Non-small cell lung cancer (NSCLC) accounted for 73.8% of neoplastic lesions (192/260): most of them were adenocarcinoma (83%, 160/192), followed by squamous carcinoma (14%, 27/192) and poorly differentiated carcinoma (3%, 5/192). In 96% of NSCLC (184/192), the diagnosis was reached either in the absence of complications or with early minor complications. PD-L1 expression was evaluated in all 192 NSCLC cytology specimens: 180 immunostainings were found to be adequate for PD-L1 testing. In 76% of cases, PD-L1 expression level was lower than 50%.

Conclusion: The findings of our study indicate that PD-L1 quantification using a cell-block approach on CT-guided FNAC is a feasible and safe technique and should be taken into account alongside with core biopsy approach, especially in case of advanced disease and/or fragile and older patients.
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http://dx.doi.org/10.5152/dir.2021.19545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963389PMC
March 2021

Case Report: All That Glisters Is Not Cancer.

Front Med (Lausanne) 2020 30;7:541629. Epub 2020 Nov 30.

Unit of Respiratory System Diseases, Department of Medical Sciences and Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo Foundation, Pavia, Italy.

Properly performed staging in non-small-cell lung cancer (NSCLC) is necessary to avoid wrong therapeutic decisions. Here we present a case which manifested as advanced NSCLC but ultimately was composed of two different and rare pathologies. The first is a TTF-1 positive axillary lymph node that could be defined either as an unusual isolated differentiated cancer of unknown primary or as an even rarer case of ectopic lung epithelium which underwent malignant transformation. The second is sarcoidosis, a sarcoid-like alteration, in remission after oral steroids. The main implication of a correct diagnosis regards patient outcome and the avoidance of toxic inappropriate systemic chemotherapy.
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http://dx.doi.org/10.3389/fmed.2020.541629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734188PMC
November 2020

Depletion of circulating IgM memory B cells predicts unfavourable outcome in COVID-19.

Sci Rep 2020 11 30;10(1):20836. Epub 2020 Nov 30.

Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.

Impaired immune responses have been hypothesised to be a possible trigger of unfavourable outcomes in coronavirus disease 2019 (COVID-19). We aimed to characterise IgM memory B cells in patients with COVID-19 admitted to an internal medicine ward in Northern Italy. Overall, 66 COVID-19 patients (mean age 74 ± 16.6 years; 29 females) were enrolled. Three patients (4.5%; 1 female) had been splenectomised and were excluded from further analyses. Fifty-five patients (87.3%) had IgM memory B cell depletion, and 18 (28.6%) died during hospitalisation (cumulative incidence rate 9.26/100 person-week; 5.8-14.7 95% CI). All patients who died had IgM memory B cell depletion. A superimposed infection was found in 6 patients (9.5%), all of them having IgM memory B cell depletion (cumulative incidence rate 3.08/100 person-week; 1.3-6.8 95% CI). At bivariable analyses, older age, sex, number of comorbidities, and peripheral blood lymphocyte count < 1500/µl were not correlated with IgM memory B cell depletion. A discrete-to-marked reduction of the B-cell compartment was also noticed in autoptic spleen specimens of two COVID-19 patients. We conclude that IgM memory B cells are commonly depleted in COVID-19 patients and this correlates with increased mortality and superimposed infections.
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http://dx.doi.org/10.1038/s41598-020-77945-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705651PMC
November 2020

Loading Imatinib inside targeted nanoparticles to prevent Bronchiolitis Obliterans Syndrome.

Sci Rep 2020 11 26;10(1):20726. Epub 2020 Nov 26.

Department of Respiratory Diseases, IRCCS Policlinico San Matteo Foundation, Pavia, Italy.

