Safety and efficacy of frameless stereotactic robot-assisted intraparenchymal brain lesion biopsies versus image-guided biopsies: a bicentric comparative study.

PURPOSE: User-friendly robotic assistance and image-guided tools have been developed in the past decades for intraparenchymal brain lesion biopsy. These two methods are gradually becoming well accepted and are performed at the discretion of the neurosurgical teams. However, only a few data comparing their effectiveness and safety are available. METHODS: Population-based parallel cohorts were followed from two French university hospitals with different surgical methods and defined geographical catchment regions (September 2019 to September 2022). In center A, frameless robot-assisted stereotactic intraparenchymal brain lesion biopsies were performed, while image-guided intraparenchymal brain lesion biopsies were performed in center B. Pre-and postoperative clinical, radiological, and histomolecular features were retrospectively collected and compared. RESULTS: Two hundred fifty patients were included: 131 frameless robot-assisted stereotactic intraparenchymal brain lesion biopsies in center A and 119 image-guided biopsies in center B. The clinical, radiological, and histomolecular features were comparable between the two groups. The diagnostic yield (96.2% and 95.8% respectively; p = 1.000) and the overall postoperative complications rates (13% and 14%, respectively; p = 0.880) did not differ between the two groups. The mean duration of the surgical procedure was longer in the robot-assisted group (61.9 ± 25.3 min, range 23-150) than in the image-guided group (47.4 ± 11.8 min, range 25-81, p < 0.001). In the subgroup of patients with anticoagulant and/or antiplatelet therapy administered preoperatively, the intracerebral hemorrhage > 10 mm on postoperative CT scan was higher in the image-guided group (36.8%) than in the robot-assisted group (5%, p < 0.001). CONCLUSION: In our bicentric comparative study, robot-assisted stereotactic and image-guided biopsies have two main differences (shorter time but more frequent postoperative hematoma for image-guided biopsies); however, both techniques are demonstrated to be safe and efficient.

New Histoprognostic Factors to Consider for the Staging of Colon Cancers: Tumor Deposits, Invasive Tumor Infiltration and High-Grade Budding.

Colorectal cancer is a major public health issue due to its high incidence and mortality. It is, therefore, essential to identify histological markers for prognostic purposes and to optimize the therapeutic management of patients. The main objective of our study was to analyze the impact of new histoprognostic factors, such as tumor deposits, budding, poorly differentiated clusters, mode of infiltration, the intensity of inflammatory infiltrate and the type of tumor stroma, on the survival of patients with colon cancer. Two hundred and twenty-nine resected colon cancers were fully histologically reviewed, and survival and recurrence data were collected. Survival was analyzed using Kaplan-Meier curves. A univariate and multivariate Cox model was constructed to identify prognostic factors for overall survival and recurrence-free survival. The median overall survival of the patients was 60.2 months and the median recurrence-free survival was 46.9 months. Overall survival and recurrence-free survival were significantly worse in the presence of isolated tumor deposits (log rank = 0.003 and 0.001, respectively) and for an infiltrative type of tumor invasion (log rank = 0.008 and 0.02, respectively). High-grade budding was associated with a poor prognosis, with no significant difference. We did not find a significant prognostic impact of the presence of poorly differentiated clusters, the intensity of the inflammatory infiltrate or the stromal type. In conclusion, the analysis of these recent histoprognostic factors, such as tumor deposits, mode of infiltration, and budding, could be integrated into the results of pathological reports of colon cancers. Thus, the therapeutic management of patients could be adjusted by providing more aggressive treatments in the presence of some of these factors.

Pediatric spinal pilocytic astrocytomas form a distinct epigenetic subclass from pilocytic astrocytomas of other locations and diffuse leptomeningeal glioneuronal tumours.

