Guillaume Gauchotte

Respiratory epithelial adenomatoid hamartoma of the nose: an updated review.

Background This study was designed to update clinical and imaging features as well as treatment outcomes of the nasal respiratory epithelial adenomatoid hamartoma (REAH). Data sources included case reports, original articles, and reviews published in English or French in PubMed from 1995 to date. Methods Only published articles that met Wenigs histological criteria for the diagnosis of REAH were included. Results REAH is not rare and is probably underdiagnosed. It is usually observed in the fifth decade of life with a 3:2 male/female predilection. REAH can be represented in two forms: as an isolated lesion (less frequent) or in association with an inflammatory process (especially nasal polyposis). It was observed in 35–48% of patients undergoing endoscopic endonasal surgery for nasal polyposis. Its origin is found, in most cases, in the olfactory cleft, which is exhibited on computed tomography (CT) scans by widened opacified olfactory clefts without bone erosion. Resection of REAH from the olfactory clefts does not worsen, but instead, can improve the sense of smell after surgery. Conclusion Looking for REAH on CT scans and during endoscopic examination can lead to its diagnosis and help avoid aggressive surgical procedures and their complications. Endoscopic resection is the treatment of choice. The removal of REAH constitutes a specific surgery on the olfactory clefts, which can improve nasal obstruction as well as sense of smell. Whether REAH can be defined as a hamartoma, an inflammatory reactive process, or a neoplastic lesion remains to be determined.

Evidence for BRAF V600E and H3F3A K27M double mutations in paediatric glial and glioneuronal tumours

In this short report, we describe three interesting cases of paediatric glial and glioneuronal tumours harbouring both BRAF V600E and H3F3A K27M mutations. Low grade gliomas and glioneuronal tumours (LGG and LGGNT) are the most common paediatric central nervous system (CNS) neoplasms. They include in particular World Health Organization (WHO) grade I pilocytic astrocytomas (PAs), grade II pleomorphic xanthoastrocytomas (PXAs) and gangliogliomas (GGs). Despite their slow growth, incomplete, surgically resected tumours can relapse and cause considerable morbidity and premature death. Recent molecular studies reported that PXA and GG display BRAF V600E mutation [1–3], whereas PA are mainly characterized by KIAA1549:BRAF fusion genes [4–6]; both alterations constitutively activate the BRAF/MEK signalling pathway. In contrast, mutations in H3F3A gene (especially the H3F3A K27M mutation) encoding for histone H3.3, commonly occur in diffuse paediatric high-grade gliomas (HGGs), including diffuse intrinsic pontine gliomas and glioblastomas that preferentially arise at midline locations and carry a dismal prognosis [7–10]. According to recent data, H3F3A K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumourigenesis [11]. Two recent studies, conducted by the same consortium involved in the Paediatric Cancer Genome Project, reported cases with BRAF V600E and H3F3A K27M double mutation; one was reported in a study focused on whole-genome sequencing of paediatric LGG [12] and the other was described by analysing the genomic landscape of paediatric HGG [13]. These results indicate some overlap between the genetic alterations of paediatric LGG and HGG. Here, BRAF and H3F3A mutations were assessed in a small set of LGG and LGGNT diagnosed as PXA, GG and unclassified glial/glioneuronal tumours, and we report three new cases with BRAF V600E and H3F3A K27M double mutation. Clinical characteristics and follow-up of these patients are detailed. Patients’ main clinical and molecular data are summarized in Table 1. Tumours of 25 patients (age at diagnosis less than 20 years) were centrally reviewed by the French Groupe d’Etude en Neuropathologie Oncologique Pédiatrique (GENOP) network and were included in this retrospective study. They encompassed PXAs (five cases), GGs (eight cases) and 12 cases reported as unclassified glial/ glioneuronal tumours for which precise diagnosis remained difficult. Nevertheless, the GENOP discussed various possible diagnoses for these cases; they are reported in Table 1. All patients underwent surgery between 2002 and 2011. For all patients, the following clinical data were collected: age at diagnosis, sex, tumour location and follow-up (date of relapse, date of last medical examination and clinical status at last medical examination). Tumour specimens were obtained according to a protocol approved by the local institutional review board and ethics committee and conducted according to the national regulations. All patients included in this study have provided their written consent. In all cases, surgical specimens were fixed in formalin and embedded in paraffin. Areas of viable and representative tumour were selected and marked by a pathologist (DFB). Then tumour DNA was extracted, and DNA sequences were analysed as previously described [3]. Because of their rarity, pathological diagnosis of paediatric tumours of the CNS may be highly challenging. Therefore, a group of referent paediatric neuropathologists was formed in France (GENOP) with the aim of harmonizing neuropathological diagnosis of these tumours. For our 12 cases in which diagnosis was difficult, the GENOP central review allowed the distinction between diffuse and circumscribed glioma and between benign and malignant tumours, and a better recognition *Both authors equally contributed to this work.

Skin wounds vitality markers in forensic pathology: An updated review.

