Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis.

Germline mutations of BRCA1 predispose women to breast and ovarian cancers. However, the downstream mediators of BRCA1 function in tumor suppression remain elusive. We found that human BRCA1-associated breast cancers have lower levels of SIRT1 than their normal controls. We further demonstrated that mammary tumors from Brca1 mutant mice have low levels of Sirt1 and high levels of Survivin, which is reversed by induced expression of Brca1. BRCA1 binds to the SIRT1 promoter and increases SIRT1 expression, which in turn inhibits Survivin by changing the epigenetic modification of histone H3. Absence of SIRT1 blocks the regulation of Survivin by BRCA1. Furthermore, we demonstrated that activation of Sirt1 and inhibition of Survivin expression by resveratrol elicit a more profound inhibitory effect on Brca1 mutant cancer cells than on Brca1-wild-type cancer cells both in vitro and in vivo. These findings suggest that resveratrol treatment serves as an excellent strategy for targeted therapy for BRCA1-associated breast cancer.

Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma.

Glypican-3 (GPC3) has emerged as a candidate therapeutic target in hepatocellular carcinoma (HCC), but the oncogenic role of GPC3 in HCC is poorly understood. Here, we report a human heavy-chain variable domain antibody, HN3, with high affinity (Kd = 0.6 nM) for cell-surface-associated GPC3 molecules. The human antibody recognized a conformational epitope that requires both the amino and carboxy terminal domains of GPC3. HN3 inhibited proliferation of GPC3-positive cells and exhibited significant inhibition of HCC xenograft tumor growth in nude mice. The underlying mechanism of HN3 action may involve cell-cycle arrest at G1 phase through Yes-associated protein signaling. This study suggests a previously unrecognized mechanism for GPC3-targeted cancer therapy.

miR-638 mediated regulation of BRCA1 affects DNA repair and sensitivity to UV and cisplatin in triple-negative breast cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) represents 15 to 20% of all types of breast cancer; however, it accounts for a large number of metastatic cases and deaths, and there is still no effective treatment. The deregulation of microRNAs (miRNAs) in breast cancer has been widely reported. We previously identified that miR-638 was one of the most deregulated miRNAs in breast cancer progression. Bioinformatics analysis revealed that miR-638 directly targets BRCA1. The aim of this study was to investigate the role of miR-638 in breast cancer prognosis and treatment. METHODS: Formalin-fixed, paraffin-embedded (FFPE) breast cancer samples were microdissected into normal epithelial and invasive ductal carcinoma (IDC) cells, and total RNA was isolated. Several breast cancer cell lines were used for the functional analysis. miR-638 target genes were identified by TARGETSCAN-VERT 6.2 and miRanda. The expression of miR-638 and its target genes was analyzed by real-time qRT-PCR and Western blotting. Dual-luciferase reporter assay was employed to confirm the specificity of miR-638 target genes. The biological function of miR-638 was analyzed by MTT chemosensitivity, matrigel invasion and host cell reactivation assays. RESULTS: The expression of miR-638 was decreased in IDC tissue samples compared to their adjacent normal controls. The decreased miR-638 expression was more prevalent in non-TNBC compared with TNBC cases. miR-638 expression was significantly downregulated in breast cancer cell lines compared to the immortalized MCF-10A epithelial cells. BRCA1 was predicted as one of the direct targets of miR-638, which was subsequently confirmed by dual-luciferase reporter assay. Forced expression of miR-638 resulted in a significantly reduced proliferation rate as well as decreased invasive ability in TNBC cells. Furthermore, miR-638 overexpression increased sensitivity to DNA-damaging agents, ultraviolet (UV) and cisplatin, but not to 5-fluorouracil (5-FU) and epirubicin exposure in TNBC cells. Host cell reactivation assays showed that miR-638 reduced DNA repair capability in post UV/cisplatin-exposed TNBC cells. The reduced proliferation, invasive ability, and DNA repair capabilities are associated with downregulated BRCA1 expression. CONCLUSIONS: Our findings suggest that miR-638 plays an important role in TNBC progression via BRCA1 deregulation. Therefore, miR-638 might serve as a potential prognostic biomarker and therapeutic target for breast cancer.

Methylation of the Selected TP53 Introns in Advanced-Stage Ovarian Carcinomas.

