H3 K27M mutation in rosette-forming glioneuronal tumors: a potential diagnostic pitfall

According to the fifth edition of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS), diffuse midline glioma H3 K27-altered is a grade 4 infiltrative glioma that arises from midline anatomical structures and is characterized by the loss of H3 K27me3 and co-occurring H3 K27M mutation or EZHIP overexpression. However, the H3 K27M mutation has also been observed in circumscribed gliomas and glioneuronal tumors arising in midline anatomical structures, which may result in diagnostic pitfalls.Rosette-forming glioneuronal tumor (RGNT) is a CNS WHO grade 1 neoplasm that histologically features neurocytic and glial components and originates in midline anatomical structures.This study aimed to assess whether RGNTs, similar to other midline tumors, may exhibit immunohistochemical loss of H3 K27me3 and harbor the H3 K27M mutation.All seven analyzed RGNTs displayed immunohistochemical loss of H3 K27me3 in all tumor cells or H3 K27me3 mosaic immunostaining. In one case, H3 K27me3 loss was associated with the H3 K27M mutation, whereas the other six cases did not exhibit any H3 mutations or EZHIP overexpression. During a follow-up period of 23 months, the H3 K27M-mutant case remained unchanged in size despite partial resection, indicating that the H3 mutation may not confer higher biological aggressiveness to RGNT.The immunohistochemical loss of H3 K27me3 co-occurring with the H3 K27M mutation may result in the potential misdiagnosis of RGNT, especially in cases of small biopsy specimens consisting of only the glial component

Transarterial Chemoembolization for Hepatocellular Carcinoma in Clinical Practice: Temporal Trends and Survival Outcomes of an Iterative Treatment

BACKGROUND: Transarterial chemoembolization (TACE) is one of the most frequently applied treatments for hepatocellular carcinoma (HCC) worldwide. In this study, we aimed at evaluating whether and how TACE application and repetition, as well as the related outcome, have changed over the last three decades in Italy. METHODS: Data of 7,184 patients with HCC were retrieved from the Italian Liver Cancer (ITA.LI.CA) database. Patients were divided according to the period of diagnosis in six cohorts: P1 (1988–1993), P2 (1994–1998), P3 (1999–2004), P4 (2005–2009), P5 (2010–2014), and P6 (2015–2019). All the analyses were repeated in the overall patient population and in Barcelona Clinic Liver Cancer (BCLC) B patients, who are the subgroup of HCC patients originally supposed to receive TACE according to guidelines. TACE was defined as either the first or the main (more effective) treatment. RESULTS: The proportion of patients receiving TACE as first or main therapy declined over time, and less than 50% of BCLC B patients were treated with chemoembolization from P3 onward. Conversely, TACE was widely used even outside the intermediate stage. Survival of TACE-treated patients progressively increased from P1 to P6. Although TACE was performed only once in the majority of patients, there was an increasing proportion of those receiving 2 or ≥3 treatments sessions over time. The overall survival (OS) of patients undergoing repeated treatments was significantly higher compared to those managed with a single TACE (median OS 40.0 vs. 65.0 vs. 71.8 months in 1, 2, and ≥3 TACE groups, respectively; p < 0.0001). However, after a first-line TACE, the adoption of curative therapies provided longer survival than repeating TACE (83.0 vs. 42.0 months; p < 0.0001), which in turn was associated with better outcomes compared to systemic therapies or best supportive care (BSC). CONCLUSIONS: Despite a decline in the percentage of treated patients over time, TACE has still an important role in the management of HCC patients. The survival of TACE-treated patients gradually improved over time, probably due to a better patient selection. Iterative TACE is effective, but an upward shift to curative therapies provides better outcomes while transition to systemic therapies and BSC leads to a worse prognosis

De novo variants predicting haploinsufficiency for DIP2C are associated with expressive speech delay.