Wound age evaluation is one of the most challenging issues in forensic pathology. In the first minutes or hours, standard histological examination may not determine whether the wound was inflicted in the pre- or post-mortem period. While red blood cell infiltration is classically considered as a sign of vital reaction, several studies have shown that extravasation of blood cells may also occur after death and cannot be used as a reliable marker in the diagnosis of wound vitality. Numerous studies about wound vitality are available in the literature. They have evaluated markers involved in coagulation or inflammation, using various methods such as enzymology, molecular biology or immunohistochemistry. In this update, we first introduce some methodological principles. Then, we review the main studies available in the literature. Immunohistochemistry seems to be the most valuable method, given its easy application and the possibility to analyse the localization of the molecules of interest. Some markers are promising, such as CD15, TNFα, IL-6, IL-1β, TGFα or TGFβ1. Prior to their application in daily practice, these early results need to be confirmed with other studies, conducted by independent teams and integrating multiple controls. Most notably, the antibodies have to be tested in numerous post-mortem wounds. Indeed, a critical risk of overexpression in post-mortem wounds is present. Some promising markers have been later invalidated because of post-mortem false positivity. Finally, optimal sensitivity and specificity values could probably be reached by combining several markers, validated by large groups of pre- and post-mortem wounds.

Methyl(R217)HuR and MCM6 are inversely correlated and are prognostic markers in non small cell lung carcinoma.

OBJECTIVES In non small cell lung carcinoma (NSCLC), earlier studies supported a prognostic value of intra-cytoplasmic HuR expression. HuR is a RNA binding protein previously shown to stimulate proliferation, but the link between HuR and proliferation in NSCLC has not yet been evaluated. The first objective of this study was to analyze the expression of HuR in a series of NSCLC and to correlate this to two proliferation markers, Ki-67 and MCM6. As potential post-transcriptional regulatory mechanisms for HuR expression, two miRNAs, miR16 and miR519, were also analyzed. Finally, because HuR methylation could be involved in its nucleocytoplasmic shuttling, the expression of methyl(R217)HuR and its relation to cancer survival were determined. MATERIALS AND METHODS Immunohistochemistry was used to evaluate the expression of HuR, methy(R217)HuR, Ki-67 and MCM6 in a series of 190 NSCLCs. The level of miR16 and miR519 was determined by qRT-PCR. RESULTS Higher cytoplasmic HuR staining was found in tumor vs. control paired normal lung (p<0.0001), but without correlation with survival. The level of methyl(R217)HuR was correlated both significantly with intra-cytoplasmic HuR staining (p<0.001), and overall survival (p=0.01). MCM6 correlated to a poorer overall survival (p<0.01). Both MCM6 and Ki-67 were positively correlated with HuR nuclear staining (p<0.0001 and p<0.001, respectively). On the contrary, MCM6 and Ki-67 correlated inversely to methyl(R217)HuR (p<0.001 and p=0.01, respectively). The levels of miR16 and miR519 were significantly lower in tumor tissue vs. paired normal lung (p<0.0001), but only miR519 correlated inversely to HuR expression (p=0.01). CONCLUSION While overall cytoplasmic HuR level was higher in tumor tissues, we found unexpectedly that methyl(R217)HuR was a marker of good prognosis. Furthermore, our data suggest that HuR level could be regulated by miR519. Finally, we demonstrated that Ki-67 and MCM6, both correlated with HuR, are valuable markers of poor prognosis in NSCLC.

Predictors of respiratory epithelial adenomatoid hamartomas of the olfactory clefts in patients with nasal polyposis.

To look for predictors of respiratory epithelial adenomatoid hamartomas (REAH) development in patients operated for nasal polyposis (NP) by adjusting on confounding factors.

Impact of uterine balloon tamponade on the use of invasive procedures in severe postpartum hemorrhage

The aim of this study was to assess the impact of tamponade when uterotonic agents fail, on the need for surgery or interventional radiology.

Interactions between glioma and pregnancy: insight from a 52-case multicenter series.

OBJECTIVE The goal of this study was to provide insight into the influence of gliomas on gestational outcomes, the impact of pregnancy on gliomas, and the identification of patients at risk. METHODS In this multiinstitutional retrospective study, the authors identified 52 pregnancies in 50 women diagnosed with a glioma. RESULTS For gliomas known prior to pregnancy (n = 24), we found the following: 1) An increase in the quantified imaging growth rates occurred during pregnancy in 87% of cases. 2) Clinical deterioration occurred in 38% of cases, with seizures alone resolving after delivery in 57.2% of cases. 3) Oncological treatments were immediately performed after delivery in 25% of cases. For gliomas diagnosed during pregnancy (n = 28), we demonstrated the following: 1) The tumor was discovered during the second and third trimesters in 29% and 54% of cases, respectively, with seizures being the presenting symptom in 68% of cases. 2) The quantified imaging growth rates did not significantly decrease after delivery and before oncological treatment. 3) Clinical deterioration resolved after delivery in 21.4% of cases. 4) Oncological treatments were immediately performed after delivery in 70% of cases. Gliomas with a high grade of malignancy, negative immunoexpression of alpha-internexin, or positive immunoexpression for p53 were more likely to be associated with tumor progression during pregnancy. Deliveries were all uneventful (cesarean section in 54.5% of cases and vaginal delivery in 45.5%), and the infants were developmentally normal. CONCLUSIONS When a woman harboring a glioma envisions a pregnancy, or when a glioma is discovered in a pregnant patient, the authors suggest informing her and her partner that pregnancy may impact the evolution of the glioma clinically and radiologically. They strongly advise a multidisciplinary approach to management. ■ CLASSIFICATION OF EVIDENCE Type of question: association; study design: case series; evidence: Class IV.