Objective: Advanced-stage ovarian cancer (OC) is among the most fatal female genital tract neoplasms worldwide. Although different genetic mechanisms have been shown to be involved in ovarian carcinogenesis, the role of TP53 introns methylation is still unresolved. We performed methylation analysis of introns 1, 3, and 4 of the TP53 to identify patterns in primary stage III OCs, corresponding metastases, and healthy tissues. Methods: The study involved samples of paraffin-embedded tissues obtained from 80 patients with stage III OCs, who underwent surgery at the Department of Gynecology and Gynecologic Oncology of the Military Institute of Medicine in Warsaw, Poland. Altogether, 40 serous-type G2/3 OCs and 40 endometrioid-type G2/3 OCs were included. From the same patient, metastatic and normal tissues were simultaneously analyzed. As a control group, 80 tissue samples were collected from patients after bariatric operations. Human ovarian cancer A2780 cell line was also investigated. Total genomic DNA was isolated from paraffin-embedded tissue blocks and the methylation analysis was performed by bisulfite DNA conversion, DNA amplification with specific primers, cloning, and DNA sequencing. Results: All of the samples of intron 1 of TP53 were un-methylated in OCs, metastatic tissues, and in healthy tissues from the same patient. Also, no methylation of TP53 intron 1 was detected in cells from the human A2780 ovarian cancer cell line and in all samples from control group. In all samples, introns 3 and 4 of the TP53 were methylated in primary tumors, metastatic tissue, and in healthy tissue from the same patient, in human A2780 ovarian cell line, and in DNA samples from healthy patients. None of the clinicopatholocal features was related to the TP53 introns methylation status. Conclusions: Our data on TP53 introns methylation sheds new light on the mechanism of p53 activity for a better understanding of cancer biology. The study suggests the existence of an additional regulation rule of TP53 activity that involves demethylation-methylation mechanisms. Methylation at introns 3 and 4 may also overall help in protecting TP53 against damage by viral restrictases or viral DNA integration.

Tumor-infiltrating immune cells: triggers for tumor capsule disruption and tumor progression?

BACKGROUND: Our previous studies of human breast and prostate cancer have shown that aberrant immune cell infiltration is associated with focal tumor capsule disruption and tumor cell budding that facilitate invasion and metastasis. Our current study attempted to determine whether aberrant immune cell infiltration would have similar impact on colorectal cancer (CRC). MATERIALS AND METHODS: Tissue sections from 100 patients with primary CRC were assessed for the frequencies of focal basement membrane (BM) disruption, muscularis mucosa (MM) fragmentation, and tumor cell dissemination in epithelial structures adjacent and distal to infiltrating lymphoid aggregates using a panel of biomarkers and quantitative digital imaging. RESULTS: Our study revealed: (1) epithelial structures adjacent to lymphoid follicles or aggregates had a significantly higher (p<0.001) frequency of focally disrupted BM, dissociated epithelial cells in the stroma, disseminated epithelial cells within lymphatic ducts or blood vessels, and fragmented MM than their distal counterparts, (2) a majority of dissociated epithelial cells within the stroma or vascular structures were immediately subjacent to or physically associated with infiltrating immune cells, (3) the junctions of pre-invasive and invasive lesions were almost exclusively located at sites adjacent to lymphoid follicles or aggregates, (4) infiltrating immune cells were preferentially associated with epithelial capsules that show distinct degenerative alterations, and (5) infiltrating immune cells appeared to facilitate tumor stem cell proliferation, budding, and dissemination. CONCLUSIONS: Aberrant immune cell infiltration may have the same destructive impact on the capsule of all epithelium-derived tumors. This, in turn, may selectively favor the proliferation of tumor stem or progenitor cells overlying these focal disruptions. These proliferating epithelial tumor cells subsequently disseminate from the focal disruption leading to tumor invasion and metastasis.

Synchronously occurring endometrioid carcinomas of the uterine corpus and uterine cervix preceded by different precancerous lesions: A case study and a literature review.

The incidence of two synchronous carcinomas originating from the uterine corpus and uterine cervix, both endometrioid subtypes, is exceedingly rare. Herein, we presented synchronous early stage G1 adenocarcinoma of the uterine corpus with cervical G2 endometrioid adenocarcinoma. Although both neoplasms displayed the same histological subtype, they differed significantly according to the histological grading or clinical stage of the disease. Finally, it is worth emphasizing that both tumors were preceded by different precancerous lesions, atypical endometrial hyperplasia (AEH) and foci of endometriosis localized within the uterine cervix. Although AEH is a well-known precancerous condition of endometrioid carcinoma, the mechanisms resulting in the malignant transformation of endometriosis foci to the cervical endometrioid carcinoma are still a matter of controversy. We briefly summarized the impact of different precancerous lesions on the development of synchronous female genital tract neoplasms with the same histotype.

