Role of ATG4 Autophagy-Related Protein Family in the Lower Airways of Patients with Stable COPD.

Autophagy is a complex physiological pathway mediating homeostasis and survival of cells degrading damaged organelles and regulating their recycling. Physiologic autophagy can maintain normal lung function, decrease lung cellular senescence, and inhibit myofibroblast differentiation. It is well known that autophagy is activated in several chronic inflammatory diseases; however, its role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and the expression of autophagy-related genes (ATGs) in lower airways of COPD patients is still controversial. The expression and localization of all ATG proteins that represented key components of the autophagic machinery modulating elongation, closure, and maturation of autophagosome membranes were retrospectively measured in peripheral lungs of patients with stable COPD (n = 10), control smokers with normal lung function (n = 10), and control nonsmoking subjects (n = 8) using immunohistochemical analysis. These results show an increased expression of ATG4 protein in alveolar septa and bronchiolar epithelium of stable COPD patients compared to smokers with normal lung function and non-smoker subjects. In particular, the genes in the ATG4 protein family (including ATG4A, ATG4B, ATG4C, and ATG4D) that have a key role in the modulation of the physiological autophagic machinery are the most important ATGs increased in the compartment of lower airways of stable COPD patients, suggesting that the alteration shown in COPD patients can be also correlated to impaired modulation of autophagic machinery modulating elongation, closure, and maturation of autophagosomes membranes. Statistical analysis was performed by the Kruskal-Wallis test and the Mann-Whitney U test for comparison between groups. A statistically significant increased expression of ATG4A (p = 0.0047), ATG4D (p = 0.018), and ATG5 (p = 0.019) was documented in the bronchiolar epithelium as well in alveolar lining for ATG4A (p = 0.0036), ATG4B (p = 0.0054), ATG4C (p = 0.0064), ATG4D (p = 0.0084), ATG5 (p = 0.0088), and ATG7 (p = 0.018) in patients with stable COPD compared to control groups. The ATG4 isoforms may be considered as additional potential targets for the development of new drugs in COPD.

MiRNAs and Microbiota in Non-Small Cell Lung Cancer (NSCLC): Implications in Pathogenesis and Potential Role in Predicting Response to ICI Treatment.

Lung cancer (LC) is one of the most prevalent cancers in both men and women and today is still characterized by high mortality and lethality. Several biomarkers have been identified for evaluating the prognosis of non-small cell lung cancer (NSCLC) patients and selecting the most effective therapeutic strategy for these patients. The introduction of innovative targeted therapies and immunotherapy with immune checkpoint inhibitors (ICIs) for the treatment of NSCLC both in advanced stages and, more recently, also in early stages, has revolutionized and significantly improved the therapeutic scenario for these patients. Promising evidence has also been shown by analyzing both micro-RNAs (miRNAs) and the lung/gut microbiota. MiRNAs belong to the large family of non-coding RNAs and play a role in the modulation of several key mechanisms in cells such as proliferation, differentiation, inflammation, and apoptosis. On the other hand, the microbiota (a group of several microorganisms found in human orgasms such as the gut and lungs and mainly composed by bacteria) plays a key role in the modulation of inflammation and, in particular, in the immune response. Some data have shown that the microbiota and the related microbiome can modulate miRNAs expression and vice versa by regulating several intracellular signaling pathways that are known to play a role in the pathogenesis of lung cancer. This evidence suggests that this axis is key to predicting the prognosis and effectiveness of ICIs in NSCLC treatment and could represent a new target in the treatment of NSCLC. In this review, we highlight the most recent evidence and data regarding the role of both miRNAs and the lung/gut microbiome in the prediction of prognosis and response to ICI treatment, focusing on the link between miRNAs and the microbiome. A new potential interaction based on the underlying modulated intracellular signaling pathways is also shown.

Programmed Cell Death Ligand 1 (PD-L1) Immunohistochemical Expression in Advanced Urothelial Bladder Carcinoma: An Updated Review with Clinical and Pathological Implications.