Pediatric spinal low-grade glioma (LGG) and glioneuronal tumours are rare, accounting for less 2.8-5.2% of pediatric LGG. New tumour types frequently found in spinal location such as diffuse leptomeningeal glioneuronal tumours (DLGNT) have been added to the World Health Organization (WHO) classification of tumours of the central nervous system since 2016, but their distinction from others gliomas and particularly from pilocytic astrocytoma (PA) are poorly defined. Most large studies on this subject were published before the era of the molecular diagnosis and did not address the differential diagnosis between PAs and DLGNTs in this peculiar location. Our study retrospectively examined a cohort of 28 children with LGGs and glioneuronal intramedullary tumours using detailed radiological, clinico-pathological and molecular analysis. 25% of spinal PAs were reclassified as DLGNTs. PA and DLGNT are nearly indistinguishable in histopathology or neuroradiology. 83% of spinal DLGNTs presented first without leptomeningeal contrast enhancement. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that spinal PAs formed a unique methylation cluster distinct from reference midline and posterior fossa PAs, whereas spinal DLGNTs clustered with reference DLGNT cohort. FGFR1 alterations were found in 36% of spinal tumours and were restricted to PAs. Spinal PAs affected significantly younger patients (median age 2 years old) than DLGNTs (median age 8.2 years old). Progression-free survival was similar among the two groups. In this location, histopathology and radiology are of limited interest, but molecular data (methyloma, 1p and FGFR1 status) represent important tools differentiating these two mitogen-activated protein kinase (MAPK) altered tumour types, PA and DLGNT. Thus, these molecular alterations should systematically be explored in this type of tumour in a spinal location.

The Use of Pro-Angiogenic and/or Pro-Hypoxic miRNAs as Tools to Monitor Patients with Diffuse Gliomas.

IDH (isocitrate dehydrogenase) mutation, hypoxia, and neo-angiogenesis, three hallmarks of diffuse gliomas, modulate the expression of small non-coding RNAs (miRNA). In this paper, we tested whether pro-angiogenic and/or pro-hypoxic miRNAs could be used to monitor patients with glioma. The miRNAs were extracted from tumoral surgical specimens embedded in the paraffin of 97 patients with diffuse gliomas and, for 7 patients, from a blood sample too. The expression of 10 pro-angiogenic and/or pro-hypoxic miRNAs was assayed by qRT-PCR and normalized to the miRNA expression of non-tumoral brain tissues. We confirmed in vitro that IDH in hypoxia (1% O2, 24 h) alters pro-angiogenic and/or pro-hypoxic miRNA expression in HBT-14 (U-87 MG) cells. Then, we reported that the expression of these miRNAs is (i) strongly affected in patients with glioma compared to that in a non-tumoral brain; (ii) correlated with the histology/grade of glioma according to the 2016 WHO classification; and (iii) predicts the overall and/or progression-free survival of patients with glioma in univariate but not in a multivariate analysis after adjusting for sex, age at diagnosis, and WHO classification. Finally, the expression of miRNAs was found to be the same between the plasma and glial tumor of the same patient. This study highlights a panel of seven pro-angiogenic and/or pro-hypoxic miRNAs as a potential tool for monitoring patients with glioma.

Progestin-related WHO grade II meningiomas behavior-a single-institution comparative case series.

WHO grade II progestin-related meningiomas have been reported in recent series but we found no previous study describing their long-term outcome. Our study aimed to evaluate patients operated on for high-grade intracranial meningioma and who underwent long-term exposure to high dose of cyproterone acetate, nomegestrol acetate, and chlormadinone acetate. Our study retrospectively included 9 patients with high-grade progestin-related intracranial meningioma between December 2006 and September 2021. In each patient, clinico-radiological follow-up was performed every 6 months after diagnosis and treatment withdrawal recommendation. The mean progestative exposure was 11.4 years. Edema existence or absence of cleft sign on MRI were the key factors for surgical indication. All patients underwent surgery. Adjuvant radiotherapy was indicated in 1 patient, and Gamma Knife radiosurgery was proposed in 2 other patients for a second location of meningioma. Six patients harbored a grade II chordoid meningioma subtype with 100% PR expression and 3 patients a grade II atypical meningioma subtype with lower PR expression. The mean follow-up was 8.1 years and none of the 9 patients presented with a recurrence. Patients with grade II progestin-related meningiomas have less tumor recurrence after surgery than patients with sporadic grade II meningiomas, especially after progestin withdrawal. The presence/appearance of peri-meningioma edema and the absence of cleft sign before volumetric change should suggest the existence of an underlying WHO grade II meningiomas. In these cases, surgical resection may immediately be considered and adjuvant radiotherapy should be reserved for proven recurrence cases.

Deciphering Promoter Hypermethylation of Genes Encoding for RASSF/Hippo Pathway Reveals the Poor Prognostic Factor of RASSF2 Gene Silencing in Colon Cancers.

