A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle.

Chordoid glioma is a rare brain tumor thought to arise from specialized glial cells of the lamina terminalis along the anterior wall of the third ventricle. Despite being histologically low-grade, chordoid gliomas are often associated with poor outcome, as their stereotypic location in the third ventricle makes resection challenging and efficacious adjuvant therapies have not been developed. Here we performed genomic profiling on 13 chordoid gliomas and identified a recurrent D463H missense mutation in PRKCA in all tumors, which localizes in the kinase domain of the encoded protein kinase C alpha (PKCα). Expression of mutant PRKCA in immortalized human astrocytes led to increased phospho-ERK and anchorage-independent growth that could be blocked by MEK inhibition. These studies define PRKCA as a recurrently mutated oncogene in human cancer and identify a potential therapeutic vulnerability in this uncommon brain tumor.

Differential Expression of Cytochrome C Oxidase Subunit I Along the Colorectal Adenoma: Carcinoma Progression.

Loss in apoptosis competence often results in augmented genomic instability contributing to carcinogenesis. Cytochrome c oxidase subunit I (CcOI) can help assess apoptosis resistance in paraffin-embedded biopsies. In total, 50 colorectal cases including 10 control cases of colectomy for non-neoplastic condition, 15 cases of adenomatous colorectal polyps, and 25 cases of colorectal carcinoma were investigated in this retrospective study for immunohistochemical expression of CcOI. The staining pattern of CcOI was assessed and indices of aberrant expression were calculated as crypt-restricted loss and overall decreased immunostaining (ODI). ODI calculated in the adenocarcinoma tumor tissue was designated as Tr ODI. The crypt-restricted loss and ODI indices of the aberrant CcOI expression are significantly higher in the adenomatous polyps group (2.5% and 47.54%) and in the non-neoplastic mucosa among adenocarcinoma group (2.78% and 49.1%) when they are compared with the control group (0.55% and 7.32%) (P<0.001). A highly significant correlation was noted between Tr ODI and the tumor grade, the nodal status, and the stage among adenocarcinomas. In conclusion, colonic tumors arise in a field of crypts with aberrations in CcOI expression. This aberration is linked to biologically aggressive tumors. CcOI immunostaining may be applied on mucosal samples from patients with colonic adenomatous polyps and patients with previous cancer colon resection to determine individuals who are in need for frequent colonoscopies and/or chemopreventive strategies. Future follow-up studies are warranted to determine the level of expression predictive of recurrence or progression.

Failure of the vascular hypothesis of multiple sclerosis in a rat model of chronic cerebrospinal venous insufficiency.

Chronic cerebrospinal venous insufficiency (CCSVI) is a series of stenotic malformations in the cerebrospinal venous outflow routes, which is postulated to cause multiple sclerosis (MS). The hypotheses assumed that CCSVI leads to iron deposition which triggers inflammation and demyelination in MS. Invasive endovascular treatment of CCSVI was initiated based on the previous theory. The present study was designed to validate this hypothesis using a rat model of CCSVI. Bilateral jugular vein ligation (JVL) was performed on female albino rats (n = 15), and sham-operated rats (n = 15) were used as a control group. The rats were followed clinically for eight months and neurological examination detected no weakness or paralysis in the operated rats. At the end of the experiment, the rats were sacrificed and the brains were processed for histopathological examination of tissue sections stained by hematoxylin and eosin, myelin stain, silver impregnation, iron stain and immunohistochemical preparations for GFAP, CD68 and CD45. Semithin sections stained with toluidine blue were also examined. In the JVL group, increased iron deposition in the white matter was detected. An increase in the size and number of astrocytes along with increased GFAP immunoreactivity denoting reactive gliosis was also noted in the JVL group. However, no signs of demyelination, inflammation or axonopathy were detected. This study revealed that iron deposition in the JVL group as a model for CCSVI was not associated with cardinal histopathological findings of MS. It is therefore recommended that the invasive endovascular treatment of CCSVI should be reconsidered and further controlled clinical studies be carried out to provide a better understanding of the pathogeneses of MS..

Spinal intramedullary hamartoma with acute presentation in a 13-month old infant: case report.

True hamartomas of the spinal cord are very rare, and although several have been reported in the literature, there are few detailed radiological and pathological descriptions of the condition. There is also considerable overlap with other entities, the most common being spinal cord teratomas. The authors report the case of a 13-month-old child with a supragluteal sacral dimple who presented with acute neurological deterioration. MRI of the spine revealed a big intramedullary lesion with heterogeneous signal intensity. A near-total resection was performed, and histopathological examination demonstrated findings consistent with a spinal cord hamartoma. The authors believe that careful preoperative evaluation and rigorous pathological examination are mandatory to establish diagnosis and direct further management of cases in which such a lesion is suspected.

Perspectives on the immunologic microenvironment of astrocytomas.