The management of advanced bladder carcinoma involves a multidisciplinary approach, but the prognosis remains poor for many patients. The immune system plays a crucial role in this disease, influencing both tumor development and response to treatment, and exploiting the immune system against the tumor can be a valuable strategy to destroy neoplastic cells. This is the biological principle underlying Bacillus Calmette-Guérin (BCG) use and, more recently, immune checkpoint inhibitors (ICIs), like PD-1 (programmed death-1)/PD-L1 (programmed death-ligand 1) inhibitors. In fact, one of the best studied immune checkpoints is represented by the PD-1/PD-L1 axis, which is a well-known immune escape system adopted by neoplastic bladder cells. PD-L1 expression has been associated with a higher pathologic stage and has shown prognostic value in bladder carcinoma. Interestingly, high-grade bladder cancers tend to express higher levels of PD-1 and PD-L1, suggesting a potential role of such an axis in mediating disease progression. Immunotherapy with PD-1 and PD-L1 inhibitors has therefore emerged as a valuable treatment option and has shown efficacy in advanced bladder cancer patients, with high PD-L1 expression levels associated with better treatment responses. Our review aims to provide a comprehensive overview of the role of PD-L1 in advanced bladder cancer, focusing on its implications for treatment decisions and the prediction of treatment response. Overall, our work aims to contribute to the understanding of PD-L1 as a predictive biomarker and highlight its role in shaping therapeutic approaches for advanced bladder cancer.

Histologic Evaluation of Thyroid Nodules Treated with Thermal Ablation: An Institutional Experience.

Thyroid nodules are a common, benign condition with a higher prevalence in women, individuals with iodine deficiency, and radiation exposure. Treatment options for benign thyroid nodules include pharmaceutical therapy, thyroidectomy, and thermal ablation (TA). TA, including laser ablation (LA), radiofrequency ablation (RFA), and microwave ablation (MWA), is a procedure that uses heat to cause tissue necrosis. It is commonly used for large, firm, benign, non-functioning thyroid nodules that cause severe symptoms or pain when surgery is not recommended or desired. When thyroid nodules do not respond to TA, they undergo surgery to resolve the symptoms and clarify the diagnosis. This study aims to analyze the histological alterations found in surgically excised TA-treated thyroid nodules and to evaluate the morphological criteria of differential diagnosis between benign and malignant nodules, establishing whether the alterations observed on the histological sample are a consequence of TA or indicative of neoplastic disease. For this purpose, the adoption of ancillary methods, such as immunohistochemistry, is fundamental to distinguish the artifacts induced by TA from the typical morphological characteristics of malignant neoplasms.

Low and Ultra-Low HER2 in Human Breast Cancer: An Effort to Define New Neoplastic Subtypes.

HER2-low and ultra-low breast cancer (BC) have been recently proposed as new subcategories of HER2 BC, supporting a re-consideration of immunohistochemical negative scores of 0, 1+ and the 2+/in situ hybridization (ISH) negative phenotype. In the present review, we outline the criteria needed to exactly distinguish HER2-low and ultra-low BC. Recent clinical trials have demonstrated significant clinical benefits of novel HER2 directing antibody-drug conjugates (ADCs) in treating these groups of tumors. In particular, trastuzumab-deruxtecan (T-Dxd), a HER2-directing ADC, has been recently approved by the US Food and Drug Administration as the first targeted therapy to treat HER2-low BC. Furthermore, ongoing trials, such as the DESTINY-Breast06 trial, are currently evaluating ADCs in patients with HER2-ultra low BC. Finally, we hope that new guidelines may help to codify HER2-low and ultra-low BC, increasing our knowledge of tumor biology and improving a targetable new therapeutical treatment.

BRAF-AXL-PD-L1 Signaling Axis as a Possible Biological Marker for RAI Treatment in the Thyroid Cancer ATA Intermediate Risk Category.

