Neutrophilic granulocyte-derived B-cell activating factor supports B cells in skin lesions in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by painful inflamed nodules, abscesses, and pus-draining tunnels appearing in axillary, inguinal, and perianal skin areas. HS lesions contain various types of immigrated immune cells. OBJECTIVE: This study aimed to characterize mediators that support lesional B/plasma cell persistence in HS. METHODS: Skin samples from several cohorts of HS patients and control cohorts were assessed by mRNA sequencing, quantitative PCR on reverse-transcribed RNA, flow cytometry, and immunohistofluorescence. Blood plasma and cultured skin biopsy samples, keratinocytes, dermal fibroblasts, neutrophilic granulocytes (neutrophils), monocytes, and B cells were analyzed. Complex systems biology approaches were used to evaluate bulk and single-cell RNA sequencing data. RESULTS: Proportions of B/plasma cells, neutrophils, CD8+ T cells, and M0 and M1 macrophages were elevated in HS lesions compared to skin of healthy and perilesional intertriginous areas. There was an association between B/plasma cells, neutrophils, and B-cell activating factor (BAFF, aka TNFSF13B). BAFF was abundant in HS lesions, particularly in nodules and abscesses. Among the cell types present in HS lesions, myeloid cells were the main BAFF producers. Mechanistically, granulocyte colony-stimulating factor in the presence of bacterial products was the major stimulus for neutrophils' BAFF secretion. Lesional upregulation of BAFF receptors was attributed to B cells (TNFRSF13C/BAFFR and TNFRSF13B/TACI) and plasma cells (TNFRSF17/BCMA). Characterization of the lesional BAFF pathway revealed molecules involved in migration/adhesion (eg, CXCR4, CD37, CD53, SELL), proliferation/survival (eg, BST2), activation (eg, KLF2, PRKCB), and reactive oxygen species production (eg, NCF1, CYBC1) of B/plasma cells. CONCLUSION: Neutrophil-derived BAFF supports B/plasma cell persistence and function in HS lesions.

An integrative approach of digital image analysis and transcriptome profiling to explore potential predictive biomarkers for TGFß blockade therapy.

Increasing evidence suggests that the presence and spatial localization and distribution pattern of tumor infiltrating lymphocytes (TILs) is associate with response to immunotherapies. Recent studies have identified TGFß activity and signaling as a determinant of T cell exclusion in the tumor microenvironment and poor response to PD-1/PD-L1 blockade. Here we coupled the artificial intelligence (AI)-powered digital image analysis and gene expression profiling as an integrative approach to quantify distribution of TILs and characterize the associated TGFß pathway activity. Analysis of T cell spatial distribution in the solid tumor biopsies revealed substantial differences in the distribution patterns. The digital image analysis approach achieves 74% concordance with the pathologist assessment for tumor-immune phenotypes. The transcriptomic profiling suggests that the TIL score was negatively correlated with TGFß pathway activation, together with elevated TGFß signaling activity observed in excluded and desert tumor phenotypes. The present results demonstrate that the automated digital pathology algorithm for quantitative analysis of CD8 immunohistochemistry image can successfully assign the tumor into one of three infiltration phenotypes: immune desert, immune excluded or immune inflamed. The association between "cold" tumor-immune phenotypes and TGFß signature further demonstrates their potential as predictive biomarkers to identify appropriate patients that may benefit from TGFß blockade.

