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The lack of axonal regeneration in the injured adult mammalian spinal cord leads to permanent functional disabilities. The inability of neurons to regenerate their axon is appreciably due to an inhospitable environment made of an astrocytic scar. We generated mice knock-out for glial fibrillary acidic protein and vimentin, the major proteins of the astrocyte cytoskeleton, which are upregulated in reactive astrocytes. These animals, after a hemisection of the spinal cord, presented reduced astroglial reactivity associated with increased plastic sprouting of supraspinal axons, including the reconstruction of circuits leading to functional restoration. Therefore, improved anatomical and functional recovery in the absence of both proteins highlights the pivotal role of reactive astrocytes in axonal regenerative failure in adult CNS and could lead to new therapies of spinal cord lesions.

Objective(s): Smooth muscle tumors of uncertain malignant potential are rare uterine neoplasms. Their identification through imaging is still limited due to the few available descriptions in the scientific literature. The objective of this paper is to provide clinical and ultrasound features that could support an early identification of these neoplasms., Study Design: We retrospectively evaluated preoperative sonographic data of patients receiving a histopathological diagnosis of smooth muscle tumors of uncertain malignant potential between 2014 and 2019 at the S. Anna Hospital (Turin, Italy), a tertiary gynecological center. Tumors were characterized on the basis of ultrasound images using terms and definitions according to the morphological uterus sonographic assessment group., Results: A total of fourteen patients with smooth muscle tumors of uncertain malignant potential (20 lesions, including 18 pure and 2 with associated leiomyosarcoma) were identified. The median age was 47 years (range 28-77) and nine (64%) patients were of reproductive age. Six patients (43%) were asymptomatic, two (14%) presented with abdominal pain, two (14 %) with menorrhagia and four (29%) with both symptoms. Two (14%) patients developed local recurrences as uterine smooth muscle tumor of uncertain malignant potential and leiomyosarcoma, respectively. At ultrasound imaging, nine (69%) smooth muscle tumors of uncertain malignant potential were poorly or moderately vascularized and nine (82%) showed both circumferential and intra-lesional flows. Only three (15%) showed shadowing. The outlines were well-defined in seventeen cases (85%) and most (90%) showed isoechoic or mixed echogenicity with microcystic anechoic areas in fourteen (70%) of cases., Conclusion(s): Sonographic features of smooth muscle tumors of uncertain malignant potential may vary and a pathognomonic description has not been recognized. However, the identification of single or multiple lesions with specific ultrasound features should raise the suspicion of tumors of uncertain malignant potential. These features include isoechogenicity or mixed echogenicity, regular borders, presence of internal microcystic and anechoic areas, circumferential and intralesional vascularization ranging from minimal to high and absence of shadowing., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Identifying cancer drivers and actionable mutations is critical for precision oncology. In epithelial ovarian cancer (EOC) the majority of mutations lack biological or clinical validation. We fully characterized 43 lines of Patient-Derived Xenografts (PDXs) and performed copy number analysis and whole exome sequencing of 12 lines derived from naïve, high grade EOCs. Pyrosequencing allowed quantifying mutations in the source tumours. Drug response was assayed on PDX Derived Tumour Cells (PDTCs) and in vivo on PDXs. We identified a PIK3R1 W624R variant in PDXs from a high grade serous EOC. Allele frequencies of PIK3R1 W624R in all the passaged PDXs and in samples of the source tumour suggested that it was truncal and thus possibly a driver mutation. After inconclusive results in silico analyses, PDTCs and PDXs allowed the showing actionability of PIK3R1 W624R and addiction of PIK3R1 W624R carrying cells to inhibitors of the PI3K/AKT/mTOR pathway. It is noteworthy that PIK3R1 encodes the p85α regulatory subunit of PI3K, that is very rarely mutated in EOC. The PIK3R1 W624R mutation is located in the cSH2 domain of the p85α that has never been involved in oncogenesis. These data show that patient-derived models are irreplaceable in their role of unveiling unpredicted driver and actionable variants in advanced ovarian cancer., Competing Interests: The authors declare no competing interests.