The use of radioiodine therapy (RIT) is debated in intermediate-risk differentiated thyroid cancer (DTC) patients. The understanding of the molecular mechanisms involved in the pathogenesis of DTC can be useful to refine patient selection for RIT. We analyzed the mutational status of BRAF, RAS, TERT, PIK3 and RET, and the expression of PD-L1 (as a CPS score), the NIS and AXL genes and the tumor-infiltrating lymphocytes (TIL, as the CD4/CD8 ratio), in the tumor tissue in a cohort of forty-six ATA intermediate-risk patients, homogeneously treated with surgery and RIT. We found a significant correlation between BRAF mutations and a less than excellent (LER, according to 2015 ATA classification) response to RIT treatment (p = 0.001), higher expression of the AXL gene (p = 0.007), lower expression of NIS (p = 0.045) and higher expression of PD-L1 (p = 0.004). Moreover, the LER patient group had a significantly higher level of AXL (p = 0.0003), a lower level of NIS (p = 0.0004) and a higher PD-L1 level (p = 0.0001) in comparison to patients having an excellent response to RIT. We also found a significant direct correlation between the AXL level and PD-L1 expression (p < 0.0001) and a significant inverse correlation between AXL and NIS expression and TILs (p = 0.0009 and p = 0.028, respectively). These data suggest that BRAF mutations and AXL expression are involved in LER among DTC patients and in the higher expression of PD-L1 and CD8, becoming new possible biomarkers to personalize RIT in the ATA intermediate-risk group, as well as the use of higher radioiodine activity or other possible therapies.

Hurthle cell carcinoma in childhood: A retrospective analysis of five cases and review of pediatric literature.

BACKGROUND: the available studies on Hurthle cell carcinoma (HCC) in pediatric age are scarce and based on isolated case reports. Aims of the present study were to review the available pediatric literature on HCC (2000-2019), to describe the cohort of children with this cancer histotype, and to estimate its relative prevalence in pediatric age. PROCEDURE: We retrospectively reconstructed an HCC course in five patients < 19 years who were identified in our departments during the period 2000-2019, and we reviewed the available pediatric studies on this differentiated thyroid cancer (DTC) variant. RESULTS: HCC occurred with a relative prevalence of 5.8% at a median chronological age of 12.5 years. None of HCC patients exhibited, at diagnosis, thyroid dysfunction, extensive lateral neck disease, or distant metastases, and all showed a persistent remission over time. Three patients showed, at diagnosis, antecedents of other diseases (Hashimoto's thyroiditis, neurofibromatosis type 1, and osteosarcoma). CONCLUSIONS: (1) In childhood, the relative prevalence of HCC among different thyroid cancer histotypes is 5.8%, that is close to the one previously reported both in the general population and in other less numerous children's cohorts; (2) HCC may develop even early, at the age of 7; (3) in childhood, HCC does not seem to have a more aggressive behavior when compared with other DTC histotypes; (4) antecedents of other diseases are not infrequent in the history of children with HCC.

The increasing prevalence of chronic lymphocytic thyroiditis in papillary microcarcinoma.

Although the incidence of some malignancy has decreased over the recent years, this is not the case of papillary thyroid microcarcinoma (PTMC), whose incidence has increased worldwide. Most PTMC are found incidentally after histological examination of specimens from surgery for benign thyroid disease. Hashimoto's thyroiditis, whose incidence has also increased, coexists in about one in three PTMC patients. Three different mechanisms have been proposed to clarify the association between chronic lymphocytic thyroiditis and PTMC, namely tumor development/growth by: (i) TSH stimulation, (ii) expression of certain proto-oncogenes, (iii) chemokines and other molecules produced by the lymphocytic infiltrate. Whether Hashimoto's thyroiditis protects against lymph node metastasis is debated. Overall, autommune thyroiditis seems to contribute to the favorable prognosis of PTMC. Major limitations of the studies so far performed include: (i) retrospective design, (ii) limited statistical power, (iii) high risk of selection bias, (iv) and predominant Asian ethnicity of patients. Full genetic profiling of both diseases and identification of environmental factors capable to trigger them, as well as well-powered prospective studies on different ethnical groups, may help understand their causal association and why their frequencies are continuing raising.

Case report on pathogenetic link between gluten and IgA nephropathy.

