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Competing Interests: The authors declare no conflict of interest.

Background: Post-mortem studies can provide important information for understanding new diseases and small autopsy case series have already reported different findings in COVID-19 patients., Methods: We evaluated whether some specific post-mortem features are observed in these patients and if these changes are related to the presence of the virus in different organs. Complete macroscopic and microscopic autopsies were performed on different organs in 17 COVID-19 non-survivors. Presence of SARS-CoV-2 was evaluated with immunohistochemistry (IHC) in lung samples and with real-time reverse-transcription polymerase chain reaction (RT-PCR) test in the lung and other organs., Results: Pulmonary findings revealed early-stage diffuse alveolar damage (DAD) in 15 out of 17 patients and microthrombi in small lung arteries in 11 patients. Late-stage DAD, atypical pneumocytes, and/or acute pneumonia were also observed. Four lung infarcts, two acute myocardial infarctions, and one ischemic enteritis were observed. There was no evidence of myocarditis, hepatitis, or encephalitis. Kidney evaluation revealed the presence of hemosiderin in tubules or pigmented casts in most patients. Spongiosis and vascular congestion were the most frequently encountered brain lesions. No specific SARS-CoV-2 lesions were observed in any organ. IHC revealed positive cells with a heterogeneous distribution in the lungs of 11 of the 17 (65%) patients; RT-PCR yielded a wide distribution of SARS-CoV-2 in different tissues, with 8 patients showing viral presence in all tested organs (i.e., lung, heart, spleen, liver, colon, kidney, and brain)., Conclusions: In conclusion, autopsies revealed a great heterogeneity of COVID-19-associated organ injury and the remarkable absence of any specific viral lesions, even when RT-PCR identified the presence of the virus in many organs.

Background: Lymphocytic variant hypereosinophilic syndrome is characterized by marked over-production of eosinophilopoietic factor(s) by dysregulated T cells leading to eosinophil expansion. In most cases, these T cells are clonal and express a CD3 - CD4 + phenotype. As this is a rare disorder, presenting manifestations, disease course, treatment responses, and outcome are not well-characterized. Materials and Methods: In this retrospective single-center observational study, we reviewed medical files of all patients with persistent hypereosinophilia seen between 1994 and 2019 in whom CD3 - CD4 + T cells were detected. Data collection included clinical and biological findings at presentation, treatment responses, disease course, and serial CD3 - CD4 + T cell counts. Results: Our cohort comprises 26 patients, including 2 with hypereosinophilia of undetermined significance. All 24 symptomatic patients had cutaneous lesions and/or angioedema, and fasciitis was present in several cases. The aberrant T cell subset represented 2% or less total lymphocytes in 11 subjects. TCR gene rearrangement patterns on whole blood were polyclonal in these cases, while they all had serum CCL17/TARC levels above 1,500 pg/ml. Disease manifestations were mild and did not require maintenance therapy in roughly one third of the cohort, while two thirds required long-term oral corticosteroids and/or second-line agents. Among these, interferon-alpha was the most effective treatment option with a response observed in 8/8 patients, one of whom was cured of disease. Treatment had to be interrupted in most cases however due to poor tolerance and/or development of secondary resistance. Anti-interleukin-5 antibodies reduced blood eosinophilia in 5/5 patients, but clinical responses were disappointing. A sub-group of 5 patients had severe treatment-refractory disease, and experienced significant disease- and treatment-related morbidity and mortality, including progression to T cell lymphoma in three. Conclusions: This retrospective longitudinal analysis of the largest monocentric cohort of CD3 - CD4 + T cell associated lymphocytic variant hypereosinophilic syndrome published so far provides clinicians confronted with this rare disorder with relevant new data on patient presentation and outcome that should help tailor therapy and follow-up to different levels of disease severity. It highlights the need for novel therapeutic options, especially for the subset of patients with severe treatment-refractory disease. Future research efforts should be made toward understanding CD3 - CD4 + T cell biology in order to develop new treatments that target primary pathogenic mechanisms., (Copyright © 2020 Carpentier, Verbanck, Schandené, Heimann, Trépant, Cogan and Roufosse.)

Aims: Glioblastoma (GBM) is the most common and lethal malignant brain tumor in adults. Glioma stem cells (GSCs) are implicated in this poor prognosis and in radio(chemo-)resistance. We have previously demonstrated that among potentially highly specific GSC markers oligodendrocyte lineage transcription factor 2 (OLIG2) appears to be the most specific and cyclin D2 (CCND2) the only one related to cell cycle regulation. The purpose of this work was to investigate the clinical significance and the evolution of OLIG2 and CCND2 protein expression in GBM., Methods and Results: Immunohistochemical expression analysis of Olig2 and Ccnd2 was carried out on a cohort of human paired GBM samples comparing initial resections with local recurrent tumors after radiation therapy (RT) alone or radio-chemotherapy with temozolomide (RT-TMZ). Uni- and multivariate logistic regression analysis revealed that significant risk factors predicting early mortality (<12 months) are: subtotal surgery for recurrence, time to recurrence <6 months, Ccnd2 nuclear expression at initial surgery ≥30%, and Olig2 nuclear expression <30% at second surgery after RT alone and RT-TMZ., Conclusions: We demonstrated that patients for whom nuclear expression of Olig2 becomes low (<30%) after adjuvant treatments have a significantly shorter time to recurrence and survival reflecting most probably a proneural to mesenchymal transition of the GSCs population. We also highlighted the fact that at initial surgery, high nuclear expression (≥30%) of CCND2, a G1/S regulator specific of GSCs, has a prognostic value and is associated with early mortality (<12 months)., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Four-and-a-half LIM-domain protein 2 (FHL2) is a multifunctional scaffolding protein regulating signalling cascades and gene transcription. It shuttles between focal adhesions and the nucleus where it signals through direct interaction with a number of proteins including β-catenin. The multiplicity of molecular pathways affected by FHL2 suggests an important role in several physiological and pathological events. The function of FHL2 in cancer is particularly intriguing, since it may act as an oncoprotein or as a tumour suppressor in a tissue-dependent fashion. In this review we present the current knowledge on the role of FHL2 in carcinogenesis, with emphasis on the digestive tract. We discuss the overexpression of FHL2 in colorectal, gastric and pancreatic cancer, the downregulation in hepatocellular carcinoma and the role of FHL2 in epithelial-mesenchymal transition. We briefly look at the potential role of FHL2 in the tumoural microenvironment and discuss how FHL2 expression and function might influence cancer treatment. Before implementation of FHL2 as a biomarker by pathologists, antibody validation should, however, be carried out.