Chemotherapy outcome predictive effectiveness by the Oncogramme: pilot trial on stage-IV colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) remains a major public concern. While conventional chemotherapeutic regimens have proved useful against advanced/metastatic diseases, progresses are to be made to effectively cure the large portion of patients not benefiting from these treatments. One direction to improve response rates is to develop chemosensitivity and resistance assays (CSRAs) efficiently assisting clinicians in treatment selection process, an already long preoccupation of oncologists and researchers. Several methods have been described to this day, none achieving yet sufficient reliability for recommended use in the clinical routine. METHODS: We led a pilot study on 19 metastatic CRC patients evaluating capacity of the Oncogramme, a standardized process using tumor ex vivo models, to provide chemosensitivity profiles and predict clinical outcome of patients receiving standard CRC chemotherapeutics. Oncogramme responses were categorized according to the method of percentiles to assess sensitivity, specificity and concordance. RESULTS: We report from a primary analysis a success rate of 97.4 %, a very good sensitivity (84.6 %), a below-average specificity (33.3 %), along with a global agreement of 63.6 % and a concordance between Oncogramme results and patients' responses (Kappa coefficient) of 0.193. A supplementary analysis, focusing on CRC patients with no treatment switch over a longer time course, demonstrated improvement in specificity and concordance. CONCLUSIONS: Results establish feasibility and usefulness of the Oncogramme, prelude to a larger-scale trial. Advantages and drawbacks of the procedure are discussed, as well as the place of CSRAs within the future arsenal of methods available to clinicians to individualize treatments and improve patient prognosis. TRIAL REGISTRATION: ClinicalTrials.gov database, registration number: NCT02305368.

Study of MET protein levels and MET gene copy number in 72 sinonasal intestinal-type adenocarcinomas.

BACKGROUND: Sinonasal intestinal-type adenocarcinomas (ITACs) have a poor prognosis, and are defined on the basis of their morphological similarities to colorectal adenocarcinomas. MET signaling pathway is involved in oncogenesis in various cancers. Nothing is currently known about the role of MET in ITACs. METHODS: In a series of 72 ITACs, we investigated MET protein levels by immunohistochemistry (IHC) and gene copy number by in situ hybridization. These findings were analyzed as a function of clinical data, histological typing, and patient outcome. RESULTS: MET protein was overproduced in 64% of cases and chromosome 7 polysomy was observed in 52% of cases. No tumor displayed MET amplification. The presence of mucinous or solid histological components, T3/T4 tumors, and incomplete resection were associated with a poor outcome. CONCLUSION: MET is overproduced in about two third of ITACs, suggesting a role for the MET signaling pathway in the oncogenesis of these tumors.

[Two cases reports of pancreatic endocrine microadenoma incidentally found]. / Découverte fortuite de micro-adénome endocrine pancréatique : à propos de deux cas.

A 59-year-old male, was admitted to our hospital for a tumor of the pancreatic tail. Serum CEA and CA 19-9 levels were normal. Splenopancreasectomy found a desmoid tumour. A 69-year-old male was referred to our institution for chronic anemia and inflammatory syndrome with splenomegaly. Splenectomy showed an important splenic congestion and siderosis. Both patients had a type 2 diabetes mellitus. Furthermore, histological examination revealed pancreatic endocrine microadenomas. The two patients' postoperative course was unremarkable. Eleven and 24 months respectively after the diagnosis, the patients are alive and well, with no tumor recurrence.

[Large cell calcifying Sertoli cell tumour: A case report]. / La tumeur à cellules de Sertoli à grandes cellules calcifiantes : à propos d'un cas.

A 19-year-old male Caucasian, without prior medical history, noticed a painless right testicular mass. Physical examination revealed neither gynecomastia nor abnormal skin pigmentation. Serum alpha-fetoprotein, ß-HCG and testosterone levels were normal. Sonography depicted an intratesticular diffusely hyperechoic lesion with acoustic shadowing. The patient underwent right orchiectomy. Histology revealed a benign large cell calcifying Sertoli cell tumour. This tumour is rare and may be associated with genetic abnormalities.

Epidermal growth factor receptor expression and KRAS and BRAF mutations: study of 39 sinonasal intestinal-type adenocarcinomas.