Myopericytomas (MPC) are rare mesenchymal tumors, originating from the perivascular myoid cells. They predominantly occur in the skin and superficial soft tissues of the extremities, while visceral involvement is rare. Histological features and clinical course are usually benign. To the best of our knowledge, MPC is still an uncharacterized tumor entity of the female internal genital tract. We describe three MPC cases involving the female internal genital tract: (1) a uterine wall MPC arising in a 49-year-old woman with progressive pelvic/abdominal pain; (2) a cervix MPC of a 49-year-old woman who presented with metrorrhagia, and (3) a MPC presenting as a simple ovarian cyst in a 26-year-old woman with pain located in the left iliac fossa. All patients were surgically treated, and recurrence occurred in two cases. The histological and immunohistochemical findings, supporting the diagnosis of MPC, are presented; in particular, one case showed characteristics pointing towards an uncertain biological behavior/low-grade malignancy. A literature search was conducted to identify previous reports of gynecological MPC and for possible alternative diagnoses. Leiomyoma, epithelioid leiomyoma, angioleiomyoma, perivascular epithelioid cell tumor, solitary fibrous tumor, and low-grade endometrial stromal sarcoma should be considered in the differential diagnosis. Awareness of possible occurrence of this rare neoplasm in the female genital tract is important to reach a correct diagnosis in the spectrum of mesenchymal tumors. Considering the risk of recurrence, we recommend careful evaluation of surgical margins and complete surgical removal whenever possible.

Karyotyping and aCGH are routinely used to identify genetic determinants of major congenital malformations (MCMs) in fetal deaths or terminations of pregnancy after prenatal diagnosis. Pathogenic rearrangements are found with a variable rate of 9-39% for aCGH. We collected 33 fetuses, 9 with a single MCM and 24 with MCMs involving 2-4 organ systems. aCGH revealed copy number variants in 14 out of 33 cases (42%). Eight were classified as pathogenic which account for a detection rate of 24% (8/33) considering fetuses with 1 or more MCMs and 33% (8/24) taking into account fetuses with multiple malformations only. Three of the pathogenic variants were known microdeletion syndromes (22q11.21 deletion, central chromosome 22q11.21 deletion, and TAR syndrome) and 5 were large rearrangements, adding up to >11 Mb per subject and comprising strong phenotype-related genes. One of those was a de novo complex rearrangement, and the remaining 4 duplications and 2 deletions were 130-900 kb in size, containing 1-7 genes, and were classified as variants of unknown clinical significance. Our study confirms aCGH as a powerful technique to ascertain the genetic etiology of fetal major congenital malformations., (© 2015 S. Karger AG, Basel.)

A case of superficially invasive cutaneous squamous cell carcinoma (SCC) of the sole containing numerous mucin-producing vacuolated cells resembling "signet-ring" cells is reported. The 2 cellular components of the tumor, both squamous and mucinous, were atypical with pleomorphic nuclei, and expressed the same immunophenotype, consistent in weak and focal positivity for cytokeratin 5/6 and epithelial membrane antigen (EMA) and weak cytoplasmic and nuclear positivity for p16. Real-time PCR genotyping demonstrated the presence of high-risk human papillomavirus (HPV) type 18. We diagnose our case as "cutaneous SCC with mucinous metaplasia" and discuss the differential diagnoses with other skin tumors exhibiting mucin-containing cells, in particular with adenosquamous carcinoma and mucoepidermoid carcinoma. Although HPV 18 is not uncommon in cervico-vaginal pathology, where is often associated with mucinous adenocarcinoma or adenosquamous carcinoma of the cervix, its detection has been rarely reported in cutaneous SCC. In our case, the association of mucinous metaplasia and oncogenic high-risk HPV 18 in a cutaneous SCC may be of interest to the dermatopathologist. Further observations need to confirm whether the histopathologic finding of mucinous metaplasia in an atypical squamous cell proliferation could be a clue for investigating the presence of oncogenic high-risk HPV infection, with particular regard to HPV 18 subtype.

One kidney was taken from each of 100 pigs at slaughter; 50 had gross lesions of multifocal interstitial nephritis and 50 had no gross lesions. Forty-nine of the affected kidneys had lesions that were characterised by the presence of either a few randomly distributed or numerous widely disseminated pale foci, 1 to 3 mm in diameter, on the cortical surface (white-dotted kidneys). Microscopically, these focal inflammatory lesions often had a distinct lymphofollicular pattern (follicular nephritis). Lesions of chronic vasculitis were observed in 21 of the affected kidneys. Histologically, the control kidneys had only small and sparse inflammatory foci. Standard bacterial cultures of kidneys of both groups were not significant, and cultures for the isolation of leptospires were all negative. Virological examination of the kidney homogenates by PCR did not reveal any porcine reproductive and respiratory syndrome virus and only a few cases were positive for the porcine circovirus type 1. However, porcine parvovirus (PPV) and porcine circovirus type 2 (PCV-2) were detected in many kidneys of both groups but in a significantly higher proportion of the kidneys with interstitial nephritis. There was a significant association between the lesions and the presence of PPV and PCV-2 with odds ratios of 7.5 (P<0.0001) and 3.4 (P=0.0074), respectively, and the odds ratio increased to 22.7 (P<0.0001) when both viruses were identified in the same kidney. However, a subsample of kidneys taken from both groups were negative by immunohistochemistry for the presence of PPV and PCV-2 antigens.