Bronchiolitis Obliterans Syndrome seriously reduces long-term survival of lung transplanted patients. Up to now there is no effective therapy once BOS is established. Nanomedicine introduces the possibility to administer drugs locally into lungs increasing drug accumulation in alveola reducing side effects. Imatinib was loaded in gold nanoparticles (GNP) functionalized with antibody against CD44 (GNP-HCIm). Lung fibroblasts (LFs) were derived from bronchoalveolar lavage of BOS patients. GNP-HCIm cytotoxicity was evaluated by MTT assay, apoptosis/necrosis and phosphorylated-cAbl (cAbl-p). Heterotopic tracheal transplantation (HTT) mouse model was used to evaluate the effect of local GNP-HCIm administration by Alzet pump. GNP-HCIm decreased LFs viability compared to Imatinib (44.4 ± 1.8% vs. 91.8 ± 3.2%, p < 0.001), inducing higher apoptosis (22.68 ± 4.3% vs. 6.43 ± 0.29; p < 0.001) and necrosis (18.65 ± 5.19%; p < 0.01). GNP-HCIm reduced cAbl-p (0.41 GNP-HCIm, 0.24 Imatinib vs. to control; p < 0.001). GNP-HCIm in HTT mouse model by Alzet pump significantly reduced tracheal lumen obliteration (p < 0.05), decreasing apoptosis (p < 0.05) and TGF-β-positive signal (p < 0.05) in surrounding tissue. GNP-HCIm treatment significantly reduced lymphocytic and neutrophil infiltration and mast cells degranulation (p < 0.05). Encapsulation of Imatinib into targeted nanoparticles could be considered a new option to inhibit the onset of allograft rejection acting on BOS specific features.
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http://dx.doi.org/10.1038/s41598-020-77828-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693282PMC
November 2020

FANCA, TP53, and del(5q)/RPS14 alterations in a patient with T-cell non-Hodgkin lymphoma and concomitant Fanconi anemia and Li-Fraumeni syndrome.

Cancer Genet 2021 Aug 31;256-257:179-183. Epub 2020 Oct 31.

Medical Genetics Unit, Department of Molecular Medicine, University of Pavia, Via Forlanini 14, 27100 Pavia, Italy.

We traced the neoplastic history (from 5 to 11 years of age) of a child with concomitant Fanconi anemia and Li-Fraumeni syndrome. Interestingly, the patient developed a highly malignant T-cell non-Hodgkin lymphoma (NHL), which does not represent the typical tumor type in the two aforementioned syndromes, presumably due to the underlying genomic instability. By using a combination of molecular and immunohistochemical approaches, we characterized the accumulation of multiple genetic alterations in a single patient, with both germline (parentally inherited biallelic FANCA variants and a likely de novo nonsense variant in TP53) and somatic (TP53 loss of heterozygosity and 5q interstitial deletion) contributions. Our findings support the interplay of TP53 and FANC genes in DNA damage response pathways and further highlight the genetic heterogeneity of lymphomas as well as the contribution of genomic instability to lymphomagenesis.
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http://dx.doi.org/10.1016/j.cancergen.2020.10.003DOI Listing
August 2021

CT-guided biopsy in the differential diagnosis of Sjogren syndrome associated cystic lung disease: A case of lung nodular AL- amyloidosis.

Radiol Case Rep 2020 Nov 14;15(11):2331-2334. Epub 2020 Sep 14.

Division of Rheumatology, University and IRCCS Policlinico S. Matteo Foundation, Pavia, Italy.

Pulmonary involvement in Sjogren syndrome (SS) could manifest as cystic lung disease (CLD). CLD in SS includes lymphocytic interstitial pneumonia (LIP) and pulmonary amyloidosis. Differential diagnosis usually requires surgical lung biopsy, whereas CT-guided percutaneous fine needle aspiration biopsy (CT-FNAB) has not yet explored. We describe the case of a 63-year-old never smoker Caucasian female with a SS diagnosis who displayed a newly detected diffuse CLD at high-resolution computed tomography, though totally asymptomatic. Given the favorable location of one big lesion at the superior left lobe, a CT-FNAB was proposed instead of a more invasive SLB. At histology examination a diagnosis of pulmonary nodular AL kappa amyloidosis in the context of SS was established. In conclusion, CT-FNAB might represent an alternative and less invasive diagnostic procedure than SLB in the differential diagnosis of CLD, even if further research is needed. Moreover, this case presents an unusual association between SS and pulmonary nodular AL kappa amyloidosis, with pulmonary nodules and cysts without systemic manifestations.
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http://dx.doi.org/10.1016/j.radcr.2020.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501412PMC
November 2020

Primary central nervous system lymphoma mimicking autoimmune encephalitis: the role of autoantibody testing.

Neurol Sci 2021 03 29;42(3):1193-1196. Epub 2020 Sep 29.

Department of Neurology, IRCCS Mondino Foundation, University of Pavia, via Mondino 2, 27100, Pavia, Italy.

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http://dx.doi.org/10.1007/s10072-020-04739-1DOI Listing
March 2021

Fibrotic progression and radiologic correlation in matched lung samples from COVID-19 post-mortems.

Virchows Arch 2021 Mar 28;478(3):471-485. Epub 2020 Sep 28.