The disconnected (disco)-interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase-associated protein 1 (DMAP1) binding domain, Acyl-CoA synthetase domain and AMP-binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues in vertebrates, Disco-interacting protein 2 homolog A (DIP2A), Disco-interacting protein 2 homolog B (DIP2B), and Disco-interacting protein 2 homolog C (DIP2C), are highly conserved and expressed widely in the central nervous system. Although there is evidence that DIP2C plays a role in cognition, reports of pathogenic variants in these genes are rare and their significance is uncertain. We present 23 individuals with heterozygous DIP2C variants, all manifesting developmental delays that primarily affect expressive language and speech articulation. Eight patients had de novo variants predicting loss-of-function in the DIP2C gene, two patients had de novo missense variants, three had paternally inherited loss of function variants and six had maternally inherited loss-of-function variants, while inheritance was unknown for four variants. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects, and bicuspid aortic valve). Minor facial anomalies were inconsistent but included a high anterior hairline with a long forehead, broad nasal tip, and ear anomalies. Brainspan analysis showed elevated DIP2C expression in the human neocortex at 10-24 weeks after conception. With the cases presented herein, we provide phenotypic and genotypic data supporting the association between loss-of-function variants in DIP2C with a neurocognitive phenotype

Development and Validation of a New Prognostic System for Patients with Hepatocellular Carcinoma

Background: Prognostic assessment in patients with hepatocellular carcinoma (HCC) remains controversial. Using the Italian Liver Cancer (ITA.LI.CA) database as a training set, we sought to develop and validate a new prognostic system for patients with HCC. Methods and Findings: Prospective collected databases from Italy (training cohort, n = 3,628; internal validation cohort, n = 1,555) and Taiwan (external validation cohort, n = 2,651) were used to develop the ITA.LI.CA prognostic system. We first defined ITA.LI.CA stages (0, A, B1, B2, B3, C) using only tumor characteristics (largest tumor diameter, number of nodules, intra- and extrahepatic macroscopic vascular invasion, extrahepatic metastases). A parametric multivariable survival model was then used to calculate the relative prognostic value of ITA.LI.CA tumor stage, Eastern Cooperative Oncology Group (ECOG) performance status, Child–Pugh score (CPS), and alpha-fetoprotein (AFP) in predicting individual survival. Based on the model results, an ITA.LI.CA integrated prognostic score (from 0 to 13 points) was constructed, and its prognostic power compared with that of other integrated systems (BCLC, HKLC, MESIAH, CLIP, JIS). Median follow-up was 58 mo for Italian patients (interquartile range, 26–106 mo) and 39 mo for Taiwanese patients (interquartile range, 12–61 mo). The ITA.LI.CA integrated prognostic score showed optimal discrimination and calibration abilities in Italian patients. Observed median survival in the training and internal validation sets was 57 and 61 mo, respectively, in quartile 1 (ITA.LI.CA score ≤ 1), 43 and 38 mo in quartile 2 (ITA.LI.CA score 2–3), 23 and 23 mo in quartile 3 (ITA.LI.CA score 4–5), and 9 and 8 mo in quartile 4 (ITA.LI.CA score > 5). Observed and predicted median survival in the training and internal validation sets largely coincided. Although observed and predicted survival estimations were significantly lower (log-rank test, p < 0.001) in Italian than in Taiwanese patients, the ITA.LI.CA score maintained very high discrimination and calibration features also in the external validation cohort. The concordance index (C index) of the ITA.LI.CA score in the internal and external validation cohorts was 0.71 and 0.78, respectively. The ITA.LI.CA score’s prognostic ability was significantly better (p < 0.001) than that of BCLC stage (respective C indexes of 0.64 and 0.73), CLIP score (0.68 and 0.75), JIS stage (0.67 and 0.70), MESIAH score (0.69 and 0.77), and HKLC stage (0.68 and 0.75). The main limitations of this study are its retrospective nature and the intrinsically significant differences between the Taiwanese and Italian groups. Conclusions: The ITA.LI.CA prognostic system includes both a tumor staging—stratifying patients with HCC into six main stages (0, A, B1, B2, B3, and C)—and a prognostic score—integrating ITA.LI.CA tumor staging, CPS, ECOG performance status, and AFP. The ITA.LI.CA prognostic system shows a strong ability to predict individual survival in European and Asian populations