The aim of this study was to assess the biological characteristics of four new malignant mesothelioma (MM) cell lines. Since simian virus (SV)40 sequences have been recently detected in MM, SV40 large T antigen (Tag) expression was also analysed. MM cell lines were characterized by morphological, ultrastructural and cytogenetic analysis. Expression of Tag and of relevant MM markers was studied by immunocytochemistry, surface antigens by indirect immunofluorescence and immunomodulating cytokines by enzyme-linked immunosorbent assay (ELISA). The four MM cell lines, established from pleural effusions, showed a slow proliferation rate and pleomorphic changes during culture. Cell lines expressed vimentin, cytokeratins 8 and 18, and the mesothelial antigen recognized by HBME-1 monoclonal antibody, but not carcinoembryonic antigen. Surface human leukocyte antigen (HLA)-class I and intercellular adhesion molecule (ICAM)-1 molecules were present on all the cell lines. While HLA class II and CD86 were constitutively undetectable, HLA-class II was present after interferon (IFN)-gamma stimulation. All cell lines displayed abnormal karyotypes with chromosome 6 abnormalities. Transforming growth factor (TGF)-beta2 and interleukin (IL)-6 were constitutively secreted, while tumour necrosis factor (TNF)-alpha was secreted only in response to lipopolysaccharide. Intranuclear Tag was expressed in two cell lines. The persistence of large T antigen with human leukocyte antigen class I and intercellular adhesion molecule-1 positivity may point to large T antigen as a target for cytotoxic T-lymphocyte-based immunotherapy in some malignant mesothelioma patients.

The long latency period between asbestos exposure and the onset of malignant mesothelioma (MM) suggests that a multistep tumorigenesis process occurs whilst the capability of asbestos fibres to interfere directly with chromosomes focuses on the critical role of the chromosomal abnormalities in this neoplasm. The aim of our study was to identify any recurrent chromosomal changes in ten primary MM cell cultures derived from pleural effusions of patients with MM from the same geographic area and environmental and/or occupational exposure to asbestos fibers. Cytogenetic analysis was performed in accordance with International System for Human Cytogenetic Nomenclature. Our results confirmed a great number of cytogenetic abnormalities in MM cells. Recurrent loss of the long arms of chromosome 6 (6q-) was the most frequent abnormality detected (four epithelial and two mixed subtypes) while, on the whole, abnormalities of chromosome 6 were found in nine out of ten cases whereas chromosome 6 was normal only in the case with fibromatous subtype. Monosomy 13 and 17 was found in five cases, monosomy 14 in four cases and 22 in three cases. Since deletion of 6q- was detected even in relatively undisturbed karyotype, we hypothesize a multistep carcinogenic process in which deletion of 6q- is an early event in the development and progression of malignant mesothelioma.

Lipoblastic differentiation in fibrous mesotheliomas is an extremely rare occurrence. We present the histological and immunohistochemical features of a case of localized peritoneal mesothelioma with lipoblastic differentiation in an 80-year old man and discuss the differential diagnosis with liposarcoma.

Upon exposure to collagen sponges, cultured adult human mesothelial cells were shown to differentiate into hematopoietic cells similar to those of the red bone marrow. This transformation was confirmed by morphological analysis and by cell immunoreactivity toward specific antibodies directed to antigens of the hematopoietic cell lines at various stages of differentiation. Besides demonstrating that the pluri-potentiality of the mesothelium persist into adulthood, this observation suggests that the process of differentiation may also be influenced by the structural organization of the microenvironment hosting the mesothelial cells.

A series of 722 lung carcinomas, surgically resected and typed some years ago according to the 1967 WHO classification, was independently reviewed by 2 observers in order to test the reproducibility of histopathological typing when using the criteria of the 1981 WHO classification. Typing was fully agreed upon in 87% of cases. Agreement was very high for squamous-cell, small-cell and adeno-carcinomas (kappa = 0.87, 0.89 and 0.85, respectively) while adenosquamous (kappa = 0.56) and large-cell (kappa = 0.71) carcinomas were more controversial categories. A consensus diagnosis was formulated for lesions with discrepant diagnoses. When comparing the final typing to the previous typing based on the 1967 WHO classification, squamous- and large-cell carcinomas were reduced respectively by 22% and 33% and adenocarcinomas increased by 94% of the original number. The 1981 "adenosquamous carcinoma" category included 2.8% of the tumours, while the corresponding 1967 category "combined epidermoid and adenocarcinoma" was empty. These changes must be taken into account when considering epidemiological studies, especially those aiming at evaluation of the secular trends of lung cancer by cell type.