The most likely but largely ignored triggering factor for breast (or all) cancer invasion.

Breast cancer development and progression are believed to be a sequential process, from normal to hyperplastic, to in situ, and to invasive and metastatic stages. Given that over 90% of cancer deaths are caused by invasive and metastatic lesions, countless factors and multiple theories have been proposed as the triggering factor for the cascade of actions of cancer invasion. However, those factors and theories are largely based on the studies of cell lines or animal models. In addition, corresponding interventions based on these factors and theories have failed to reduce the incidence rate of invasive and metastatic lesions, suggesting that previous efforts may have failed to arm at the right target. Considering these facts and observations, we are proposing "A focal aberrant degeneration in the myoepithelial cell layer (MECL) as the most likely triggering factor for breast cancer invasion". Our hypothesis is based on our recent studies of breast and multiple other cancers. Our commentary provides the rationale, morphologic, immunohistochemical, and molecular data to support our hypotheses. As all epithelium-derived cancers share a very similar architecture, our hypothesis is likely to be applicable to invasion of all cancer types. We believe that human tissue-derived data may provide a more realistic roadmap to guide the clinic practice.

Differences in community structure of gastrointestinal tract between Helicobacter pylori positive patients and negative patients with gastric cancer.

Gastric cancer is one of the most severe cancers, while the relationship between Helicobacter pylori (H. pylori) and gastric cancer are still in dispute, and little work has been done to explore the microbial diversity between H. pylori positive patients and negative patients. In the present work, a total of 43 gastric cancer patients and 10 healthy 53 participants were enrolled to compare the microbial differences in community structure in gastrointestinal tract between H. pylori positive patients and negative patients with gastric cancer. Our results indicated that the abundance and diversity of gastrointestinal microbiota was slight lower in gastric cancer patients than that in healthy participants especially in intestine, while the abundance of some potential pathogens, e.g. Streptococcus, Lactobacillus, Akkermansia and Halomones were higher in H. pylori positive patients than H. pylori negative patients. Therefore, our work suggests the various microbial diversity between H. pylori positive patients and H. pylori negative patients with gastric cancer, which contribute to deepen the understanding of the role of H. pylori in gastric carcinogenesis and progression.

The most effective but largely ignored target for prostate cancer early detection and intervention.

Over the past two decades, the global efforts for the early detection and intervention of prostate cancer seem to have made significant progresses in the basic researches, but the clinic outcomes have been disappointing: (1) prostate cancer is still the most common non-cutaneous cancer in Europe in men, (2) the age-standardized prostate cancer rate has increased in nearly all Asian and African countries, (3) the proportion of advanced cancers at the diagnosis has increased to 8.2% from 3.9% in the USA, (4) the worldwide use of PSA testing and digital rectal examination have failed to reduce the prostate cancer mortality, and (5) there is still no effective preventive method to significantly reduce the development, invasion, and metastasis of prostate cancer… Together, these facts strongly suggest that the global efforts during the past appear to be not in a correlated target with markedly inconsistent basic research and clinic outcomes. The most likely cause for the inconsistence appears due to the fact that basic scientific studies are traditionally conducted on the cell lines and animal models, where it is impossible to completely reflect or replicate the in vivo status. Thus, we would like to propose the human prostate basal cell layer (PBCL) as "the most effective target for the early detection and intervention of prostate cancer". Our proposal is based on the morphologic, immunohistochemical and molecular evidence from our recent studies of normal and cancerous human prostate tissues with detailed clinic follow-up data. We believe that the human tissue-derived basic research data may provide a more realistic roadmap to guide the clinic practice and to avoid the potential misleading from in vitro and animal studies.

Leukocyte-mediated cell dissemination and metastasis: findings from multiple types of human tumors.