Extra-axial anaplastic astroblastoma in a 67-year-old woman

Astroblastoma is a rare glial neoplasia of the central nervous system. It is histologically defined by the presence of neoplastic cells with non- or slightly tapering processes arranged around blood vessels (astroblastic rosettes) and conventionally subdivided into well-differentiated and anaplastic. It commonly affects children and young adults, although cases and due to its superficial location in the brain cortex, it can mimic an extra-axial mass on magnetic resonance imagining. Herein, we describe a unique case of pure extra-axial anaplastic astroblastoma in an elderly woman. Awareness that astroblastoma may be also extra-axial and affect older subjects, may be helpful for its identification and differential diagnosis toward more common entities at this site and age of onset, and for appropriate therapeutic management as well

Hearing Restoration During Vestibular Schwannoma Surgery With Transcanal Approach: Anatomical and Functional Preliminary Report

Objective: Hearing restoration has always been a dream in vestibular schwannoma (VS) surgery. The aim of this study is to describe an endoscopic assisted transcanal retrocochlear approach to the internal auditory canal (IAC) with total removal of the VS; simultaneously we assessed the anatomical and functional aspects of hearing restoration with cochlear implant (CI). Study Design: A retrospective case series. Setting: Tertiary referral center. Patients: Six patients affected by VS involving the fundus of the IAC (Koos stage I\u2013II) were included in this study. The patients already demonstrated symptoms of IAC involvement by the neuroma, with severe to profound hearing loss. Interventions: Transcanal microscopic, endoscopic assisted, approach was chosen for total tumor removal. Preoperative and intraoperative electrophysiological monitoring was performed using electrically evoked auditory brainstem responses (EABR) to evaluate preservation of cochlear function.Main Outcome and Measures: A retrospective evaluation of electrophysiological data collected during surgeries has been conducted; clinical outcomes, surgical complications, and postoperative radiological evaluations were also considered. Results: Total tumor removal was achieved in all patients with no major complications. One patient showed temporary facial palsy (HB stage II). We were able to preserve cochlear function in five out of six patients. In those patients intraoperative monitoring with EABR was performed after tumor removal with good responses. Conclusions: Transcanal retrocochlear approach for VS removal allows preservation of cochlea and cochlear nerve function. This is the first step towards developing an effective surgical technique for VS removal and hearing rehabilitation with CI

Response to Letter to The Editor "Transcanal Transpromontorial Approach to Vestibular Schwannoma: Are We There Yet?"

To the Editor: We are glad to see the interest always shown by the authors of the Letter towards our work through years. Some observations must be clarified, as they appear related to the author's misunderstanding of our article content and of the surgical technique adopted

CNS tumor with CREBBP::BCORL1 Fusion and pathogenic mutations in BCOR and CREBBP: expanding the spectrum of BCOR-altered tumors

: The fifth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors introduced the new tumor type CNS tumor with BCOR internal tandem duplication (ITD), characterized by a distinct DNA methylation profile and peculiar histopathological features, including a circumscribed growth pattern, ependymoma-like perivascular pseudorosettes, microcystic pattern, absent or focal GFAP immunostaining, OLIG2 positivity, and BCOR immunoreactivity. We describe a rare case of a CNS tumor in a 45-year-old man with histopathological and immunohistochemical features overlapping the CNS tumor with BCOR internal tandem duplication (ITD) but lacking BCOR immunostaining and BCOR ITD. Instead, the tumor showed CREBBP::BCORL1 fusion and pathogenic mutations in BCOR and CREBBP, along with a DNA methylation profile matching the "CNS tumor with EP300:BCOR(L1) fusion" methylation class. Two CNS tumors with fusions between CREBBP, or its paralog EP300, and BCORL1, and approximately twenty CNS tumors with CREBBP/EP300::BCOR fusions have been reported to date. They exhibited similar ependymoma-like features or a microcystic pattern, along with focal or absent GFAP immunostaining, and shared the same DNA methylation profile. Given their morphological and epigenetic similarities, circumscribed CNS tumors with EP300/CREBBP::BCOR(L1) fusions and CNS tumors with BCOR ITD may represent variants of the same tumor type. The ependymoma-like aspect coupled with the lack of diffuse GFAP immunostaining and the presence of OLIG2 positivity are useful clues for recognizing these tumors in histopathological practice. The diagnosis should be confirmed after testing for BCOR(L1) gene fusions and BCOR ITD

