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Primary leptomeningeal medulloblastoma (PL-MB) in adults is a rare disease with a severe prognosis. A 35-year-old woman presented with headaches, diplopia, and gait ataxia, with triventricular hydrocephalus and descent of the cerebellar tonsils beyond the foramen magnum. Endoscopic third ventriculostomy was performed. Six months later, headaches recurred. Dilatation of the supratentorial ventricular system and massive cerebellar swelling without contrast-enhancing nodularities were reported. Occipitocervical decompression with duraplasty was performed. A bioptic diagnosis of PL-MB was made. Craniospinal irradiation and chemotherapy were administered. After 18 months, no recurrence was observed.Few cases of PL-MB have been reported: patients die before treatment or within a few days after surgery. Our long-term survival could be ascribable to a slow clinical presentation and an early diagnosis that allowed surgical treatment and the administration of a combined chemoradiotherapy protocol. Cerebellar swelling, even without associated enhancing lesions, with or without hydrocephalus, should be a neuroradiological alarm sign, and PL-MB should be considered.

The diagnosis and classification of primary Sjögren's syndrome (pSS) relies on labial biopsy, whereas the role of open parotid biopsy is mainly reserved to evaluate the lymphoproliferative complications. Recently ultrasound-guided core needle biopsy (US-guided CNB) appeared as a novel and safe technique useful in lymphoma assessment, however, its potential role in the diagnosis of pSS has never been assessed.The main aim of this study was to evaluate the diagnostic value of US-guided CNB of the parotid glands in patients affected by pSS.Patients affected by pSS who underwent US-guided CNB for a suspected glandular lymphoma were included. Adequacy of the samples and histopathological features related to pSS were analysed.US-guided CNB was performed on 29 parotid glands. The biopsied samples were adequate for diagnosis in 28/29 (96.5%) cases. Fifteen patients showed pathologic features of parotid lymphoma. Among the remaining patients, 9/13 presented focus score≥1; LELs were present in 8/13 patients, and GCs in 11/13. In 8 cases the histological features were coherent with MESA/LESA. Acinar atrophy, fibrosis and duct dilatation were also evaluated.This preliminary study suggests the possible usefulness of US-guided CNB for the diagnosis of pSS by enabling the collection of adequate salivary gland tissue to assess the FS, GCs, LELs, and other histopathologic features also useful in the management of pSS patients.

Objective Persistent (≥2 months) major salivary gland enlargement in primary SS (pSS) patients is a well-known sign of possible involvement by B cell lymphoma. The study aimed to evaluate the diagnostic accuracy and safety of US-guided core needle biopsy (CNB) of major salivary glands compared with open surgical biopsy. Methods Prospective pSS patients (cases) with clinically persistent salivary gland enlargement underwent US-guided CNB and were compared with retrospective pSS patients (controls) submitted to open surgical biopsy. The features analysed were pre-biopsy clinical and laboratory findings, adequacy of the material for histology and diagnostic-rendered and biopsy-related complications (reported by the patient with a questionnaire and clinically verified). Results Thirteen cases underwent US-guided CNB: in nine, biopsy was performed on the parotid gland and in four it was performed on the submandibular gland. Sufficient material was obtained for pathological diagnosis in all samples. The final diagnoses were 5 (38.5%) B cell lymphoma, 1 (7.7%) lymphoepithelial sialadenitis, 4 (30.7%) other sialadenitis (granulomatous consistent with sarcoidosis, IgG4-related disease, chronic sclerosing, diffuse chronic) and 3/13 (23.1%) miscellaneous lesions. Thirteen controls underwent open surgical biopsy of the parotid. In one, inadequate material was obtained, while in 12 (92.3%) the pathologic diagnoses were 4 (33.3%) B cell lymphoma, 2 (16.7%) lymphoepithelial sialadenitis, 4 (33.3%) uncertain lymphoproliferative lesions and 2 (16.7%) miscellaneous lesions. Six cases (46.1%) reported six transient complications and 12/13 (92.3%) controls had 2 persistent and 14 transient complications. Conclusion US-guided CNB represents a novel, clinically relevant and safe approach for the management of pSS patients with parotid or submandibular persistent enlargement.

Objective Parotid swelling (PSW) is a major predictor of non-Hodgkin’s lymphoma (NHL) in primary SS (pSS). However, since detailed information on the time of onset and duration of PSW is scarce, this was investigated to verify whether it may lead to further improved prediction. NHL localization was concomitantly studied to evaluate the role of the parotid gland microenvironment in pSS-related lymphomagenesis. Methods A multicentre study was conducted among patients with pSS who developed B cell NHL during follow-up and matched controls that did not develop NHL. The study focused on the history of salivary gland and lachrymal gland swelling, evaluated in detail at different times and for different durations, and on the localization of NHL at onset. Results PSW was significantly more frequent among the cases: at the time of first referred pSS symptoms before diagnosis, at diagnosis and from pSS diagnosis to NHL. The duration of PSW was evaluated starting from pSS diagnosis, and the NHL risk increased from PSW of 2–12 months to >12 months. NHL was prevalently localized in the parotid glands of the cases. Conclusion A more precise clinical recording of PSW can improve lymphoma prediction in pSS. PSW as a very early symptom is a predictor, and a longer duration of PSW is associated with a higher risk of NHL. Since lymphoma usually localizes in the parotid glands, and not in the other salivary or lachrymal glands, the parotid microenvironment appears to be involved in the whole history of pSS and related lymphomagenesis.