Our previous studies revealed that leukocyte infiltration could trigger human breast and prostate tumor invasion through focal disruptions of the tumor capsule, which selectively favors monoclonal proliferation of tumor progenitors or a biologically more aggressive cell clone overlying the focal disruptions. Our current study, involving multiple types of human tumors, further shows that leukocyte infiltration could also trigger tumor metastasis through the following pathways: [1] more leukocytes migrate to focally disrupted tumor capsules, which forms leukocyte aggregates surrounding newly formed tumor cell clusters, [2] the physical movement of leukocytes into proliferating tumor cells disrupts the intercellular junctions and cell-surface adhesion molecules, causing the disassociation of tumor cells from the tumor core, [3] leukocytes are conjoined with some of these tumor cells through plasma membrane fusion, creating tumor cell-leukocyte chimeras (TLCs), and [4] the leukocyte of TLCs impart migratory capacity to associated tumor cell partners, physically dragging them to different tissue sites. Our findings suggest a novel pathway for tumor cell dissemination from the primary sites and the subsequent journey to new sites. Our findings also provide a unique explanation for the cellular mechanism of leukocytes on tumor invasion and metastasis. If confirmed, our hypothesis and technical approach may significantly facilitate early detection and intervention of tumor invasion and metastasis.

Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species.

Recent pregnancy correlates with decreased survival for breast cancer patients compared with non-pregnancy-associated breast cancer. We hypothesize that postpartum mammary involution induces metastasis through wound-healing programs known to promote cancer. It is unknown whether alternatively activated M2 macrophages, immune cells important in wound-healing and experimental tumorigenesis that also predict poor prognosis for breast cancer patients, are recruited to the normal involuting gland. Macrophage markers CD68, CSF-1R, and F4/80 were examined across the pregnancy and involution cycle in rodent and human mammary tissues. Quantitative immunohistochemistry revealed up to an eightfold increase in macrophage number during involution, which returned to nulliparous levels with full regression. The involution macrophages exhibit an M2 phenotype as determined by high arginase-1 and low inducible nitric oxide synthase staining in rodent tissue, and by mannose receptor expression in human breast tissue. M2 cytokines IL-4 and IL-13 also peaked during involution. Extracellular matrix (ECM) isolated from involuting rat mammary glands was chemotactic for macrophages compared with nulliparous mammary ECM. Fibrillar collagen levels and proteolysis increased dramatically during involution, and denatured collagen I acted as a strong chemoattractant for macrophages in cell culture, suggesting proteolyzed fibrillar collagen as a candidate ECM mediator of macrophage recruitment. M2 macrophages, IL-4, IL-13, fibrillar collagen accumulation, and proteolysis of collagen are all components of tumor promotional microenvironments, and thus may mediate promotion of breast cancers arising in the postpartum setting.

Putative biomarkers and targets of estrogen receptor negative human breast cancer.

Breast cancer is a progressive and potentially fatal disease that affects women of all ages. Like all progressive diseases, early and reliable diagnosis is the key for successful treatment and annihilation. Biomarkers serve as indicators of pathological, physiological, or pharmacological processes. Her2/neu, CA15.3, estrogen receptor (ER), progesterone receptor (PR), and cytokeratins are biomarkers that have been approved by the Food and Drug Administration for disease diagnosis, prognosis, and therapy selection. The structural and functional complexity of protein biomarkers and the heterogeneity of the breast cancer pathology present challenges to the scientific community. Here we review estrogen receptor-related putative breast cancer biomarkers, including those of putative breast cancer stem cells, a minor population of estrogen receptor negative tumor cells that retain the stem cell property of self-renewal. We also review a few promising cytoskeleton targets for ER alpha negative breast cancer.

Downregulation of miR-375 contributes to ERBB2-mediated VEGFA overexpression in esophageal cancer.

Esophageal cancer (EC) is a lethal cancer with an extremely aggressive nature and poor survival rate. However, the molecular mechanisms driving the occurrence and progression of EC are not well understood. MicroRNAs (miRNAs) are small RNA molecules that regulate the expression of protein-coding genes. miRNA-mediated gene regulation plays an important role in EC. By cross-referencing studies from NCBI, we found that microRNA-375 (miR-375) is one of the most frequently downregulated miRNAs in EC. We assessed expression of miR-375 in EC cell lines and primary EC tissues and their matched normal tissues. We found significant downregulation of miR-375 in both cell lines and EC tissues. Forced expression of miR-375 attenuated EC cell proliferation and invasion. Human epidermal growth factor receptor 2 (HER2, ERBB2), a known proto-oncogene, was identified here as one of the potential target genes of miR-375. Ectopic expression of miR-375 significantly suppressed the expression of ERBB2 and subsequently downregulated one of its target genes, vascular endothelial growth factor A (VEGFA), which is related to cancer invasion and metastasis. These findings suggest that miR-375 acts as a tumor suppressor by blocking the ERBB2/VEGFA pathway with the potential to modulate the occurrence and/ or progression of EC.