BACKGROUND: The microenvironment of astrocytomas includes infiltrative inflammatory cells that are dynamic in nature, possibly reflecting tumor biology. We evaluated the inflammatory cell infiltrate in astrocytic tumors aiming for a better understanding of their immunobiology. METHODS: Immunohistochemical expression of CD68, CD3, and CD20 was investigated in 21 glioblastomas, 21 anaplastic astrocytomas, 13 diffuse astrocytomas, and 18 pilocytic astrocytomas. The inflammatory infiltrate was classified based on microanatomic location as perivascular and intratumoral, and subsequently graded semiquantitatively. RESULTS: Perivascularly, CD68-positive infiltrate was noted in 71.4% of glioblastomas compared with 14.3% of anaplastic astrocytomas (P = 0.0001), 7.7% of diffuse astrocytomas (P = 0.0001), and 33.3% of pilocytic astrocytomas (P = 0.017). Intratumorally, 85.7% of glioblastomas exhibited CD68-positive infiltrate compared with 42.9% of anaplastic astrocytomas (P = 0.004), 38.5% of diffuse astrocytomas (P = 0.008), and 33.3% of pilocytic astrocytomas (P = 0.001). Among diffusely infiltrating astrocytomas, intratumoral CD3-positive infiltrate was only associated with glioblastoma. A CD20-positive infiltrate was only detected in the perivascular space of a single case of diffuse astrocytoma. CONCLUSION: These data indicate a distinct immune profile in the glioblastoma microenvironment primarily related to the prevalence of macrophages. Thus, novel glioblastoma therapies should address this key CD68-positive population and its possible role in generating an antitumor immune response.

Diagnostic value of progesterone receptor and p53 expression in uterine smooth muscle tumors.

BACKGROUND: The diagnosis of uterine smooth muscle tumors depends on a combination of microscopic features. However, a small number of these tumors still pose difficult diagnostic challenges. AIM: To investigate progesterone receptor (PR) and p53 expression in leiomyomas (LMs), atypical leiomyomas (ALMs), smooth muscle tumors of uncertain malignant potential (STUMP), and leiomyosarcomas (LMSs) and to evaluate the potential utility of the selected immunohistochemical markers in differentiating these tumors. MATERIALS AND METHODS: Immunohistochemical expression of PR and p53 was investigated in 41 uterine smooth muscle tumors comprising: 15 LMS, 4 STUMP, 6 ALM and 16 LM. Quantitative evaluation of PR and p53 expression was graded on a scale from 0 to 3+. RESULTS: Leiomyosarcomas showed reduced PR expression. All LMs as well as ALMs and STUMP were stained intensely for PR. Conversely, LMS was strongly stained with p53, while the three non-sarcomatous groups (STUMP, ALM, LM) were either entirely negative or weakly stained for p53. Regarding both PR and p53 expression, the difference between the LMS group and the three non-sarcomatous groups was highly significant (p < 0.001). Combined high PR - low p53 expression was seen in all the 26 examined cases of the non-sarcomatous group including the STUMP cases and none of the LMS cases. Therefore, it represents a "benign" profile with 100% specificity in diagnosis of a non-sarcomatous tumor. CONCLUSION: Immunohistochemistry for PR and p53 is valuable as an adjunct tool to morphological assessment of problematic uterine smooth muscle tumors.

Differential expression of cyclin D1 in human pituitary tumors: relation to MIB-1 and p27/Kip1 labeling indices.

BACKGROUND: Pituitary tumors are a common form of endocrine neoplasia. However few studies assessed the expression of the principal cyclin regulating checkpoint exit, cyclin D1. Cyclin D1 expression in pituitary tumors and its possible relation to MIB-1 and p27/Kip1 labeling indices (LIs) was explored. DESIGN: We studied a total of 199 pituitaries, including normal pituitaries (n=7), pituitary adenomas (n=187), and pituitary carcinoma (n=5). All tissues were tested as cores of archived tissue microarrays that were immunostained for cyclin D1, MIB-1 and p27 using a standard technique. Tissue cores were subjected to automated analysis to evaluate the staining LIs. RESULTS: No cyclin D1 positive cells in the normal anterior pituitary gland was found. Sparse nuclear staining was noted in pituitary tumors. Higher expression of cyclin D1 was noted in pituitary carcinomas compared to adenomas (p<0.001), in non-functioning adenomas compared to functioning ones (p<0.001) in macroadenomas versus microadenomas (p=0.017) and in recurrent non recurrent adenomas (p<0.001). Cyclin D1 LI and MIB-1 LI were related among adenomas (p<0.001) and carcinomas (p=0.041). p27 LI was neither related to pituitary adenoma recurrence nor invasion. CONCLUSIONS: Expression of cyclin D1 in pituitary tumors is related to cell proliferation, recurrence, and metastatic potential. Nuclear cyclin D1 expression is a good marker of aggressive behavior in pituitary tumors.