The aims of this study were to assess the frequency of promoter hypermethylation of the genes encoding the Ras associated domain family (RASSF)/Hippo pathway, as well as the impact on overall (OS) and progression-free survival (PFS) in a single-center retrospective cohort of 229 patients operated on for colon cancers. Hypermethylation status was investigated by methylation-specific PCR on the promoters of the RASSF1/2, STK4/3 (encoding Mammalian Ste20-like protein 1 and 2 (MST1 and 2), respectively), and LATS1/2 genes. Clinicopathological characteristics, recurrence-free survival, and overall survival were analysed. We found the RASSF/Hippo pathway to be highly silenced in colon cancer, and particularly RASSF2 (86%). The other promoters were hypermethylated with a lesser frequency of 16, 3, 1, 10 and 6%, respectively for RASSF1, STK4, STK3, LATS1, and LATS2 genes. As the hypermethylation of one RASSF/Hippo family member was by no means exclusive from the others, 27% of colon cancers displayed the hypermethylation of at least two RASSF/Hippo member promotors. The median overall survival of the cohort was 60.2 months, and the median recurrence-free survival was 46.9 months. Survival analyses showed a significantly poorer overall survival of patients when the RASSF2 promoter was hypermethylated (p = 0.03). The median OS was 53.5 months for patients with colon cancer with a hypermethylated RASSF2 promoter versus still not reached after 80 months follow-up for other patients, upon univariate analysis (HR = 1.86, [95% CI: 1.05-3.3], p < 0.03). Such difference was not significant for relapse-free survival as in multivariate analysis. A logistic regression model showed that RASSF2 hypermethylation was an independent factor. In conclusion, RASSF2 hypermethylation is a frequent event and an independent poor prognostic factor in colon cancer. This biomarker could be investigated in clinical practice.

Somatic PIK3CA Mutations in Sporadic Cerebral Cavernous Malformations.

BACKGROUND: Cerebral cavernous malformations (CCMs) are common sporadic and inherited vascular malformations of the central nervous system. Although familial CCMs are linked to loss-of-function mutations in KRIT1 (CCM1), CCM2, or PDCD10 (CCM3), the genetic cause of sporadic CCMs, representing 80% of cases, remains incompletely understood. METHODS: We developed two mouse models harboring mutations identified in human meningiomas with the use of the prostaglandin D2 synthase (PGDS) promoter. We performed targeted DNA sequencing of surgically resected CCMs from patients and confirmed our findings by droplet digital polymerase-chain-reaction analysis. RESULTS: We found that in mice expressing one of two common genetic drivers of meningioma - Pik3ca H1047R or AKT1 E17K - in PGDS-positive cells, a spectrum of typical CCMs develops (in 22% and 11% of the mice, respectively) instead of meningiomas, which prompted us to analyze tissue samples from sporadic CCMs from 88 patients. We detected somatic activating PIK3CA and AKT1 mutations in 39% and 1%, respectively, of lesion tissue from the patients. Only 10% of lesions harbored mutations in the CCM genes. We analyzed lesions induced by the activating mutations Pik3ca H1074R and AKT1 E17K in mice and identified the PGDS-expressing pericyte as the probable cell of origin. CONCLUSIONS: In tissue samples from sporadic CCMs, mutations in PIK3CA were represented to a greater extent than mutations in any other gene. The contribution of somatic mutations in the genes that cause familial CCMs was comparatively small. (Funded by the Fondation ARC pour la Recherche contre le Cancer and others.).

Sustained Response and Rationale of Programmed Cell Death-1-Targeting for Progressive Multifocal Leukoencephalopathy.

In this study, we report a complete (clinical, radiological, and virological) sustained (1 year) response after nivolumab salvage therapy in a progressive multifocal leukoencephalopathy patient. Analyses of the cells infiltrate in a pretreatment brain biopsy suggest that parenchymal programmed cell death-L1+ macrophages could be the T-cells partnership in immune exhaustion and virus escape.

Intra-Alveolar Haemorrhage Complicating IgA Vasculitis: A Case Report, Literature Review and Discussion of Treatment.

INTRODUCTION: Immunoglobulin A vasculitis (IgAV) is a small-vessel vasculitis with IgA-dominant immune deposits. IgAV frequently involves the skin, gastrointestinal tract, joints and kidneys. In contrast to other types of small-vessel vasculitis, IgAV is rarely complicated by intra-alveolar haemorrhage (IAH). METHODS/RESULTS: We describe a patient with relapsing bladder cancer who presented with IAH during the course of IgAV successfully treated with corticosteroids alone. CONCLUSION: This case report reminds us that IgAV can manifest with IAH. There are no robust data to support the systematic use of cyclophosphamide or plasma exchange as first-line therapy for IgAV with IAH. LEARNING POINTS: Intra-alveolar haemorrhage in IgA vasculitis is an uncommon but important condition.The treatment strategies for IgA vasculitis and intra-alveolar haemorrhage and their rare association are discussed with reference to the literature.