Anatomic Pathology Unit, Department of Surgical Science and Integrated Diagnostics (DISC), University of Genova, Genova, Italy.

Data on the pathology of COVID-19 are scarce; available studies show diffuse alveolar damage; however, there is scarce information on the chronologic evolution of COVID-19 lung lesions. The primary aim of the study is to describe the chronology of lung pathologic changes in COVID-19 by using a post-mortem transbronchial lung cryobiopsy approach. Our secondary aim is to correlate the histologic findings with computed tomography patterns. SARS-CoV-2-positive patients, who died while intubated and mechanically ventilated, were enrolled. The procedure was performed 30 min after death, and all lung lobes sampled. Histopathologic analysis was performed on thirty-nine adequate samples from eight patients: two patients (illness duration < 14 days) showed early/exudative phase diffuse alveolar damage, while the remaining 6 patients (median illness duration-32 days) showed progressive histologic patterns (3 with mid/proliferative phase; 3 with late/fibrotic phase diffuse alveolar damage, one of which with honeycombing). Immunohistochemistry for SARS-CoV-2 nucleocapsid protein was positive predominantly in early-phase lesions. Histologic patterns and tomography categories were correlated: early/exudative phase was associated with ground-glass opacity, mid/proliferative lesions with crazy paving, while late/fibrous phase correlated with the consolidation pattern, more frequently seen in the lower/middle lobes. This study uses an innovative cryobiopsy approach for the post-mortem sampling of lung tissues from COVID-19 patients demonstrating the progression of fibrosis in time and correlation with computed tomography features. These findings may prove to be useful in the correct staging of disease, and this could have implications for treatment and patient follow-up.
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http://dx.doi.org/10.1007/s00428-020-02934-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521863PMC
March 2021

Ultrastructural Evidence of Direct Viral Damage to the Olfactory Complex in Patients Testing Positive for SARS-CoV-2.

JAMA Otolaryngol Head Neck Surg 2020 10;146(10):972-973

Medical Direction, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy.

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http://dx.doi.org/10.1001/jamaoto.2020.2366DOI Listing
October 2020

From Interconnection between Genes and Microenvironment to Novel Immunotherapeutic Approaches in Upper Gastro-Intestinal Cancers-A Multidisciplinary Perspective.

Cancers (Basel) 2020 Jul 29;12(8). Epub 2020 Jul 29.

Department of Medical Sciences and Infective Diseases, Unit of Respiratory Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo Foundation and University of Pavia Medical School, 27000 Pavia, Italy.

Despite the progress during the last decade, patients with advanced gastric and esophageal cancers still have poor prognosis. Finding optimal therapeutic strategies represents an unmet need in this field. Several prognostic and predictive factors have been evaluated and may guide clinicians in choosing a tailored treatment. Data from large studies investigating the role of immunotherapy in gastrointestinal cancers are promising but further investigations are necessary to better select those patients who can mostly benefit from these novel therapies. This review will focus on the treatment of metastatic esophageal and gastric cancer. We will review the standard of care and the role of novel therapies such as immunotherapies and CAR-T. Moreover, we will focus on the analysis of potential predictive biomarkers such as Modify as: Microsatellite Instability (MSI) and PD-L1, which may lead to treatment personalization and improved treatment outcomes. A multidisciplinary point of view is mandatory to generate an integrated approach to properly exploit these novel antiproliferative agents.
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http://dx.doi.org/10.3390/cancers12082105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465773PMC
July 2020

Direct endothelial damage and vasculitis due to SARS-CoV-2 in small bowel submucosa of COVID-19 patient with diarrhea.

J Med Virol 2021 01 24;93(1):61-63. Epub 2020 Jun 24.

Unit of Pathology, Department of Molecular Medicine, University of Pavia and IRCCS Policlinico S. Matteo, Pavia, Italy.

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http://dx.doi.org/10.1002/jmv.26119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300801PMC
January 2021

An underrated copmlication of the organs' transplantations

Ann Ital Chir 2020 ;91:298-309

Introduction: Tacrolimus is routinely used to prevent rejection after organs' transplantation. Neurotoxicity is underrated side effect, where no typical clinical, radiological, or histopathological patterns have yet been found. The present study is targeted to a review of the literature on tacrolimus-induced neurotoxicity secondary to organs' transplantation, aimed to its prompt diagnosis.

Materials And Methods: Multiple PubMed searches were performed to review relevant articles regarding tacrolimusinduced neurotoxicity. An illustrative case is also presented.