Cytoplasmic overexpression of RNA-binding protein HuR is a marker of poor prognosis in meningioma, and HuR knockdown decreases meningioma cell growth and resistance to hypoxia

HuR regulates cytoplasmic mRNA stability and translatability, and the HuR expression level has been shown to correlate with poor disease outcome in several cancer types; however, the prognostic value and potential pro‐oncogenic properties of HuR in meningioma remain unclear. Thus, in the present study, we analysed 85 meningioma tissue samples to establish the relationship between HuR expression, tumour cell proliferation, and/or patient survival. In addition, we examined the anti‐proliferative effects of HuR knockdown in two meningioma cell lines (IOMM‐Lee and Ben‐Men‐1) and conducted transcriptome‐wide analyses (IOMM‐Lee cells) to elucidate the molecular consequences of HuR knockdown. The results of the present study showed HuR cytoplasmic expression to correlate positively with tumour grade (p = 1.2 × 10−8) and negatively with progression‐free and overall survival (p = 0.01) time in human meningioma tissues. In vitro, siHuR‐induced HuR knockdown was shown to reduce the growth of both Ben‐Men‐1 (p = 2 × 10−8) and IOMM‐Lee (p = 4 × 10−9) cells. Transcriptome analyses revealed HuR knockdown in IOMM‐Lee cells to deregulate the HIF1A signalling pathway (p = 1.5 × 10−6) and to up‐regulate the expression of genes essential for the assembly of the cytoplasmic mRNA processing body, global genome nucleotide‐excision repair, poly(A)‐specific ribonuclease activity, the positive regulation of apoptosis and of cell cycle arrest, and the negative regulation of RNA splicing [p(FDR) < 0.001]. Interestingly, HuR knockdown under hypoxic culture conditions further potentiated the effects of HuR knockdown on cell growth, apoptosis, and HIF1A expression. We thus conclude that cytoplasmic HuR expression is a marker of poor prognosis in meningioma and that HuR is a promising potential therapeutic target for use in tumours refractory to standard therapies. Copyright

Natural course and prognosis of anaplastic gangliogliomas: a multicenter retrospective study of 43 cases from the French Brain Tumor Database

Background Anaplastic gangliogliomas (GGGs) are rare tumors whose natural history is poorly documented. We aimed to define their clinical and imaging features and to identify prognostic factors. Methods Consecutive cases of anaplastic GGGs in adults prospectively entered into the French Brain Tumor Database between March 2004 and April 2014 were screened. After diagnosis was confirmed by pathological review, clinical, imaging, therapeutic, and outcome data were collected retrospectively. Results Forty-three patients with anaplastic GGG (median age, 49.4 y) from 18 centers were included. Presenting symptoms were neurological deficit (37.2%), epileptic seizure (37.2%), or increased intracranial pressure (25.6%). Typical imaging findings were unifocal location (94.7%), contrast enhancement (88.1%), central necrosis (43.2%), and mass effect (47.6%). Therapeutic strategy included surgical resection (95.3%), adjuvant radiochemotherapy (48.8%), or radiotherapy alone (27.9%). Median progression-free survival (PFS) and overall survival (OS) were 8.0 and 24.7 months, respectively. Three- and 5-year tumor recurrence rates were 69% and 100%, respectively. The 5-year survival rate was 24.9%. Considering unadjusted significant prognostic factors, tumor midline crossing and frontal location were associated with shorter OS. Temporal and parietal locations were associated with longer and shorter PFS, respectively. None of these factors remained statistically significant in multivariate analysis. Conclusions We report a large series providing clinical, imaging, therapeutic, and prognostic features of adult patients treated for an intracerebral anaplastic GGG. Our results show that pathological diagnosis is difficult, that survivals are only slightly better than for glioblastomas, and that complete surgical resection followed with adjuvant chemoradiotherapy offers longer survival.

Une vascularite isolée du col et de l'isthme utérins

Isolated lesions of vasculitis are described in different organs, notably female genital tract. Exhaustive clinic and paraclinic exams are necessary to exclude an occult systemic vasculitis. We report a case of vasculitis that was restricted to uterine cervix and isthmus, fortuitously discovered by a 45-years-old woman after hysterectomy. At histological examination, necrotizing vasculitis of small and medium-sized arteries was found, suggesting diagnosis of polyarteritis nodosa. There was no argument for systemic vasculitis.