Prospective Non-Randomized Study of Intraoperative Assessment of Surgical Resection Margin of Colo-Rectal Liver Metastases.

Introduction: More than 50% of patients with colorectal cancer (CRC) develop liver metastases during the natural course of disease. Surgical resection is currently the most potentially curative method in the treatment of colorectal liver metastases (CRLM). The goal of surgery is to achieve a negative resection margin (RM) of at least 1 mm, which provides the best prognosis for patients. The RM can be assessed by the pathologist of the resected liver specimen (RLS) and by the surgeon intraoperatively. The aim of this research paper is to determine the degree of agreement on intraoperative assessment of the RM by the surgeon and histopathological RM assessment by the pathologist. Material and methods: This prospective non-randomized double-blind study was approved by the Ethics Committee of the Oncology Institute of Vojvodina and registered on ClinicalTrials.gov #NCT04634526. The study was conducted at the Oncology Institute of Vojvodina, Sremska Kamenica, Serbia. An experienced hepatobiliary surgeon assessed RM for every specimen intra-operatively, immediately after CRLM resection. Resected CRLM lesions were analyzed by two experienced pathologists. These data were compared with pathological RM assessment as a "gold standard". RM of 1 mm or more was rated as negative RM (RM-). Disease-free survival (DFS) and recurrence rate was calculated by RM status defined by surgeon and by pathologist. Results: From 01 January 2015 to 31 August 2019, 98 patients were enrolled in the study. There were 219 RLS with 245 CRLM. The surgeon registered positive RM (RM+) of <1mm in 41 (18.7%) RLS. Taking the result of the histopathological assessment (HPA) as the "gold standard", it was determined that RM was true positive in 32 (14.6%) cases. False positive RM was found in 9 (4.1%) cases. False negative RM was found in 20 (9.1%) cases. True negative RM was found in 158 (72.2%) cases. Sensitivity of surgical assessment (SA) of RM+ was 61.5% (32/52). Specificity of SA of RM+ was 94.6% (158/167). The positive predictive value (PPV) was 78.0% (32/41), while the negative predictive value (NPV) was 88.8% (158/178). The overall accuracy of the RM+ SA was 86.8% (190/219). There was no statistically significant difference in the assessment of RM+ per RLS by surgeon and pathologists (p=0.061), but it was significant when analyses per patients was performed (p=0.017). Recurrence rate for RM+ patients was 48.1% (13/27, p=0.05) for SA and 35.0% (14/40, p=0.17) for HPA. Three year DFS for RM- and RM+ was 66.5% and 27.9% (p=0.04), respectively, by SA, and 64.8% and 42.1% (p=0.106), respectively, by HPA. Conclusion: Intraoperative assessment of RM- by surgeon of RLS is clinically meaningful. There is not a statistically significant difference in the assessment of RM+ by surgeon and pathologists per RLS, but it was statically significant on a per patient basis. RM determined by surgeon has better prognostic impact on recurrence rate and 1- and 3-year DFS than standard histopathological assessment.

Antibiotics for cancer treatment: A double-edged sword.

Various antibiotics have been used in the treatment of cancers, via their anti-proliferative, pro-apoptotic and anti-epithelial-mesenchymal-transition (EMT) capabilities. However, increasingly studies have indicated that antibiotics may also induce cancer generation by disrupting intestinal microbiota, which further promotes chronic inflammation, alters normal tissue metabolism, leads to genotoxicity and weakens the immune response to bacterial malnutrition, thereby adversely impacting cancer treatment. Despite the advent of high-throughput sequencing technology in recent years, the potential adverse effects of antibiotics on cancer treatments via causing microbial imbalance has been largely ignored. In this review, we discuss the double-edged sword of antibiotics in the field of cancer treatments, explore their potential mechanisms and provide solutions to reduce the potential negative effects of antibiotics.

BP1, a homeoprotein, is significantly expressed in prostate adenocarcinoma and is concordant with prostatic intraepithelial neoplasia.