Results: Twenty articles published between 1997 and 2019 were identified and reviewed. Clinical manifestations of tacrolimus-induced neurotoxicity varied. MRI showed subcortical white matter involvement in most cases. Symptoms and radiological signs occurred at various drug dosages and blood tacrolimus levels. Tacrolimus discontinuation resulted in disappearance or marked reduction of neurological symptoms and imaging lesions in every case.

Conclusion: Neurotoxicity is an underrated reversible side effect of chronic tacrolimus administration after organs' transplantation. Its prompt diagnosis, based on T2 and FLAIR MRI sequences neuroimaging combined with stereotactic biopsy, allows the discontinuation of the drug and a recovery of the patient in most of the cases.

Key Words: Stereotactic Biopsy, Neurotoxicity, Tacrolimus, Transplant Complications, Transplantation, Tumorlike Lesion.
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August 2021

Imaging Accuracy in Preoperative Staging of T3-T4 Laryngeal Cancers.

Cancers (Basel) 2020 Apr 26;12(5). Epub 2020 Apr 26.

Unit of Pathology, Department of Molecular Medicine, University of Pavia, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy.

Background: Preoperative imaging impacts treatment planning and prognosis in laryngeal cancers. We investigated the accuracy of standard computed tomography (CT) in evaluating tumor invasions at critical glottic areas.

Methods: CT scans of glottic cancers treated by partial or total laryngectomy between Jan 2015 and Aug 2019 were reviewed to assess levels of tumor invasion at critical glottic subsites. CT accuracy in the identification of tumor extensions was determined against the gold standard of histopathological analysis of surgical samples.

Results: This study included 64 patients. In the anterior commissure, CT showed high rates of false positives at all levels (sensitivity 56.2-70%, specificity 87.8-92.3%); in the anterior vocal fold, it overestimated the deep invasion (19.5% specificity, 90.3% sensitivity), while it underestimated the extralaryngeal spread (63.6% sensitivity, 98.1% specificity). In the posterior paraglottic space (pPGS), false negative results were more frequent for superficial extensions (25% sensitivity, 95.8% specificity) and deep invasions (58.8% sensitivity, 82.3% specificity). Shorter disease-specific and disease-free survivals were associated with pStage IV (: 0.045 and 0.008) and with the pathological involvement of pPGS (: 0.045 and 0.015).

Conclusions: Negative prognostic correlation of pPGS involvement was confirmed on histopathological data. CT staging did not provide a satisfactory prognostic stratification and should be complemented with magnetic resonance imaging.
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http://dx.doi.org/10.3390/cancers12051074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281313PMC
April 2020

Tissue Engineered Esophageal Patch by Mesenchymal Stromal Cells: Optimization of Electrospun Patch Engineering.

Int J Mol Sci 2020 Mar 4;21(5). Epub 2020 Mar 4.

Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy.

Aim of work was to locate a simple, reproducible protocol for uniform seeding and optimal cellularization of biodegradable patch minimizing the risk of structural damages of patch and its contamination in long-term culture. Two seeding procedures are exploited, namely static seeding procedures on biodegradable and biocompatible patches incubated as free floating (floating conditions) or supported by CellCrown insert (fixed conditions) and engineered by porcine bone marrow MSCs (p-MSCs). Scaffold prototypes having specific structural features with regard to pore size, pore orientation, porosity, and pore distribution were produced using two different techniques, such as temperature-induced precipitation method and electrospinning technology. The investigation on different prototypes allowed achieving several implementations in terms of cell distribution uniformity, seeding efficiency, and cellularization timing. The cell seeding protocol in stating conditions demonstrated to be the most suitable method, as these conditions successfully improved the cellularization of polymeric patches. Furthermore, the investigation provided interesting information on patches' stability in physiological simulating experimental conditions. Considering the in vitro results, it can be stated that the in vitro protocol proposed for patches cellularization is suitable to achieve homogeneous and complete cellularizations of patch. Moreover, the protocol turned out to be simple, repeatable, and reproducible.
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http://dx.doi.org/10.3390/ijms21051764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084816PMC
March 2020

Multidisciplinary Approach in the Early Detection of Undiagnosed Connective Tissue Diseases in Patients With Interstitial Lung Disease: A Retrospective Cohort Study.

Front Med (Lausanne) 2020 18;7:11. Epub 2020 Feb 18.

Division of Rheumatology, University and IRCCS Policlinico S. Matteo Foundation, Pavia, Italy.