Idelalisib, a selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, is a newly approved second-line drug for patients with chronic lymphocytic leukemia. Recent clinical trials have suggested a possible association between idelalisib treatment and development of progressive multifocal leukoencephalopathy (PML) due to John Cunningham virus (JCV) reactivation. Nevertheless, clinical course and radiological and pathological features of idelalisib-induced PML still need to be clarified. We provide here the first clinicopathological description of idelalisib-associated PML in a patient who developed epilepsia partialis continua (EPC) as the first manifestation of the disease. Since EPC could present without electroencephalogram alterations, it is crucial to recognize the clinical features of this epileptic condition. EPC is characterized by the presence of repetitive, irregular, clonic jerking, often associated with hemiparesis and involvement of distal rather than proximal muscle groups. Moreover, we highlight the importance of brain biopsy in selected cases when there is a high clinical suspicion of PML, despite negative JCV testing in the cerebrospinal fluid. The pathological finding of prominent inflammatory infiltrate observed here was consistent with a diagnosis of immune reconstitution inflammatory syndrome (IRIS). IRIS is often associated with PML as a paradoxical worsening of clinical symptoms due to an overreacting immune response, in the context of previous immunosuppression. The unprecedented pathologic observation of IRIS in idelalisib-associated PML provides further insights into the pathogenesis of this rare neurological side effect.

Primary Sjögren’s syndrome (pSS) is a chronic and heterogeneous disorder characterized by a wide spectrum of glandular and extra-glandular features. The hallmark of pSS is considered to be the immune-mediated involvement of the exocrine glands and B-cell hyperactivation. This leads pSS patients to an increased risk of developing lymphoproliferative diseases, and persistent (>2 months) major salivary gland enlargement is a well-known clinical sign of possible involvement by B cell lymphoma. Better stratification of the patients may improve understanding of the mechanism underlying the risk of lymphoproliferative disorder. Here, we summarize the role of different imaging techniques and a bioptic approach in pSS patients, focusing mainly on the role of salivary gland ultrasonography (SGUS) and a US-guided core needle biopsy (Us-guided CNB) as diagnostic and prognostic tools in pSS patients with persistent parotid swelling.

Extraskeletal myxoid chondrosarcoma is a rare form of malignant mesenchymal neoplasm mainly localized into the limbs, particularly in the thigh and popliteal fossa. It has been classified as a low-grade sarcoma so far, but it shows a tendency to relapse and metastasize. In the early stage of disease, surgery represents the only chance of cure. In case of diffuse metastatic disease, systemic chemotherapy with anthracyclines is the standard of care. In this paper, we present a case of a patient affected by this rare disease and the analysis of radiological, surgical and histopathological aspects.

Simple Summary 5-ALA Fluorescence Guided Surgery aims at extending the boundaries of glioblastoma (GBM) resection. It is based on the use of a fluorescent dye, 5-aminolevulinic acid (5-ALA). Depending on the fluorescence levels, it is possible to distinguish the core of the tumor, the infiltrating borders and the healthy tissue. Since GBM progression is supported by tumor cells and their interaction with the surrounding microenvironment, we hypothesized that 5-ALA intensity could identify microenvironments with different tumor supporting properties. Taking advantage of glioma-associated stem cells; a human in vitro model of the glioma microenvironment, we demonstrate that all regions of the tumor support the tumor growth, but through different pathways. This study highlights the importance of understanding the TME to obtain key information on GBM biology and develop new therapeutic approaches. Abstract The glioblastoma microenvironment plays a substantial role in glioma biology. However, few studies have investigated its spatial heterogeneity. Exploiting 5-ALA Fluorescence Guided Surgery (FGS), we were able to distinguish between the tumor core (ALA+), infiltrating area (ALA-PALE) and healthy tissue (ALA−) of the glioblastoma, based on the level of accumulated fluorescence. The aim of this study was to investigate the properties of the microenvironments associated with these regions. For this purpose, we isolated glioma-associated stem cells (GASC), resident in the glioma microenvironment, from ALA+, ALA-PALE and ALA− samples and compared them in terms of growth kinetic, phenotype and for the expression of 84 genes associated with cancer inflammation and immunity. Differentially expressed genes were correlated with transcriptomic datasets from TCGA/GTEX. Our results show that GASC derived from the three distinct regions, despite a similar phenotype, were characterized by different transcriptomic profiles. Moreover, we identified a GASC-based genetic signature predictive of overall survival and disease-free survival. This signature, highly expressed in ALA+ GASC, was also well represented in ALA PALE GASC. 5-ALA FGS allowed to underline the heterogeneity of the glioma microenvironments. Deepening knowledge of these differences can contribute to develop new adjuvant therapies targeting the crosstalk between tumor and its supporting microenvironment.