Pathogenic potential of Blastocystis hominis in laboratory mice.

Blastocystis hominis is a ubiquitous enteric protozoan whose pathogenic potential is still controversial. This study was carried out to clarify the pathogenecity of B. hominis infection and to study the proper number of parasites for mice infection. A total of 15 albino mice were orally inoculated with B. hominis and divided according to the inoculums, 10(2), 10(5), and 4 x 10(7) B. hominis forms/100 microl saline, into three groups consisting of five mice each, GI, GII GIII, respectively. In addition with group IV (uninfected control) consisting of five mice. All mice were sacrificed 2 weeks post-infection. The results revealed that all mice of GIII and two mice of GII got the infection while all mice of GI showed a completely negative result. Histopathological examination of large intestine on highly infected group (GIII) showed that B. hominis infiltrated the lamina propria, the submucosa, and the muscle layers in the form of collection of vacuolar forms. This was accompanied by active colitis with infiltration of mixed inflammatory cells. In conclusion, this study revealed that large number of B. hominis is essential for oral infection of mice and that vacuolar forms of B. hominis can invade the lamina propria, the submucosa, and even the muscle layers.

Clinicopathologic significance of molecular classification of breast cancer: relation to nottingham prognosis index.

PURPOSE: The aim of this work is to determine the possible relationship between the different profiles of molecular expression of hormone receptors and Her-2÷neu receptors to clinical and histopathological known prognostic variables for breast cancer. MATERIALS AND METHODS: A total of 110 breast carcinoma tumor samples were included. In this study 4 groups or immunohistochemical profiles were defined, based on expression of hormone receptors (estrogen and÷or progesterone) and÷or Her2÷neu (Luminal A, Luminal B, HER2 overexpressing profile, and triple-negative profile). We studied whether there were differences between them regarding clinical and histopathological variables with a known prognostic significance in addition to Nottingham Prognosis Index (NPI). RESULTS: In this series, 65 cases corresponded to Luminal A (59.1%), 18 cases (16.4%) were Luminal B, in 14 cases (12.7%) HER2 was over-expressed, while 13 cases (11.8%) were of the triple negative subtype. It is worth noting the relationship between the triple negative and HER2 over-expressing immunophenotypes and the high NPI (>3.4) in comparison with the Luminal A and Luminal B immunophenotypes (p=.029). The association of the former two types with higher tumor grade was also observed, but such association did not reach statistical significance. CONCLUSION: The subgroups without hormone receptor expression, with Her2÷neu overexpression or without (triple-negative group), have characteristics associated with variables of a poorer prognosis. KEY WORDS: Breast cancer- Hormone receptors- Her2neu- Classification- Nottingham prognosis index.

Immunohistochemical expression of survivin in breast carcinoma: relationship with clinicopathological parameters, proliferation and molecular classification.

BACKGROUND AND OBJECTIVE: Survivin is a novel member of the inhibitor of apoptosis (IAP) gene family. It is associated with more aggressive behavior and parameters of poor prognosis in most human cancers including gastric, colorectal and bladder carcinomas. However, conflicting data exist on its prognostic effect in breast cancer. This current study is designed to assess survivin expression in breast carcinoma relating results with clinicopathological parameters, proliferation (MIB-1) and molecular classification MATERIAL AND METHODS: Our retrospective study comprised of 65 archived cases of breast carcinoma. Samples from the tumor and the adjacent normal breast tissue were immunostained for survivin and MIB-1. Nuclear and cytoplasmic survivin expression was evaluated in normal breast tissue and carcinoma regarding both the intensity and the percentage of positive cells. ER, PR, HER2 were used as surrogate markers to classify the cases into four molecular subtypes. RESULTS: Survivin expression was detected in 78.5% of breast carcinomas. The adjacent normal breast tissue was immunonegative. Survivin expression showed significant association with increased tumor size (p<0.0001), high histologic grade (p=0.04), lymph node metastases (p<0.001), advanced tumor stage (p<0.0001), MIB-1 expression (p=0.02), negative estrogen receptor status (p=0.01) and negative progesterone receptor status (p<0.0001). The subcellular localization of survivin significantly related to histologic grade, stage and lymph node involvement. The percentage of TNP (triple negative phenotype) and HER2+/ER-PR- tumors expressing survivin were significantly higher compared to the Luminal subtypes (p=0.01). CONCLUSION: Survivin expression was associated with parameters of poor prognosis in breast cancer. Moreover, the cancer-specific expression of survivin, coupled with its importance in inhibiting cell death and in regulating cell division, makes it a potential target for novel cancer treatment. KEY WORDS: Breast carcinoma - Immunohistochemistry - MIB-1 - Molecular classification - Survivin.