Interstitial lung disease (ILD) encompasses a wide range of parenchymal lung pathologies with different clinical, histological, radiological, and serological features. Follow-up, treatment, and prognosis are strongly influenced by the underlying pathogenesis. Considering that an ILD may complicate the course of any connective tissue disease (CTD) and that CTD's signs are not always easily identifiable, it could be useful to screen every ILD patient for a possible CTD. The recent definition of interstitial pneumonia with autoimmune features is a further confirmation of the close relationship between CTD and ILD. In this context, the multidisciplinary approach is assuming a growing and accepted role in the correct diagnosis and follow-up, to as early as possible define the best therapeutic strategy. However, despite clinical advantages, until now, the pathways of the multidisciplinary approach in ILD patients are largely heterogeneous across different centers and the best strategy to apply is still to be established and validated. Aims of this article are to describe the organization of our multidisciplinary group for ILD, which is mainly focused on the early identification and management of CTD in patients with ILD and to show our results in a 1 year period of observation. We found that 15% of patients referred for ILD had an underlying CTD, 33% had interstitial pneumonia with autoimmune feature, and 52% had ILD without detectable CTD. Furthermore, we demonstrated that the adoption of a standardized strategy consisting of a screening questionnaire, specific laboratory tests, and nailfold videocapillaroscopy in all incident ILD proved useful in making the right diagnosis.
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http://dx.doi.org/10.3389/fmed.2020.00011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040230PMC
February 2020

The growth of non-solid neoplastic lung nodules is associated with low PD L1 expression, irrespective of sampling technique.

J Transl Med 2020 02 3;18(1):54. Epub 2020 Feb 3.

Department of Medical Sciences and Infective Diseases, Unit of Respiratory Diseases, IRCCS Policlinico San Matteo Foundation and University of Pavia Medical School, 27100, Pavia, Italy.

Background: Few data are known regarding the molecular features and patterns of growth and presentation which characterize those lung neoplastic lesions presenting as non-solid nodules (NSN).

Methods: We retrospectively reviewed two different cohorts of NSNs detected by CT scan which, after transthoracic fine-needle aspiration (FNA) and core needle biopsy (CNB) received a final diagnosis of malignancy. All the enrolled patients were then addressed to surgical removal of lung cancer nodules or to exclusive radiotherapy. Exhaustive clinical and radiological features were available for each case.

Results: In all 62 analysed cases the diagnosis of adenocarcinoma (ADC) was reached. In cytologic samples, EGFR activating mutations were identified in 2 of the 28 cases (7%); no case showed ALK/EML4 or ROS1 translocations. In the histologic samples EGFR activating mutation were found in 4 out of 25 cases (16%). PD-L1 immunostains could be evaluated in 30 cytologic samples, while the remaining 7 did not reach the cellularity threshold for evaluation. TPS was < 1% in 26 cases,  > 1% < 50% in 3, and > 50% in 1. All surgical samples showed TPS < 1%. Of the 17 cases that could be evaluated on both samples, 15 were concordantly TPS 0, and 2 showed TPS > 1% < 50 on the biopsy samples. TPS was < 1% in 14 cases, > 1%/< 5% in 4 cases, > 5%/< 50% in 2 cases, > 50% in 1 case.

Conclusions: Overall PD-L1 immunostaining documented the predominance of low/negative TPS, with high concordance in FNA and corresponding surgical samples. It can be hypothesized that lung ADC with NSN pattern and predominant in situ (i.e. lepidic) components represent the first steps in tumor progression, which have not yet triggered immune response, and/or have not accumulated a significant rate of mutations and neoantigen production, or that they belong to the infiltrated-excluded category of tumors. The negative prediction of response to immunomodulating therapy underlines the importance of rapid surgical treatment of these lesions. Notably, cell block cytology seems to fail in detecting EGFR mutations, thus suggesting that this kind of sampling technique should be not adequate in case of DNA direct sequencing.
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http://dx.doi.org/10.1186/s12967-020-02241-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998829PMC
February 2020

Transoral Robot-Assisted Surgery in Supraglottic and Oropharyngeal Squamous Cell Carcinoma: Laser Versus Monopolar Electrocautery.

J Clin Med 2019 Dec 7;8(12). Epub 2019 Dec 7.

Unit of Pathology, Department of Molecular Medicine, University of Pavia, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy.