Objective Persistent (≥2 months) major salivary gland (SG) enlargement in primary Sjögren's syndrome (pSS) patients is a well-known sign of possible involvement by B-cell lymphoma. The study aimed to evaluate the diagnostic accuracy and safety of ultrasound-guided core needle biopsy (US-guided CNB) of major SGs in comparison to open surgical biopsy. Methods Prospective pSS patients (cases) with clinically persistent SG enlargement underwent US-guided CNB, and were compared to retrospective pSS patients (controls) submitted to open surgical biopsy. The features analyzed were pre-biopsy clinical and laboratory findings, biopsy-related complications (reported by the patient with a questionnaire and clinically verified), adequacy of the material for histology and diagnosis rendered. Results Thirteen cases underwent US-guided CNB: in 9/13 biopsy was performed on the parotid and in 4/13 on the submandibular gland. Sufficient material was obtained for pathological diagnosis in all samples. The final diagnoses were: 5/13 (38.5%) B-cell lymphoma, 1/13 (7.7%) lympho-epithelial sialadenitis, 4/13 (30.7%) other sialadenitis (granulomatous consistent with sarcoidosis, IgG4-related disease, chronic sclerosing, diffuse chronic) and 3/13 (23.1%) miscellaneous lesions. Thirteen controls underwent open surgical biopsy of the parotid, in one inadequate material was obtained, in 12 (92.3%) the pathologic diagnoses were: 4/12 (33.3%) B-cell lymphoma, 2/12 (16.7%) lympho-epithelial sialadenitis, 4/12 (33.3%) uncertain lymphoproliferative lesions, 2/12 (16.7%) miscellaneous lesions. 6/13 (46.1%) cases reported 6 transient complications, and 12/13 (92.3%) controls 2 persistent and 14 transient complications. Conclusion US-guided CNB represents a novel, clinically relevant and safe approach to the management of pSS patients with parotid or submandibular persistent enlargement.

Incidentally discovered low-grade gliomas (iLGGs) are poorly reported in the literature. Still less is known about iLGG patients&rsquo, neuropsychological profile: It is unclear whether iLGG patients are cognitively proficient, thus further confirming the concept of asymptomatic. From our monoinstitutional cohort of 332 patients operated for LGG from 2000 to 2017 we selected those who underwent a neuropsychological testing (n = 217, from 2008 to 2017), and identified 24 young (mean age 38.5 &plusmn, 1.06) patients with iLGGs (16 of 24, left hemisphere iLGGs, 8 of 24 right hemisphere iLGGs). The maximum lesions overlap occurred in the left inferior frontal gyrus and in the right anterior cingulate/superior medial frontal gyrus. Patients were cognitively preserved except mild to borderline difficulties in a few of them. The analysis of the equivalent scores (a score laying below or equal to the external nonparametric tolerance limit of adjusted scores corresponding to 0, 1, 2 and 3 are intermediate) highlighted the presence of additional borderline performances. Molecular class correlated with a normal function at visual&ndash, spatial intelligence (p = 0.05) and at spatial short-term memory (p = 0.029). Results indicate that at this time of tumor growth, patients&rsquo, cognitive abilities are still functional, but are slowly approaching the borderline level.

Decades of therapeutic and molecular refinements, the prognosis of patients with glioblastoma (GBM) still remains unfavorable. Integrative clinical studies allow a better understanding of the natural evolution of GBM. To assess independent predictors of overall survival (OS) and progression free survival (PFS) clinical, surgical, molecular and radiological variables were evaluated. A novel preoperative volumetric magnetic resonance imaging (MRI) Index for tumor prognosis in GBM patients was investigated.A cohort of 195 cases of patients operated for newly GBM were analyzed. Extent of tumoral resection (EOR), tumor growth pattern, expressed by preoperative volumetric ΔT1-T2 MRI Index, molecular markers such as O6-methylguanine-DNA methyltransferase (MGMT) methylation and isocitrate dehydrogenase 1/2 (IDH1/2) mutation, were analyzed. Analysis of survival was done using Cox-proportional hazard models.The 1-, 2- years estimated OS and PFS rate for the whole population were 61% and 27%, 38% and 17%, respectively. A better survival rate, both in terms of survival and tumor progression, was observed in patient with higher EOR (P=0.000), younger age (P=0.000), MGMT methylation status (P=0.001) and lower preoperative ΔT1-T2 MRI Index (P=0.004). Regarding the tumor growth pattern a cut-off value of 0.75 was found to discriminate patient with different prognosis. Patients with a preoperative ΔT1-T2 MRI Index0.75 had a 1-year estimated OS of 67%, otherwise patients with a preoperative ΔT1-T2 MRI Index0.75 had a 1-year estimated OS of 34%.In this investigation longer survival is associated with younger age, EOR, promoter methylation of MGMT and preoperative tumor volumetric features expressed by ΔT1-T2 MRI Index The preoperative ΔT1-T2 MRI Index could be a promising prognostic factor potentially useful in GBM management. Future investigations based on multiparametric MRI data and next generation sequences analysis, may better clarify this result.