Contribution of third molar eruption to the estimation of the forensic age of living individuals.

Forensic age estimation of a living individual is frequently performed in clinical forensic medicine. Medicolegal physicians are usually called upon by the authorities to estimate the age of a living person requesting asylum or to determine whether a suspected offender is subject to juvenile or adult criminal law. Dental age is one of the parameters studied to estimate biological age. Several methods are used, and among these, analysis of the eruption of the third molar (M3) on an orthopantomogram (OPG) is one of the common methods. The objective of the study was to analyse the contribution of M3 eruption to age estimation, in particular with regard to the threshold of 18 years of age, in a sample of individuals examined in a French university hospital. The stage of wisdom tooth eruption of all individuals aged between 15 and 24 years, who had an OPG performed between 1 January 2013 and 31 December 2015, was interpreted using a three-stage scoring system. In total, 557 OPGs (340 males and 217 females) were included. None of the stage scores allowed a distinction between minors and majors, for either sex. Overall, 85% of females and 98% of males with four M3s in stage 3 (complete emergence in the occlusal plane) were majors.

Twenty-five years of French jurisprudence in criminal medical liability.

We report on a comprehensive 25-year study on criminal medical liability in France, undertaken to establish trends in the number of cases being brought before the criminal courts. We did this by interrogating the database on the Légifrance website using a Boolean equation (' pénal' (criminal) AND ' médecin' (physician) OR ' docteur' (doctor)). In total 539 cases were selected, in which the status of the physician either influenced the punishment imposed, or was a prerequisite for the commission of the offence. The results of the search produced two outcomes: offences and the dates of the most recent criminal judgements (which had been left blank). Further data were also collected: references to court cases, hearing dates, offence dates, procedural time limits, numbers of accused parties, types of punishments and physician characteristics. The number of court hearings increased from the 1980s until the late 1990s. Since then, it has remained stable at around 25 cases per year. Of the defendants appearing before the courts, 39.2% have been found guilty. On average, 10 to 13 physicians every year - that is, one per month - are punished. Those most often punished are obstetrician-gynaecologists (13%), followed by intensive care anaesthetists (11%) and then by general practitioners (6.7%). The offences most frequently occurring are manslaughter (36.5%), illegal profits (12%), unintentional injuries (11.5%) and sexual offences (10.1%). The results are most reassuring in terms of the risks posed by the practice of medicine in France. Such a risk does indeed exist; however, it is at a low level and stable.

Sudden Death Due to Undiagnosed Rheumatic Heart Disease in a Child.

We report the case of a 5-year-old boy who died from complications of rheumatic heart disease with atypical presentation. He was hospitalized for recent inflammatory and neurological symptoms. He was diagnosed with viral encephalitis. He died the day after he was discharged. The macroscopic autopsy findings were unremarkable. Histology revealed typical rheumatic heart disease. Neuropathology showed cerebral infarction due to an embolic event linked with the rheumatic valvulitis. The cause of death was determined as heart failure due to rheumatic heart disease secondary to an undiagnosed acute rheumatic fever. It is related to an autoimmune response to infection with group A streptococcus. It mainly affects children in developing countries. In our case, viral encephalitis was consistent with the medical history and the proper diagnosis was made on histological analysis. Forensic pathologists should consider this diagnosis facing a sudden unexpected death in childhood, even in industrialized countries.

Is the persistence of an epiphyseal scar of the knee a reliable marker of biological age?

Age estimation of living individuals is a regular activity in medico-legal practice. Among the available tools for determining skeletal age, some authors have stated that the disappearance of epiphyseal scars could be a useful marker. The aim of the present study was to assess whether the presence of an epiphyseal scar on the knee, as seen on a plain X-ray, was linked to biological age. A total of 988 frontal X-rays of individuals (509 females and 479 males) aged between 15 and 40 years were analyzed to see whether a scar was visible or not on each of the three epiphyses of the knee. A scar was visible for 96% of the females and 98% of the males. For each sex, scars were visible at each year of age, from 15 to 40 years. In younger females, there were 15 individuals with no scar visible on the fibula, 16 on the tibia, and 20 on the femur. For males, the ages were respectively 16, 17, and 18 years. On a frontal X-ray, the persistence of epiphyseal scars was not a marker of a recent fusion. All individuals with fully ossified knee that had no scar on the femur were older than 18 years. Further studies focusing on epiphyseal scars on MR and CT scans could be useful, as these techniques allow the more precise analysis of the epiphysis.