Sinonasal intestinal-type adenocarcinomas (ITACs) are uncommon tumors of poor prognosis defined by their similarities to colorectal adenocarcinomas. The involvement of the epidermal growth factor receptor (EGFR) pathway in colorectal adenocarcinoma oncogenesis is well established, and the same is expected to apply to ITACs. In a series of 39 ITACs, we investigated EGFR amplification and chromosome 7 polysomy by fluorescence in situ hybridization; EGFR, KRAS, and BRAF mutational status by polymerase chain reaction sequencing; EGFR variant messenger RNA expression by quantitative reverse transcriptase polymerase chain reaction; and EGFR protein expression by immunohistochemistry with antibodies targeting the extracellular domain, the intracellular domain, and the phosphorylated isoform. The findings were analyzed with respect to clinical data, histologic typing, and patient outcome. EGFR amplification was observed in 3 cases with a focal distribution. EGFR proteins were overexpressed in all these foci with both extracellular domain and intracellular domain antibodies, suggesting involvement of the whole receptor. Chromosome 7 polysomy was observed in 15 cases and was not associated with EGFR protein expression. EGFR, KRAS, or BRAF mutations were observed in 5 different cases. The EGFRvIII mutant was not detected. In all cases, EGFR variants were expressed. There was no association between these molecular features and patient survival. In conclusion, (1) our study revealed various EGFR expression patterns in ITACs, indicating tumor heterogeneity; (2) EGFR amplification should be distinguished from chromosome 7 polysomy; (3) fluorescence in situ hybridization analysis could be guided by immunohistochemistry; and (4) ITACs share common alterations of the EGFR pathway with colorectal adenocarcinomas, except for a lower frequency of KRAS and BRAF mutations.

[A rare cause of sudden cardiac failure: histiocytoid cardiomyopathy]. / Une cause rare de défaillance cardiaque brutale chez le nourrisson : la cardiomyopathie histiocytoïde.

Histiocytoid cardiomyopathy is a rare disease which occurs predominantly in the first two years of life, with a female preponderance. We report the cases of two girls (11 and 15-month-old) which were respectively referred to our institution for ventricular tachycardia and ventricular fibrillation without prodroma. Etiologic findings only showed mild cardiomyopathy. Autopsy and histologic examination led to the diagnosis of histiocytoid cardiomyopathy. Furthermore, in the first observation, agenesis of the corpus callosum was found.

Prognostic impact of CD133 mRNA expression in 48 glioblastoma patients treated with concomitant radiochemotherapy: a prospective patient cohort at a single institution.

BACKGROUND: Cancer stem cells are thought to represent the population of tumorigenic cells responsible for tumor development. The CD133 antigen has been described as a putative stem cell marker in malignant brain tumor that could identify such a tumorigenic population in a subset of glioblastoma. To date, the correlation between CD133 expression in primary glioblastoma and patient prognosis is not clearly established. To address this question we investigated the relationship between CD133 mRNA expression and patient outcome in a glioblastoma patient cohort. MATERIALS AND METHODS: The quantitative expression of CD133 stem cell antigen mRNA using real-time QRT-PCR was assessed in a cohort of 48 consecutive primary glioblastoma patients treated by chemoradiation with temozolomide. RESULTS: On multivariate survival analysis, high CD133 mRNA expression was a significant (P = 0.007) prognostic factor for adverse progression-free and overall survival independent of extent of resection (P = 0.012) and MGMT methylation status (P = 0.002). Patient age was also an independent prognosticator of overall survival (P = 0.037). Furthermore, according to the conjoined expression of CD133 mRNA and MGMT status, the patients were categorized into 3 groups with homogenous prognosis. CONCLUSIONS: These findings constitute conclusive evidence that the measurement of the mRNA expression of CD133 stem cell antigen actually impacts the survival of GBM patients.

[Pituitary melanocytoma mimicking an adenoma]. / Un mélanocytome mimant un adénome hypophysaire.