BP1 is a member of the homeobox gene superfamily of transcription factors that are essential for early development. Significant mRNA expression and immunohistochemical reactivity of BP1 is present in a majority of breast cancers and in all cases of inflammatory breast cancer. This study attempts to determine whether BP1 expression is detectable in prostate cancer, another hormone dependent solid tumor, and whether this expression correlates with histopathologic and prognostic factors. Paraffin sections from radical prostatectomy cancer specimens and from tissue microarray sections of prostate cancer, obtained from the Prostate Cancer Tissue Registry (NIH), were assayed for BP1 immunoreactivity. Immunoreactivity scoring by two independent pathologists, using a three-tiered system (0, 1+, 2+), was recorded and correlated with Gleason scoring and prostatic specific antigen (PSA) biochemical recurrence. Ki-67 (MIB-1) immunoreactivity was performed to assess proliferation. Kappa and Cochran-Mantel-Haenszel statistical analyses were used to assess interobserver agreement and pathobiologic correlations. Significant BP1 immunoreactivity (2+) was identified in approximately 70% of prostatic adenocarcinomas, whether the analysis was performed on tissue sections (50 cases) or tissue microarray platforms (123 cases). BP1 immunoreactivity was seen in <5% of normal acinar cells. The agreement between two separate observers was very good, with kappa-statistics >0.7. In tissue sections, 12 cases with paired carcinoma and prostatic intraepithelial neoplasia (PIN) showed concordance with strong immunoreactivity. Gleason scores or prostatic specific antigen (PSA) biochemical recurrences were not correlated with strong BP1 immunoreactivity. Tumor proliferation, assayed with Ki-67 (MIB-1) immunoreactivity, was higher in cancer cells that were BP1 immunoreactive, relative to those that were BP1 non-reactive. These findings suggest that BP1 is an important upstream factor in the carcinogenic pathway of prostate cancer and that the expression of BP1 may reflect or directly contribute to tumor progression and/or invasion.

Oncolytic Bacteria and their potential role in bacterium-mediated tumour therapy: a conceptual analysis.

As the human microbiota has been confirmed to be of great significance in maintaining health, the dominant bacteria in them have been applied as probiotics to treat various diseases. After the detection of bacteria in tumours, which had previously been considered a sterile region, these bacteria have been isolated and genetically modified for use in tumour therapy. In this review, we sum up the main types of bacteria used in tumour therapy and reveal the mechanisms of both wild type and engineered bacteria in eliminating tumour cells, providing potential possibilities for newly detected, genetically modified, tumour-associated bacteria in anti-tumour therapy.

Immune reconstitution inflammatory syndrome of the brain: case illustrations of a challenging entity.

Immune reconstitution inflammatory syndrome represents a spectrum of clinicopathologic entities encountered in human immunodeficiency virus-infected patients who have received highly active anti-retroviral therapy. The diagnosis is often challenging, treatment options are limited, and the prognosis is variable. To increase awareness and define the clinicopathologic features, we present our experience with 6 probable cases involving the brain, including 1 autopsy. Clinicopathologic review was supplemented by immunohistochemical analysis. There were 5 men and 1 woman, ranging in age from 34 to 47 (mean, 41; SD, 5.39) years. All patients experienced neurologic deterioration (focal deficits in 5/6) after highly active anti-retroviral therapy. All specimens showed a predominance of CD8+ lymphocytic inflammation. Concurrent CNS infections included human immunodeficiency virus encephalitis, progressive multifocal leukoencephalopathy, cryptococcal meningitis, and syphilis. One patient died, 1 was lost to follow-up, 2 improved, and 2 showed no substantial clinical changes. Subtle and overlapping features may preclude a definitive diagnosis. To capture all suspected cases, it is important to consider the possibility of this entity. In this study, the degree of CD8+ inflammation was more pronounced in the single fatal example, and mast cells were not identified in the infiltrates. Although nonspecific, imaging findings may offer clues to early diagnosis.

Correlation of p63 immunoreactivity with tumor grade in meningiomas.

Predicting tumor behavior in meningiomas based on morphologic features alone remains difficult. The present study was undertaken to assess the correlation between p63 expression and histological grade of meningiomas. A total of 37 archival intracranial meningiomas were classified into 20 grade I, 13 grade II, and 4 grade III meningiomas. Using immunohistochemical methods, staining was scored based on nuclear and/or cytoplasmic distribution as follows: 0, no staining; 1, 50% or less of the cells; 2, more than 50% of the cells. Of grade I meningiomas, 95% (19/20) lacked nuclear p63 expression and none exhibited cytoplasmic staining. Overall, 92% of grade II tumors showed nuclear expression and 31% (4/13) showed cytoplasmic expression. Grade III tumors showed an overall nuclear expression of 75% (3/4) with all exhibiting cytoplasmic staining. Our results indicate a good correlation exists between histological grade and p63 protein expression, suggesting that p63 expression might be correlated with the clinical outcome.