BackgroundEnlargement of the major salivary glands (SGs) is a major risk factor for B-cell lymphoma among patients with primary Sjögren’s syndrome (pSS). Ultrasound-guided core needle biopsy (US-guided CNB) could be a novel technique to manage SG enlargement among patients with pSS.ObjectiveAccordingly, this study’s main aim was to evaluate the safety, patient tolerance and diagnostic accuracy of US-guided CNB procedure for patients with pSS with major SG enlargement.MethodsPatients with clinical diagnosis of pSS and a clinical indication for SG biopsy consecutively underwent US-guided CNB between September 2019 and June 2021. These patients were evaluated clinically 1, 2 and 12 weeks after US-guided CNB. Patients were asked to complete a questionnaire about postprocedural complications as well as periprocedural pain, using the Visual Analogue Scale. Complications were categorised as transient (persistent (≥12 weeks).ResultsUS-guided CNB was performed on 30 major salivary glands (22 parotid glands and 8 submandibular glands). The procedure was well tolerated. Transient complications—such as haematoma, swelling—were observed among 43% of patients, and mean periprocedural pain was low. However, no persistent complications were reported during the study’s follow-up period.ConclusionUS-guided CNB represents a novel approach for the management of patients with pSS with SG enlargement. The procedure showed remarkable patient safety and tolerance, allowing adequate glandular sampling and a definite diagnosis for almost all participating patients without long-term complications.

(1) Background: Recently, it has been shown that the extent of resection (EOR) and molecular classification of low-grade gliomas (LGGs) are endowed with prognostic significance. However, a prognostic stratification of patients able to give specific weight to the single parameters able to predict prognosis is still missing. Here, we adopt classic statistics and an artificial intelligence algorithm to define a multiparametric prognostic stratification of grade II glioma patients. (2) Methods: 241 adults who underwent surgery for a supratentorial LGG were included. Clinical, neuroradiological, surgical, histopathological and molecular data were assessed for their ability to predict overall survival (OS), progression-free survival (PFS), and malignant progression-free survival (MPFS). Finally, a decision-tree algorithm was employed to stratify patients. (3) Results: Classic statistics confirmed EOR, pre-operative- and post-operative tumor volumes, Ki67, and the molecular classification as independent predictors of OS, PFS, and MPFS. The decision tree approach provided an algorithm capable of identifying prognostic factors and defining both the cut-off levels and the hierarchy to be used in order to delineate specific prognostic classes with high positive predictive value. Key results were the superior role of EOR on that of molecular class, the importance of second surgery, and the role of different prognostic factors within the three molecular classes. (4) Conclusions: This study proposes a stratification of LGG patients based on the different combinations of clinical, molecular, and imaging data, adopting a supervised non-parametric learning method. If validated in independent case studies, the clinical utility of this innovative stratification approach might be proved.

Refractory status epilepticus (RSE) is an increasingly recognized manifestation of autoimmune encephalitis, which can occur either as a paraneoplastic or non-paraneoplastic disorder. The effect of tumor removal in paraneoplastic status epilepticus has never been explored systematically, although early tumor treatment is usually recommended. In this study, we report clinical, pathological and EEG findings of a patient who developed RSE as one of multiple paraneoplastic manifestations of thymoma and the effect of thymectomy on seizure outcome. To our knowledge, this is the first report of successful treatment of RSE with tumor removal in paraneoplastic encephalitis.