Background: Monopolar electrocautery (EC) is the surgical cutting and haemostatic tool most commonly used for transoral robotic surgery (TORS). The aim of this study was to retrospectively compare EC efficacy in the treatment of patients affected by T1 or T2 oropharyngeal and supraglottic squamous cell carcinomas with the more recently introduced laser fibres.

Methods: We considered all TORS patients admitted to our department from January 2010 to June 2019. The outcomes of patients treated with Thulium: yttrium aluminium garnet (YAG) laser (TY-TORS), CO laser (CO-TORS) and EC (EC-TORS) were analysed in order to assess surgical performances, functional outcomes and postoperative complications.

Results: Twenty patients satisfied the enrolling criteria, of which nine underwent laser-TORS, and the remaining 11 underwent EC-TORS. In all candidates, TORS procedures were completed without the need for microscopic/open conversion. Close or positive margins were significantly more frequent in EC-TORS ( = 0.028). A considerable difference was found in overall functional parameters: times of nasogastric tube and tracheostomy removal and time of hospital discharge were significantly shorter in laser-TORS ( = 0.04, = 0.05, = 0.04, respectively).

Conclusions: Laser-TORS showed better results in comparison with EC-TORS in term of tumour resection margins and patient functional outcomes. Our findings can be justified with the greater tissue thermal damage caused by EC-TORS, despite prospective randomized trials and increased patient numbers being needed to confirm these preliminary conclusions.
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http://dx.doi.org/10.3390/jcm8122166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947577PMC
December 2019

Morphological analysis of ischemia-reperfusion injury in a cold ischemia model of jejunal free flap for hypopharyngeal reconstruction.

J Plast Reconstr Aesthet Surg 2020 Jan 7;73(1):103-110. Epub 2019 Aug 7.

Department of Otorhinolaryngology, University of Pavia, Foundation IRCCS Policlinico San Matteo, P.le Golgi 5, 27100 Pavia, Italy.

Background: Jejunal free flap (JFF) reconstruction is a popular treatment option for advanced hypopharyngeal cancer. Several factors including ischemia-reperfusion injury (IRI) can cause mucosal damage and progressive flap necrosis. We investigated the development and time-related progression of morphological and cellular changes in patients with JFF reconstruction including cold preservation of the graft.

Methods: Eleven patients were enrolled. Biopsies were taken during surgery from normally perfused tissue, before loop isolation (T0), at the end of back-table surgery (T1), immediately before reperfusion (T2), 15' after reperfusion (T3), and at the end of the digestive anastomoses (T4) and from the external monitor daily from the 1st to the 5th postoperative day (M1-M5). Histomorphological and immunohistochemical parameters in the intraoperative and postoperative samples were evaluated and compared.

Results: Delayed flap necrosis was observed in 2 patients. The cold ischemia phase did not negatively affect mucosal regeneration after reperfusion; morphological and cellular damage parameters returned to normal by the end of surgery or along the early postoperative period. Significant enterocyte replication activity was observed at the end of revascularization, which continued in the postoperative phase, leading to recovery of the epithelial morphological integrity and disappearance of apoptotic cells. An inflammatory infiltrate persisted in the M samples, and in a significant proportion of samples, mucosal fibrosis developed by the end of the postoperative observation.

Conclusion: Cold perfusion and preservation of the JFF can effectively limit the negative effects of IRI and to prevent short- and medium-term complications that can compromise the final outcome.
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http://dx.doi.org/10.1016/j.bjps.2019.07.004DOI Listing
January 2020

Low-Grade Papillary Schneiderian Carcinoma: Report of a Case with Molecular Characterization.

Head Neck Pathol 2020 Sep 31;14(3):799-802. Epub 2019 Aug 31.

Department of Molecular Medicine, Unit of Pathology, University of Pavia, and Foundation IRCCS Policlinico San Matteo, Via Forlanini 16, 27100, Pavia, Italy.

In 2015, Lewis et al. first described low-grade papillary Scheneiderian carcinoma (LGPSC) of the sinonasal tract. Their case resembled a sinonasal papilloma clinically and histopathologically; however, invasion and metastasis resulted in the death of the patient despite absence of malignant cytologic features. Additional reports established LGPSC as a distinct entity and characterized its immunohistochemical profile. Diffuse expression of low molecular weight cytokeratins, positivity for p16 and p53 in at least 50% of cells, a high Ki-67 index, and absence of human papillomavirus (HPV)-DNA was observed across all reported cases. We report an additional case of LGPSC and describe the clinical, histologic, and immunohistochemical features. In contrast to sinonasal papillomas, the case was negative for HPV-DNA and showed no mutations in the EGFR and KRAS hotspot regions.
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http://dx.doi.org/10.1007/s12105-019-01067-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413950PMC
September 2020

Lateral Transorbital Neuroendoscopic Approach for Intraconal Meningioma of the Orbital Apex: Technical Nuances and Literature Review.