A 62-year-old woman was referred for a pituitary tumour diagnosed because of a chronic asthenia and visual disorders. Cerebral MRI showed a pituitary tumour compressing the optic chiasm and enhanced after gadolinium injection. Biological findings showed panhypopituitarism and hyperprolactinemia. The diagnostic of pituitary macro-adenoma was performed and the patient was treated with hormone replacement therapy and dopaminergic agonist. Six months later, she presented visual disorders worsening leading to surgical excision. The diagnosis of pituitary melanocytoma was performed after anatomo-clinical confrontation. Post-operative radiation was done.

Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis.

The phenotypic heterogeneity of low-grade gliomas (LGGs) is still inconsistently explained by known molecular abnormalities in patients treated according to the present standards of care. IDH1 codon 132 and IDH2 codon 172 sequencing was performed in a series of 47 LGGs and correlated with clinical presentation, MR imaging characteristics, genomic profile and outcome. A total of 38 IDH1 mutations at codon 132 and 2 IDH2 mutations at codon 172 were found, including 35 R132H (87.5%), 2 R132C (5.0%), 1 R132S (2.5%) and 2 R172 M (5%). The IDH mutations were significantly associated with 1p19q deleted genotype (P = 0.031) and p53 expression (P = 0.014). The presence (vs. absence) of IDH mutations was associated with a better outcome (5-year survival rate, 93% vs. 51%, respectively, P = 0.000001). After adjustment for age, tumor location and size, radiologic infiltration pattern and extent of surgery, multivariate analysis confirmed that IDH mutations was an independent favorable prognostic factor (hazard ratio = 40.9; 95% CI, 2.89-578.49, P = 0.006). Furthermore, we showed that patients with IDH-nonmutated tumors were significantly older (P = 0.020) and that these tumors involved significantly more frequently the insula (P = 0.004), were larger in size (>6 cm, P = 0.047), displayed an infiltrative pattern on MRI (P = 0.007) and were all p53 negative with no 1p19q deletion (P < 10⁻6). The absence of IDH mutations in LGGs identifies a novel entity of LGGs with distinctive location, infiltrative behavior, specific molecular alterations, and dismal outcome. These findings could significantly modify the LGG classification and may represent a new tool to guide patient-tailored therapy.

Coffin-Siris syndrome with multiple congenital malformations and intrauterine death: towards a better delineation of the severe end of the spectrum.

Coffine-Siris syndrome or "fifth digit" syndrome is a multiple congenital anomaly-mental retardation syndrome with severe developmental delay, coarse facial features, hirsutism and absent fifth fingernails or toenails or fifth distal phalanges. The etiology of this syndrome remains uncertain. Here we report a stillborn male baby born from consanguineous parents who might represent a very severe form of Coffine-Siris syndrome with cardiac defect and multiple brain malformations including corpus callosum agenesis and Dandy Walker malformation. To the best of our knowledge, it is the first case leading to intrauterine death. Karyotype and array comparative genomic hybridization were normal; these results give additional support to mendelian inheritance for this syndrome. In our family, the most likely mode of inheritance is autosomal recessive and the recurrence is probably as high as 25%.

Solitary, extracutaneous, skull-based juvenile xanthogranuloma.

We report a case of an 18-month-old female who presented an occipital bone lesion with progressive growth. Imaging studies showed a left extradural, skull-based tumor partially occupying the posterior fossa. Histopathological and immunohistochemical studies confirmed a juvenile xanthogranuloma (JXG). Partial surgical resection, chemotherapy, and conformational radiotherapy were used. Exclusive extracutaneous JXG with an intracranial, vertebral, or skull-based localization is extremely rare.

Polysialic acid neural cell adhesion molecule (PSA-NCAM) is an adverse prognosis factor in glioblastoma, and regulates olig2 expression in glioma cell lines.