Background:Persistent enlargement of major salivary glands (SGs) is one of the main risk factors for B-cell lymphoma in primary Sjögren’s syndrome (pSS). The Ultrasound-guided Core Needle Biopsy (US-guided CNB) could be a novel technique for the management of SGs enlargement in pSS (1).Objectives:To evaluate the procedure safety and the patient tolerance of US-guided CNB in pSS patients with major SGs enlargement.Methods:Consecutive patients, with either definite or clinically suspected pSS, and with clinical indication for SGs biopsy due to persistent glandular enlargement were screened for US-guided CNB from September 2019 to December 2020. All patients were evaluated clinically between 1 and 2 weeks and 12 weeks following US-guided CNB. All patients were asked to complete a questionnaire to report post-procedural complications (Figure 1, English version) and intra- and post-procedural pain Visual Analogue Scale (VAS). The complications were classified as transient (Results:US-guided CNB was performed in 21 glands (12 parotid and 9 submandibular glands) in 20 pSS patients. 16/20 (80%) patients fulfilled the ACR-EULAR classification criteria for pSS (2). The mean age at the time of biopsy was 62.1 (±11.7) years. US-guided CNB was well tolerated, no long-term complications were reported in the follow-up period (mean 9.5 ±5.7 months). Only transient complications were noticed in 11 patients (55%). In particular, two cases of local swelling at the biopsy site lasting no more than 6 days, one case of local bleeding and subsequently hematoma of the submandibular area, one case of transient facial paresis (lasting less than one hour), seven cases of post-procedural mild local pain, that resolved within 10 days without the need of analgesics (Table 1). The procedure was well tolerated, with a very low reported intra-operative pain (mean VAS 1.74 ±2.49) and a mean post-operative pain VAS of 1.39 (±2.33). The biopsy sampling was diagnostic in 19/20 patients (95%).Conclusion:US-guided CNB represents a novel approach for the management of pSS patients with SGs enlargement. This procedure shows a remarkable patient safety and tolerance, allowing an adequate glandular sampling and definite diagnosis in almost all the studied patients.References:[1]Zabotti A, Zandonella Callegher S, Lorenzon M, Pegolo E, Scott CA, Tel A, et al. Ultrasound-guided core needle biopsy compared with open biopsy: a new diagnostic approach to salivary gland enlargement in Sjögren’s syndrome? Rheumatology (Oxford) 2020.[2]Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, Rasmussen A, Scofield H, Vitali C, Bowman SJ, Mariette X; International Sjögren’s Syndrome Criteria Working Group. 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren’s Syndrome: A Consensus and Data-Driven Methodology Involving Three International Patient Cohorts. Arthritis Rheumatol. 2017 Jan;69(1):35-45. doi: 10.1002/art.39859. Epub 2016 Oct 26. PMID: 27785888; PMCID: PMC5650478.Table 1.Description of complicationsComplications of US-guided CNBPatients presenting complications, n/N (%)11/20 (55%)Description of transient complicationsSwelling at biopsy site, n2Bleeding, n1Hematoma, n1Local Pain, n7Local infection, n0Sialocele or fistula, n0Anaesthesia/paraesthesia, n0Transient facial palsy (< 1 hour), n1No persistent complications reportedAll the above specified complications were transient (< 12 weeks). No persistent complications were reported in the follow up.Figure 1.Post-biopsy complication QuestionnaireDisclosure of Interests:Alen Zabotti Speakers bureau: UCB, Novartis, Janssen, Paid instructor for: Amgen, Consultant of: Janssen, Ivan Giovannini: None declared, Sara Zandonella Callegher: None declared, Valeria Manfrè: None declared, Michele Lorenzon Consultant of: not relevant for this study, Enrico Pegolo: None declared, Cathryn Ann Scott: None declared, Alessandro Tel: None declared, Massimo Robiony Consultant of: not relevant for this study, Grant/research support from: not relevant for this study, Chiara Zuiani Consultant of: not relevant for this study, Grant/research support from: not relevant for this study, Salvatore De Vita Consultant of: GSK, Roche, Grant/research support from: not relevant for this study

Meningioma is one of the most common intracranial tumors. It is benign and slow growing in the majority of cases. Given the increase in life expectancy and the number of radiological tests performed, the incidence in the elderly population (&ge, 65 years) is continuously increasing. The surgical outcomes and prognostic factors in this age group are unclear. A retrospective analysis of all the patients treated for intracranial meningiomas in two different Italian institutions was performed. The clinical, radiological, surgical and follow-up data were retrospectively reviewed. Statistical analyses were performed to identify relationships between factors and outcomes. We also carried out an economic analysis. We analyzed 321 patients with intracranial meningioma. The mean age was 72.6 years (range, 65&ndash, 90), with a female predominance (F/M, 1.41). Pre-operative deficits, cognitive impairment and seizures (p &lt, 0.001) were associated with a worse post-operative Karnofsky performance scale (KPS) score (&lt, 80). A high pre-operative KPS score was associated with a good clinical and neurological outcome (p &lt, 0.001). Being aged between 65 and 74 years, low surgical timing and Simpson removal grades of I and II were associated with a good outcome (p &lt, 0.001). The length of hospitalization was significantly related to the outcome (p &lt, 0.001). The complication rate was 14.3%. At 6-month follow-up, the mortality rate was 2.5%. The average cost was higher in patients with a pre-operative KPS score lower than 80. The outcome of intracranial-meningioma resection in elderly individuals is favorable when the pre-operative KPS score is &gt, 80. Treatment should be patient-specific, and additional factors should be considered. Patients with poor pre-operative clinical conditions might benefit from a combined strategy with partial resection and radiosurgery in order to reduce surgical timing and the complication rate.

Despite recent discoveries in genetics and molecular fields, glioblastoma (GBM) prognosis still remains unfavorable with less than 10% of patients alive 5 years after diagnosis. Numerous studies have focused on the research of biological biomarkers to stratify GBM patients. We addressed this issue in our study by using clinical/molecular and image data, which is generally available to Neurosurgical Departments in order to create a prognostic score that can be useful to stratify GBM patients undergoing surgical resection. By using the random forest approach [CART analysis (classification and regression tree)] on Survival time data of 465 cases, we developed a new prediction score resulting in 10 groups based on extent of resection (EOR), age, tumor volumetric features, intraoperative protocols and tumor molecular classes. The resulting tree was trimmed according to similarities in the relative hazard ratios amongst groups, giving rise to a 5-group classification tree. These 5 groups were different in terms of overall survival (OS) (p &lt, 0.000). The score performance in predicting death was defined by a Harrell&rsquo, s c-index of 0.79 (95% confidence interval [0.76&ndash, 0.81]). The proposed score could be useful in a clinical setting to refine the prognosis of GBM patients after surgery and prior to postoperative treatment.