World Neurosurg 2019 Nov 26;131:10-17. Epub 2019 Jul 26.

Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic Pediatric Sciences, University of Pavia, Pavia, Italy; Neurosurgery Unit, Department of Surgical Sciences, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Background: Surgical approaches to orbital apex lesions involve the medial and lateral corridors. The transorbital neuroendoscopic (TONE) approach has been recently proposed as an elegant, bone-sparing, and minimally invasive alternative for tumors of the lateral orbital compartment. However, its effectiveness compared with the standard lateral orbitotomy approach still requires confirmation. The aim of the present report was to describe the key technical aspects of the lateral trans-eyebrow TONE approach and to review the relevant reported data on the surgical management of ectopic orbital intraconal meningiomas.

Case Description: The TONE approach was used in a 63-year-old man with a diagnosis of a left ectopic intraconal meningioma of the orbital apex involving the lateral compartment. The TONE approach involves performing a lateral 3-cm eyebrow skin incision. A subperiosteal dissection of the periorbita permits intermittent medialization of the eyeball and extracapsular access to the orbital apex region. A lateral periorbital incision under full endoscopic view allows for early access to 2 different intermuscular corridors that do not require mechanical retraction of the oculomotor muscles. The reported data included studies of 23 cases of intraconal meningioma, which were usually benign, although the meningothelial variant has been associated with a greater recurrence rate.

Conclusions: In our limited experience, the lateral TONE approach proved to be an effective, feasible, versatile, and minimally invasive promising alternative to resect orbital apex meningiomas involving the lateral compartment. Its technical strengths include increased illumination and magnification of the surgical field and an unparalleled lateral view of the orbital apex.
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http://dx.doi.org/10.1016/j.wneu.2019.07.152DOI Listing
November 2019

NCOA4-RET and TRIM27-RET Are Characteristic Gene Fusions in Salivary Intraductal Carcinoma, Including Invasive and Metastatic Tumors: Is "Intraductal" Correct?

Am J Surg Pathol 2019 10;43(10):1303-1313

Institute of Biomedicine, Pathology, University of Turku, and Turku University Hospital, Turku, Finland.

Intraductal carcinoma (IC) is the new WHO designation for tumors previously encompassed by "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma (SDC) is controversial, even though they are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with histopathological features reminiscent of atypical ductal hyperplasia or ductal carcinoma in situ of the breast, showing diffuse S100 protein and mammaglobin positivity, while it is partially defined genetically. Recently, RET rearrangements including NCOA4-RET and TRIM27-RET have been described in IC. Here, we genetically characterize the largest cohort of IC to date (33 cases) including 8 cases with focal or widespread invasive growth and 1 case with lymph node metastasis. Thirty-three cases of IC were analyzed by next-generation sequencing (NGS) using the FusionPlex Solid Tumor kit (ArcherDX). Identified gene fusions were confirmed using fluorescence in situ hybridization break-apart and fusion probes and an reverse transcription polymerase chain reaction designed specifically for the detected breakpoints. Ten cases of SDC were analyzed for comparison using NGS panels that detect mutations and fusion transcripts. NGS analysis detected an NCOA4-RET fusion transcript in 11 cases of intercalated duct-type IC joining exon 7 or 8 of NCOA4 gene and exon 12 of the RET gene. Eight cases of IC had an invasive growth pattern, including one with widespread invasion and lymph node metastasis. Three invasive ICs harbored an NCOA4-RET fusion transcript, while 1 case was negative, and 2 cases were not analyzable. In addition, a novel TRIM27-RET fusion transcript between exon 3 of TRIM27 and exon 12 of RET was identified in 2 cases of IC with apocrine features, and one of them displayed invasive growth. Two IC cases with invasive growth harbored novel fusions TUT1-ETV5 and KIAA1217-RET, respectively. A total of 42.4% of the cases in this series of IC harbored fusions involving RET. Such fusion transcripts were not detected in any of the 10 SDC cases. We have confirmed NCOA4-RET as a predominant fusion in intercalated duct-type IC, including 3 cases with invasive growth pattern. A novel finding in our series was a case of widely invasive intercalated duct-type IC, with a single lymph node metastasis that revealed an NCOA4-RET fusion transcript. We also demonstrated that a subset of apocrine ICs harbored a TRIM27-RET gene fusion, including one case with invasive growth. In contrast, neither NCOA4-RET nor TRIM27-RET fusions were detected in any tested SDCs. Thus, the distinct molecular findings in IC and SDC support that the tumors are separate malignant salivary tumor entities. The presence of tumor-type-specific NCOA4-RET or TRIM27-RET translocations in a subset of widely invasive carcinomas with intercalated duct-like immunoprofiles suggests that a recharacterization of IC including its redesignation as "intercalated duct carcinoma, invasive or noninvasive" may be appropriate.
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http://dx.doi.org/10.1097/PAS.0000000000001301DOI Listing
October 2019