Background: Glioblastomas (GBMs) are the most common malignant primary brain tumours in adults and are refractory to conventional therapy, including surgical resection, radiotherapy and chemotherapy. The insulin-like growth factor (IGF) system is a complex network that includes ligands (IGFI and IGFII), receptors (IGF-IR and IGF-IIR) and high-affinity binding proteins (IGFBP-1 to IGFBP-6). Many studies have reported a role for the IGF system in the regulation of tumour cell biology. However, the role of this system remains unclear in GBMs., Methods: We investigate the prognostic value of both the IGF ligands' and receptors' expression in a cohort of human GBMs. Tissue microarray and image analysis were conducted to quantitatively analyse the immunohistochemical expression of these proteins in 218 human GBMs., Results: Both IGF-IR and IGF-IIR were overexpressed in GBMs compared with normal brain (P<10(-4) and P=0.002, respectively). Moreover, with regard to standard clinical factors, IGF-IR positivity was identified as an independent prognostic factor associated with shorter survival (P=0.016) and was associated with a less favourable response to temozolomide., Conclusions: This study suggests that IGF-IR could be an interesting target for GBM therapy.

Despite advances in surgical and adjuvant treatments, overall survival of glioblastoma (GBM) patients remains poor. The cancer stem cell concept suggests that a rare stem cell population, called glioma stem cells (GSCs), has high ability to self-renewal leading to recurrence in GBM. The identification of specific markers of GSCs would provide a powerful tool to detect and to characterise them in order to develop targeted therapies. We carried out a comparative analysis based on the identification of inter-study concordances to identify the genes that exhibit at best differential levels of expression between GSC-enriched cell cultures and differentiated tumour cell cultures from independent studies using DNA chip microarray technologies. We finally studied the protein expression of the marker we considered the most specific by immunohistochemistry and semi-quantitative analysis on a retrospective series of 18 GBMs. Of the selected studies, 32 genes were retained. Among them, eight genes were identified to be overexpressed in GSC-enriched cultures compared to differentiated tumour cell cultures. Finally, among the eight genes, oligodendrocyte lineage transcription factor 2 (OLIG2) was characterised by the most different expression level in the "GSC model" compared to the "differentiated tumour cells model". Our approach suggests that OLIG2 is the most specific GSC marker; additional investigations with careful considerations about methodology and strategies of validation are, however, mandatory.

Background and Objective: Extracting accurate information from complex biological processes involved in diseases, such as cancers, requires the simultaneous targeting of multiple proteins and locating their respective expression in tissue samples. This information can be collected by imaging and registering adjacent sections from the same tissue sample and stained by immunohistochemistry (IHC). Registration accuracy should be on the scale of a few cells to enable protein colocalization to be assessed., Methods: We propose a simple and efficient method based on the open-source elastix framework to register virtual slides of adjacent sections from the same tissue sample. We characterize registration accuracies for different types of tissue and IHC staining., Results: Our results indicate that this technique is suitable for the evaluation of the colocalization of biomarkers on the scale of a few cells. We also show that using this technique in conjunction with a sequential IHC labeling and erasing technique offers improved registration accuracies., Discussion: Brightfield IHC enables to address the problem of large series of tissue samples, which are usually required in clinical research. However, this approach, which is simple at the tissue processing level, requires challenging image analysis processes, such as accurate registration, to view and extract the protein colocalization information., Conclusions: The method proposed in this work enables accurate registration (on the scale of a few cells) of virtual slides of adjacent tissue sections on which the expression of different proteins is evidenced by standard IHC. Furthermore, combining our method with a sequential labeling and erasing technique enables cell-scale colocalization., (© The Author 2014. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.comFor numbered affiliations see end of article.)

Male breast cancer is rare. The most common histological subtypes include invasive carcinoma "of no special type" and papillary carcinoma. Other variants, including pure micropapillary carcinoma, have been described as well but are extremely rare. Pure micropapillary carcinoma has been recently characterized by a C-MYC gene amplification in women. We report here, occurring in a 73-year-old man, the first case of pure micropapillary carcinoma with amplification of the C-MYC gene., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Breast myofibroblastomas are rare benign mesenchymal tumors belonging to the group of stromal breast tumors composed of spindle-shaped cells and characterized by a broad morphologic spectrum. Among the different morphologic variants described, breast MFBs can show smooth muscle cell differentiation in very rare cases. In terms of the genetic abnormalities found in this type of tumor, a deletion of chromosome 13q14 was recently confirmed by FISH in some cases of mammary MFB. In this paper, we report an unusual case of MFB with smooth muscle differentiation showing a deletion of chromosome 13q14., (Copyright © 2014 Elsevier GmbH. All rights reserved.)