The number and the size of silver-stained intranuclear granules, which correspond to the nucleolus and nucleolar organizer regions, have been determined by means of quantitative methods in cultured primary human mesothelial cells obtained from normal, reactive and malignant mesothelium. The mean values per nucleus of the number, the total area, the average area, and the relative area of the silver-stained granules and the mean nuclear area were determined for each of the three conditions. Normal, reactive and malignant mesothelial cells differed significantly in all the features. These findings at the optical level reflect the differing rate of the nucleolar biosynthetic activity related to the different biological properties of the three cell types, and the features can be useful morphometric descriptors in the diagnostic pathology of the mesothelium.

We have investigated the growth-factor-like activity of a approximately 200-kDa, IP 8.3, cytoplasmic glycoprotein, the expression of which appears to be restricted to normal and malignant human mesothelium. This substance stimulated the growth of human mesothelioma cell cultures at greater rates than did foetal calf serum, but it failed to induce proliferation of lung carcinoma cell cultures. In addition, we have tried to trace the biosynthetic pathway of this mitogenic factor in normal human mesothelial cells by means of immuno-electron microscopy with a polyclonal antibody directed against this molecule. Positive immunogold labelling was found in the lumina of the cisternae of the endoplasmic reticulum, to a lesser extent on the outer surface of the plasma membrane, and also in structures corresponding to the coated pits. These ultrastructural findings are consistent with the hypothesis of the glycosylation of the newly synthesized protein in the endoplasmic reticulum and the subsequent uptake of the secreted molecule, which accumulates in the coated pits before internalization. The results suggest that this mitogenic glycoprotein could play a role in an autocrine growth control mechanism influencing mesothelial cell proliferation.

Modifications of gene expression may occur in hepatitis B virus (HBV)-related chronic liver diseases, possibly also involving ribosomal RNA (rRNA) genes contained in the nucleolus. Changes in the level of transcriptional activity of rRNA genes are reflected by variations in the number and/or size of the nucleoli. Therefore a quantitative analysis of the silver-stained nucleoli (AgNus) was performed in a small series of liver needle biopsies from patients with HBV+ chronic persistent hepatitis (CPH) (n = 3), HBV+ chronic active hepatitis (CAH) (n = 3) and HBV+ cirrhosis (CIR) (n = 3). In each case, 100 hepatocytes were selected. The number of the nucleoli (AgNuN), their total area (tAgNuA), the average area of each nucleolus (xAgNuA), the nuclear area (NA) and the percentage ratio of tAgNuA related to NA (rAgNuA) were determined for each hepatocyte nucleus. The pooled mean values of all the features were significantly different (p less than 0.001) among the case groups. The results point towards a remarkable increase of nucleolar activity in CAH in comparison with CPH, whereas an additional increment of this activity is associated with the progress from CAH to CIR.

A myogenic phenotype was induced in cultures of human mesothelial cells treated for 72 h with atrazine, a triazine derivative. Immunoreactivity for both myosin and myoglobin was detected in a large number of these cells, irrespective of their polygonal or spindle morphology, whereas no expression of desmin was observed. These findings support the embryological identity of mesothelium and mesoderm, the former being, in the post-embryonic stage, potentially capable of differentiation along the same lineages which the latter normally displays during embryogenesis. In the light of this concept it can be assumed that primary malignancies arising from the mesothelium have the competence to express the pluripotent nature of embryonic mesoderm, and hence the term mesodermoma is appropriate for this group of tumours, including mesotheliomas in a classical sense. A postulated mechanism for the phenotypic change of mesothelial cells is also outlined, involving atrazine conversion to 5-aza-chloro-cytidine, a probable DNA hypomethylating and gene activating agent, like its analogue 5-azacytidine.

The prognostic significance of age, sex, location of the tumor in the various lobes, size, histological type, node metastases, local extent and stage has been studied in a series of 742 surgically resected lung carcinomas. The histological type was a very important prognostic factor: the highest survival was observed in epidermoid carcinomas, followed by adenocarcinomas, anaplastic large cell carcinomas, and anaplastic small cell carcinomas. The stage, as well, except for the adenocarcinoma, bore heavily on the prognosis; however, in small stage I tumours, the postoperative survival was independent from the histological type. The presence of lymph node metastases resulted in an extremely poor survival, except for the epidermoid carcinoma. The size of the tumours, excluding adenocarcinomas, was an important prognostic factor provided lymph node metastases were absent. No significant differences in survival according to the location in different lobes could be ascertained.