Transcanal Transpromontorial Acoustic Neuroma Surgery: Results and Facial Nerve Outcomes

Background: Recently, the transcanal approach for the removal of acoustic neuromas has been introduced. Facial nerve (FN) preservation is one of the main challenges of this kind of surgery. Objective: To describe our experience in the surgical treatment of acoustic neuromas, focusing on the functional results of FN preservation after a transcanal approach. Methods: A retrospective chart review was carried out on clinical data and videos from operations on 49 patients who underwent surgery with a totally transcanal exclusive endoscopic approach for Koos stage I-II lesions, or an enlarged transcanal transpromontorial approach for Koos stage II-III tumors, between March 2012 and February 2017. Patients and tumor characteristics, clinical manifestations, radiologic features, audiological results, FN outcomes (according to the House-Brackmann [HB] grading system) and complications were evaluated. Tumors were classified according to the Koos grading system. Results: The age of the patients (34 females and 15 males) ranged from 27 to 77 years (mean age: 54.9 yr). Preoperative diagnosis was "vestibular schwannoma" in all patients. At the last follow-up (range 1-60 mo, mean 13.9 mo), 42 of 49 showed grade I HB FN function, 5 of 49 grade II HB, and 2 of 49 grade III HB. Overall, in 95.9%, FN function was preserved (grade I-II HB) with stable results at follow-up; in 4.1% of cases, FN function was reduced, but not worse than grade III. Conclusion: The transcanal approach represents a feasible, minimally invasive, and conservative technique for the management of acoustic neuromas of the internal auditory canal

Gamma Knife radiosurgery in skull base meningiomas. Preliminary experience with 50 cases

Gamma Knife radiosurgery was performed on 50 patients (10 males and 40 females) with skull base meningiomas (SBMs) between February 1993 and September 1995. The patients ranged in age from 25 to 78 years (mean age 56 years). The location of the tumors was anterior fossa (n = 4), sphenoorbital (n = 2), sellar region (n = 5), cavernous sinus (n = 26), petroclival (n = 12), and occipital foramen (n = 1). The tumor volume ranged from 0.6 to 20 cm3 (mean 8.6 cm3). The mean values for dose planning were edge isodose (EI) 46.7%, edge dose (ED) 18.0 Gy, maximum dose 39.8 Gy, average dose (AD) 25.4 Gy, and average number of isocentres 5.7. The patients were analyzed for five parameters: tumor volume ( or = 7.5 cm3); EI ( or = 50%); ED ( or = 18 Gy); AD ( or = 25 Gy), and primary versus residual or recurrent tumors. The overall frequency of tumor growth control (TGC) was 98%, with 1- and 2-year TGC rates of 97% and 100%, respectively. The most favorable neurological results were obtained with a tumor volume or = 50% (NS), ED > or = 18 Gy (NS) and with primary SBMs (p or = 7.5 cm3 (100% TGC rate), EI or = 18 Gy (100%), AD > 25 Gy (100%), in both primary SBMs (100%) and residual or recurrent SBMs (96.5%). To date, only 3 (6%) of the 50 patients have presented signs of neurological worsening related to the Gamma Knife radiosurgery. While no early complications were noted, neuroradiological follow-up did show delayed transient imaging complications (3 edema and 1 radionecrosis; 8% of all patients). In conclusion, our preliminary results seem to confirm that Gamma Knife radiosurgery is an effective and safe adjuvant or a feasible alternative primary treatment in controlling or preventing SBM progression