BACKGROUND: Glioblastoma multiforme (GBM) is the most aggressive and frequent brain tumor, albeit without cure. Although patient survival is limited to one year on average, significant variability in outcome is observed. The assessment of biomarkers is needed to gain better knowledge of this type of tumor, help prognosis, design and evaluate therapies. The neurodevelopmental polysialic acid neural cell adhesion molecule (PSA-NCAM) protein is overexpressed in various cancers. Here, we studied its expression in GBM and evaluated its prognosis value for overall survival (OS) and disease free survival (DFS). METHODS: We set up a specific and sensitive enzyme linked immunosorbent assay (ELISA) test for PSA-NCAM quantification, which correlated well with PSA-NCAM semi quantitative analysis by immunohistochemistry, and thus provides an accurate quantitative measurement of PSA-NCAM content for the 56 GBM biopsies analyzed. For statistics, the Spearman correlation coefficient was used to evaluate the consistency between the immunohistochemistry and ELISA data. Patients' survival was estimated by using the Kaplan-Meier method, and curves were compared using the log-rank test. On multivariate analysis, the effect of potential risk factors on the DFS and OS were evaluated using the cox regression proportional hazard models. The threshold for statistical significance was p = 0.05. RESULTS: We showed that PSA-NCAM was expressed by approximately two thirds of the GBM at variable levels. On univariate analysis, PSA-NCAM content was an adverse prognosis factor for both OS (p = 0.04) and DFS (p = 0.0017). On multivariate analysis, PSA-NCAM expression was an independent negative predictor of OS (p = 0.046) and DFS (p = 0.007). Furthermore, in glioma cell lines, PSA-NCAM level expression was correlated to the one of olig2, a transcription factor required for gliomagenesis. CONCLUSION: PSA-NCAM represents a valuable biomarker for the prognosis of GBM patients.

Epidermal growth factor receptor in glioblastomas: correlation between gene copy number and protein expression.

Epidermal growth factor receptor is a transmembrane receptor involved in oncogenesis, including the development of glioblastoma. We studied the prognostic significance of epidermal growth factor receptor amplification as determined by fluorescence in situ hybridization, quantitative polymerase chain reaction, and protein expression by immunohistochemistry. Ninety-nine patients exhibiting glioblastoma were included. Immunohistochemistry was performed on microarray blocks with clone 25, which recognizes both epidermal growth factor receptor wild type and vIII, and scored using a semiquantitative approach. Quantitative polymerase chain reaction and fluorescence in situ hybridization techniques were performed on frozen section: 29.3% of cases had a high epidermal growth factor receptor immunohistochemistry score (score >/=200); and of these cases, 96.5% had gene amplification by fluorescence in situ hybridization and quantitative polymerase chain reaction. Conversely, of cases with a low immunohistochemistry score, 72.9% had normal karyotype or polysomy 7 by fluorescence in situ hybridization technique; but around 25% had gene amplification by fluorescence in situ hybridization and quantitative polymerase chain reaction. In the case of protein overexpression, quantitative polymerase chain reaction and fluorescence in situ hybridization could be avoided in first intention because their positive predictive value for amplification is 97%. In multivariate analysis, there was a trend toward an association between shorter overall survival time and epidermal growth factor receptor amplification as determined by fluorescence in situ hybridization analysis. However, cases with an immunohistochemistry score less 200 require further testing by fluorescence in situ hybridization or quantitative polymerase chain reaction.

Lethal injection of potassium chloride: first description of the pathological appearance of organs.

Lethal injection of potassium chloride (KCl) can be used as a method of either suicide or homicide. As biological tests are still inadequate to differentiate endogenous from exogenous potassium, at the scene of death the cause can only be suspected. We wished to determine the usefulness of conventional pathological examination in this context and carried out a study in four fetuses after medical termination of pregnancy for serious disease. Pregnancy was terminated by KCl injection in two cases and by injection of lidocaine and sufentanil in the other two cases. In each of the two fetuses in which KCl injection was performed, macroscopic examination showed whitish deposits on the tissues and histological examination showed clumps of lanceolate crystals in the internal organs. In the two fetuses which received lidocaine and sufentanil injection, no deposits were visible on macroscopic examination and no crystals were seen on histological examination. These findings suggest that pathological study may have useful applications in forensic medicine when death by potassium injection is suspected.