Background Incidentally discovered diffuse low-grade gliomas (iLGG) are poorly documented in the literature. They are diagnosed by chance during radiological examinations. Objective To review a cohort of patients with iLGG surgically treated in our institution, analyzing clinical, molecular, and surgical aspects. Methods Clinical, radiological, and treatment data of iLGG were retrieved and compared with those of symptomatic diffuse LGGs (sLGG). Histological and molecular review was carried out as well. The extent of resection was evaluated on preoperative and postoperative T2-weighted magnetic resonance imaging. Results Thirty-four iLGG cases were identified within a monoinstitutional cohort of 332 patients operated for low-grade gliomas from 2000 to 2017. Clinically, patients with iLGG had higher preoperative karnofsky performance scale (KPS) (P = .003), smaller tumor volume (P = .0001), lower frequency of eloquent areas involvement (P = .0001), and higher rate of complete resection (P = .0001) compared to those with sLGG. No differences in the molecular profile and O6-methylguanine-DNA-methyltransferase promoter methylation were detected between iLGG and sLGG. Importantly, patients with iLGG had longer overall survival than those with sLGG (P = .0001), even when a complete surgical resection was achieved (P = .001). Conclusion Although the therapeutic strategy of iLGG is still a matter of debate, our data support the safety and the effectiveness of early surgical resection. The favorable prognosis of iLGG may be due to the higher practicability of extensive resection, noneloquent tumor location, and smaller tumor volume.

The purpose of this study was to retrospectively evaluate the use of carmustine wafers (CWs) in the management of high-grade gliomas (HGGs). The data from our monoinstitutional series was compared with studies reported in the literature. Special emphasis was placed on the evaluation of side effects and the analysis of extent of resection and molecular profile as risk factors. The implantation of CWs into the resection cavity during HGG treatment to deliver localized chemotherapy, followed by the Stupp protocol, remains debated in a clinical setting, largely due to the lack of appropriate phase III studies. Given the high expense and poorly characterized side effects associated with CW treatment, identification of patients most likely to benefit from this therapy could be clinically relevant. CWs may represent an effective and safe first-line treatment for patients with HGG that exhibit complete tumor resection and harboring a methylated MGMT promoter. Our investigation showed a much larger group of patients exhibiting long-term survival (> = 36 months), strongly supporting a potential survival benefit conferred via CW treatment. The pre-surgical definition of the MGMT promoter status could be of clinical use in identifying “good responders” to CW implantation.

Background While recent genome-wide association studies have suggested novel low-grade glioma (LGG) stratification models based on a molecular classification, we explored the potential clinical utility of patient-derived cells. Specifically, we assayed glioma-associated stem cells (GASC) that are patient-derived and representative of the glioma microenvironment. Methods By next-generation sequencing, we analyzed the transcriptional profile of GASC derived from patients who underwent anaplastic transformation either within 48 months (GASC-BAD) or ≥7 years (GASC-GOOD) after surgery. Gene set enrichment and pathway enrichment analyses were applied. The prognostic role of a nuclear factor-kappaB (NF-κB) signature derived from GASC-BAD was tested in 530 newly diagnosed diffuse LGG patients comprised within The Cancer Genome Atlas (TCGA) database. The prognostic value of the GASC upstream regulator p65 NF-κB was assessed, by univariate and multivariate Cox analyses, in a single center case study, including 146 grade II LGGs. Results The key elements differentiating the transcriptome of GASC isolated from LGG with different prognoses were mostly related to hallmarks of cancer (eg, inflammatory/immune process, NF-κB activation). Consistently, the NF-κB signature extrapolated from the GASC study was prognostic in the dataset of TCGA. Finally, the nuclear expression of the NF-kB-p65 protein, assessed using an inexpensive immunohistochemical method, was an independent predictor of both overall survival and malignant progression-free survival in 146 grade II LGGs. Conclusion This study demonstrates for the first time the independent prognostic role of NF-kB activation in LGG and outlines the role of patient-based stem cell models as a tool for precision medicine approaches.

Intraparenchymal meningiomas are very rare: only 26 cases have been diagnosed in patients younger than 20 years since 1954. They can lead to preoperative differential diagnosis mistakes due to their atypical neuroimaging appearance. A multimodal approach is thus necessary to plan a surgical procedure aiming to receive the best extent of resection while preserving the patient’s functional integrity. The authors report the case of a 7-year-old boy with a history of blurred vision, left eye deviation, and weakness on the left side of his body. Magnetic resonance imaging (MRI) revealed an intra-axial, cortical, right parietal lesion without dural attachment. MR spectroscopy and perfusion study were obtained. Since the patient was 100% left-handed, functional MRI, diffusion tensor imaging, and neuropsychological evaluation were performed before the surgical procedure. Histopathological analysis revealed the mass to be an atypical meningioma (WHO grade II). Postoperative MRI indicated complete macroscopic lesion removal. The postsurgical neuropsychological profile was not different from the profile before surgery. The boy was discharged 3 days after the surgical operation without any neurological deficits.