The Reproducibility of the Immunohistochemical PD-L1 Testing in Non-Small-Cell Lung Cancer: A Multicentric Italian Experience.

Biomed Res Int 2019 14;2019:6832909. Epub 2019 Apr 14.

University Milan Bicocca, Department of Medicine and Surgery, Milan, Italy.

An important harmonization effort was produced by the scientific community to standardize both the preanalytical and interpretative phases of programmed death-ligand 1 (PD-L1) immunohistochemical (IHC) testing in non-small-cell lung cancer (NSCLC). This analysis is crucial for the selection of patients with advanced-stage tumors eligible for treatment with pembrolizumab and potentially with other anti-PD-1/PD-L1 checkpoint inhibitors. This multicentric retrospective study evaluated the reproducibility of PD-L1 testing in the Italian scenario both for and platforms. In the evaluation of the well-known combinations (Agilent 22C3 PharmDx on Dako Autostainer versus Roche's Ventana SP263 on BenchMark), the results confirmed the literature data and showed complete overlapping between the two methods. With regard to the performances by using platforms, the combination of 22C3 with Dako Omnis or Benchmark obtained good results basically, while the 28,8 clone seemed to be associated with worse scores.
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http://dx.doi.org/10.1155/2019/6832909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487144PMC
November 2019

Dysembryoplastic Neuroepithelial Tumors: What You Need to Know.

World Neurosurg 2019 Jul 11;127:255-265. Epub 2019 Apr 11.

Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy; Neurosurgery Unit, Department of Surgical Sciences, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Objective: An updated and comprehensive review on dysembryoplastic neuroepithelial tumor (DNET) focusing on differential diagnosis, atypical presentation, seizure outcome, and risk of malignant transformation.

Methods: A PubMed/MEDLINE-based literature search has been performed using "dysembryoplastic neuroepithelial tumor" as a keyword. Two treated cases characterized by an atypical presentation have been reviewed.

Results: Of 1162 articles, 200 relevant studies have been selected. DNET is a benign mixed neuronal-glial tumor causing drug-resistant epilepsy primarily in children and young adults. The typical radiological pattern is a magnetic resonance imaging (MRI) T1-hypointense, T2-, and fluid-attenuated inversion-recovery hyperintense multicystic lesion involving the cerebral cortex with no edema. Contrast enhancement may be present and a focal cortical dysplasia is commonly associated with it. MRI diffusion, perfusion, and spectroscopy have a paramount role in the differential diagnosis. The "specific glioneuronal elements" are pathognomonic. They are positive for S100 protein, synaptofisin, neuronal nuclei, oligodendrocyte transcription factor, neurite outgrowth inhibitor, and microtubule-associated protein 2, but negative for glial fibrillary acidic protein. As opposed to v-myb avian myeloblastosis viral oncogene homolog, isocitrate dehydrogenase-1/isocitrate dehydrogenase-2 mutation and codeletion 1p-19q, fibroblast growth factor receptor 1 and BRAF V600E mutations are present. The effectiveness of surgery on seizure outcome has been established. Rare malignant transformations have been reported, especially in extra-temporal and complex forms.

Conclusions: Advanced MRI techniques are fundamental in the differential diagnosis for DNET versus other low-grade gliomas. Immuno-phenotype assessment and search for fibroblast growth factor receptor 1 and BRAF V600E mutations limit the risk of misdiagnoses. A gross total tumor removal is generally associated with a seizure-free outcome. Recurrences and malignant transformations may rarely follow, legitimizing MRI surveillance in cases of subtotal tumor resection.
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http://dx.doi.org/10.1016/j.wneu.2019.04.056DOI Listing
July 2019
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