Mouse models can provide useful information to understand molecular mechanisms of human tumorigenesis. In this study, the conditional thyroid mutagenesis of Pten and Ras genes in the mouse, which induces very aggressive follicular carcinomas (FTCs), has been used to identify genes differentially expressed among human normal thyroid tissue (NT), follicular adenoma (FA), and FTC. Global gene expression of mouse FTC was compared with that of mouse normal thyroids: 911 genes were found deregulated ± 2-fold in FTC samples. Then the expression of 45 deregulated genes in mouse tumors was investigated by quantitative RT-PCR in a first cohort of human NT, FA, and FTC (discovery group). Five genes were found significantly down-regulated in FA and FTC compared with NT. However, 17 genes were found differentially expressed between FA and FTC: 5 and 12 genes were overexpressed and underexpressed in FTC vs FA, respectively. Finally, 7 gene products, selected from results obtained in the discovery group, were investigated in a second cohort of human tumors (validation group) by immunohistochemistry. Four proteins showed significant differences between FA and FTC (peroxisomal proliferator-activated receptor-γ, serum deprivation response protein, osteoglycin, and dipeptidase 1). Altogether our data indicate that the establishment of an enriched panel of molecular biomarkers using data coming from mouse thyroid tumors and validated in human specimens may help to set up a more valid platform to further improve diagnosis and prognosis of thyroid malignancies.

The proliferative activity of breast cancer tissue can be estimated using the Ki67 biomarker. The percentage of positivity of such biomarker is correlated with proliferation and consequently with the prognosis of a breast tumor. Ki67 marked tissue samples are analyzed by an experienced pathologist who identifies the most active areas of tumor cell proliferation called hotspots, and estimates the positivity of each case. A method for the Automated Ki67 Hotspot Detection (AKHoD) is presented in this work. The main objective of the AKHoD method is to automatically and efficiently provide the pathologist with suggestions about Ki67 hotspot areas as a decision support. The input of AKHoD is a digital slide that is divided in tiles. For each tile, AKHoD provides a rough estimate of positivity and cellularity, summarized in very low resolution positivity and cellularity images. In a second step, an adaptive thresholding is applied to such positivity image to identify the most positive connected and convex areas, within cellularity limits set by current guidelines (that is, 500-2000). The method has been preliminarily validated on 50 digital slides for which three expert pathologists provided gold standard hotspots. 82% of the gold standard hotspots have been successfully recognized by the system, spending an average of 54s per slide. While further validation is needed taking into account also patients follow-up, this first experimentation suggests that the proposed method could be adequate for supporting the pathologist in hotspot detection.

Distinguishing Grover's disease from other papular dermatoses is often a troublesome task. According to two relatively recent case reports, dermoscopy may be useful in assisting the diagnosis of such a disorder by showing a peculiar pattern. The aim of this study was to evaluate the dermoscopic features of Grover's disease in a larger series of patients and correlate dermoscopy with histopathological findings. Seven patients with histopathologically confirmed Grover's disease were included in the study, with three of them displaying a Darier-like histology and the remaining four cases having a spongiotic histological pattern. The results of our study suggest that Grover's disease may display different features according to the histological subtype, with a central star-shaped/branched polygonal/roundish-oval brownish area surrounded by a whitish halo being characteristic of the Darier-like histological subtype and whitish scales over a reddish-yellowish background being characteristic of the spongiotic histological subtype.

Type 1 segmental Darier’s disease is a blaschkolinear variant of Darier’s disease resulting from a postzygotic mosaicism. Since it usually lacks diagnostic clues typical of the generalized form, including positive family history of the disease, nail and mucosal abnormalities, and/or acral involvement, its distinction from other acquired inflammatory blaschkolinear dermatoses may often be quite challenging, thus requiring histopathological examination to reach a definitive diagnosis. We report a case of type 1 segmental Darier’s disease with its dermoscopic findings in order to show the usefulness of dermoscopy in assisting the noninvasive identification of this condition.

BACKGROUND: Fine-needle aspiration cytology (FNAC) is a well-accepted procedure for the diagnosis and biological characterization of breast carcinoma. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status have a strong prognostic and predictive value in invasive breast carcinoma (IBC). ThinPrep (TP) cytology, which uses an alcohol-based fixative, is increasingly being used for immunocytochemistry. In this study, the authors compared the immunocytochemical evaluation of hormone receptors (HR) and HER2 on TP-processed FNAC with the immunohistochemical analysis performed on the corresponding formalin-fixed paraffin-embedded (FFPE) breast tumor specimens, which are considered the gold standard. METHODS: FNACs were performed on 116 primary IBCs at the time of diagnosis and subjected to immunocytochemical evaluation of HR and HER2 using the TP method. The same markers were immunohistochemical evaluated on the corresponding FFPE tissue specimens. HER2 fluorescent in situ hybridization analysis was performed only on the equivocal immunohistochemical results. RESULTS: The HR results of the TP cytology specimens showed a very good agreement with those of the corresponding FFPE tissue samples (Cohen kappa test = 0.92; concordance rate = 98%) for estrogen receptor, and a good agreement (kappa = 0.76; concordance rate = 90.9%) for progesterone receptor. A perfect agreement (kappa = 1) was observed between TP and FFPE tissue samples in evaluating HER2 status. CONCLUSIONS: Alcohol-based fixation seems not to affect the immunocytochemical evaluation of HR and HER2. Considering the high levels of agreement between the evaluation of HR and HER2, on both cytology specimens and on the corresponding FFPE tissue samples, the authors concluded that the TP technique can be routinely used for the biological characterization of IBC. Cancer (Cancer Cytopathol) 2012;. © 2012 American Cancer Society.

Background: Malignant change in the scars of discoid lupus erythematosus (DLE) is a well-known event. In most cases, tumors are of epithelial origin, particularly squamous cell carcinomas and, less frequently, basal cell carcinomas and keratoacanthomas. The onset of soft tissue sarcomas in a DLE scar is a very rare event, however, because only one case of malignant fibrous histiocytoma has been described in the literature. Objective: We describe the first documented report of atypical fibroxanthoma (AFX) arising in an old scar of DLE. Results: Although we cannot exclude an accidental association between AFX and DLE, our case emphasizes that patients with DLE may develop AFX in the context of an old scar. Conclusion: Our finding further underlines the importance of strict and long-term surveillance of people with DLE to identify and remove eventual tumors at an early stage.

Primary adenocarcinomas of the gastrointestinal tract showing a diffuse thyroid transcription factor-1 (TTF-1)-positive immunostaining are extremely uncommon and this finding in the biopsy specimen could yield to misleading diagnosis of a metastatic lung tumor. We report the clinical and pathological features of 2 cases, occurring in a 62-year-old woman and in a 66-year-old man. The first one is a gastric adenocarcinoma with liver metastasis; the other one is a gallbladder adenocarcinoma discovered during the screening for the colorectal cancer. Both the neoplasms showed a diffuse TTF-1 positivity and both the patients did not have any evidence of lung cancer. Neither a gastric adenocrcinoma with diffuse TTF-1 expression nor a TTF-1-positive gallbladder adenocarcinoma has been described before.

The one-step nucleic acid amplification (OSNA) method is an increasingly used procedure for intraoperative analysis of sentinel lymph node (SLN) status in breast cancer patients. It measures cytokeratin19 (CK19) mRNA copy numbers in homogenized samples of SLN; CK19 has been chosen for identifying node metastasis because most breast cancers express this molecule. However, to avoid false-negative OSNA results, testing the preoperative needle core biopsy (NCB) of breast carcinomas for CK19 by immunohistochemistry (IHC) has been recommended. This procedure relies on the assumption that protein expression is strictly related to mRNA expression. We developed this study to evaluate if IHC gives similar result to the molecular assay. In a series of breast cancer patients with axillary metastasis, corresponding surgically resected tumor and metastatic lymph node specimens have been tested for CK19 protein by IHC and for CK19 mRNA by real-time PCR; furthermore, CK19 immunostaining has been performed in NCBs when available. Statistical analysis revealed that (1) the immunohistochemical evaluation of CK19 in NCB is a reliable test, reflecting protein expression in the whole tumor and in the metastatic lymph node; (2) there is no correlation between CK19 protein expression and CK19 RNA level neither within the primary breast cancer nor within the metastatic node; moreover, no correlation as well has been found between protein expression in NCB and mRNA level in metastatic lymph nodes. Thus, our results suggest that there is no evidence-based reason to stain every NCB for CK19 before performing OSNA in patients with breast cancer.

Background and aim Capecitabine is an orally bioavailable prodrug that is converted to 5-fluorouracil through several enzymatic steps, the last of which is mediated by thymidine phosphorylase (TP). TP has been reported to be expressed at higher levels in cancer tissue compared with normal counterpart. The present study aimed at evaluating the potential relationship between TP expression and benefit from capecitabine in patients with metastatic breast cancer (BC). Methods Immunohistochemistry for TP and other biological markers was carried out on paraffin-embedded cancer tissues of 61 patients with BC treated with at least three cycles of capecitabine as single agent for metastatic disease. All patients had received capecitabine 1000 mg/m2 b.i.d. days 1–14 every 21 days. The following variables were analyzed as potential determinants of benefit from capecitabine: TP expression, estrogen receptor (ER) and progesterone receptor status, human epidermal growth factor receptor-2 (HER-2) status, MIB-1 expression, performance status at the beginning of capecitabine treatment, stage at diagnosis, grade, presence of visceral metastases at the beginning of capecitabine treatment, and previous chemotherapy. Results Overall, median time to progression (TTP) was 6.5 months (range 1.4–33). On multivariate analysis, ER status [hazard ratio (HR) for progression = 0.31; 95% confidence interval (CI) = 0.15–0.64; P = 0.002], presence of visceral metastases at the beginning of capecitabine treatment (HR = 2.30; 95% CI = 1.21–4.39; P = 0.01), and capecitabine as first- or second-line treatment (HR = 2.28; 95% CI = 1.21–4.32; P = 0.01) independently predicted TTP. TP was highly expressed in 34 of 61 cases (55.7%). In the subgroup of patients with TP-expressing tumor, TTP was significantly longer in patients who received anthracyclines and taxanes before capecitabine (median TTP 7.5 versus 3.3 months, P = 0.01, log-rank test). Similarly, patients with a TP-positive tumor showed a longer TTP if they received taxanes before capecitabine than patients with TP-positive tumor who did not receive this treatment (7.3 versus 3.4 months, P = 0.03). Conclusions These data provide further evidence that TP expression in BC could represent a biomarker of sensitivity to capecitabine treatment. Prospective studies with translational approach are desirable to confirm the predictive and prognostic role of TP.