BACKGROUND: A relationship between IgA nephropathy (IgAN) and celiac disease (CD) has been reported. We show the pathogenetic link for the first time. CASE PRESENTATION: A 39-year-old man with cystic fibrosis (CF) and CF-related diabetes started to present gross hematuria, back pain and headache. At admission, laboratory analysis showed increase in serum creatinine of 1.5 mg/dl, together with hematuria and mild proteinuria (1 g/24 h). He underwent a renal biopsy to investigate the cause of hematuria and renal failure. Biopsy was consistent with IgAN. In view of patient reported dyspepsia, an upper gastrointestinal endoscopy with duodenal biopsies was undertaken and was normal. We looked for mucosal deposits of tTG-2 in the duodenum and the renal mesangium. tTG-2 deposits were found both in the duodenum and in renal biopsies, where they topographically replicated mesangial IgA deposits. After one year on a continued gluten containing diet, the patient developed a Marsh 2 type duodenal pathology. CONCLUSIONS: Our findings suggest a connection between CD and IgAN in terms of an immune-mediated gluten-induced pathogenesis even in the absence of villous atrophy and serum celiac autoantibodies.

Autophagy in advanced low- and high-grade tubular adenocarcinomas of the stomach: An ultrastructural investigation.

Autophagy represents a catabolic process in which cellular protein and organelles are engulfed into autophagosomes, digested in lysosomes and reutilized for the cellular metabolism. In neoplastic conditions, autophagy may act either as a tumour suppressor avoiding the accumulation of damaged proteins and organelles or as a mechanism of cell survival promoting the tumour growth. Although enhanced autophagy has been reported in hypoxic areas of solid tumors, there are only few ultrastructural reports concerning the relationships between autophagy and tumor grade. In the present study, we have performed an ultrastructural investigation aimed to document autophagy in a cohort of advanced gastric carcinomas of tubular type, correlating the observed findings with low and high tumor grade. Among 71 surgically resected cases of advanced gastric carcinomas, we have selected twelve low-grade and thirteen high-grade tubular adenocarcinomas. Autophagic vacuoles (AV) were only occasionally found in low-grade tubular carcinomas, while they constituted a frequent finding in high-grade ones (p < 0.01). Moreover, in high-grade tubular adenocarcinomas, our data revealed a morphologic association between autophagy and nuclear changes, such as multinucleation, micronucleation and nuclear buds, largely considered as ultrastructural aspects of mitotic instability. However, an increased autophagy was associated with organelle-poor cytoplasm or a senescent phenotype, characterized by lipofuscin granules and cytoplasmic vacuoles. In the light of our observations, it may be suggested that autophagy should be considered a phenomenon mainly related to the cellular differentiation and tumor progression.

Immunohistochemical Expression of Aquaporin-1 in Fluoro-Edenite-Induced Malignant Mesothelioma: A Preliminary Report.

BACKGROUND: The immunohistochemical expression of aquaporin-1 (AQP1) in asbestos-related malignant pleural mesothelioma (MPM) is emerging as a useful prognostic indicator of improved survival. A significantly increased incidence of MPM in a small town in southern Italy was ascribed to exposure to fluoro-edenite (FE), a naturally occurring asbestos fiber. We investigated the immunohistochemical expression of AQP1 in patients affected by FE-related MPM; taking into consideration its suggested independent prognostic role, its possible correlation with clinicopathological parameters and patient outcome was also evaluated. METHODS: Ten patients were selected for this study, as neoplastic tissue blocks, clinical and follow-up data were available. The immunohistochemical overexpression of AQP1 was defined as ≥50% of tumor cells showing membranous staining. RESULTS: Six cases showed AQP1 expression in ≥50% of tumor cells; in this group, a significant association of AQP1 overexpression with an increased median overall survival (OS) of 26.3 months was observed. By contrast, four patients exhibited an AQP1 score of <50% of stained cells, with a shorter median OS of 8.9 months. CONCLUSIONS: The present study represents further confirmation of the hypothesized prognostic role of AQP1, which seems a reliable prognostic indicator.

Cytohistological and immunohistochemical characteristics of spindle-shaped mesenchymal neoplasms occurring in the gastrointestinal tract.

The purpose of the present review is to analyze the cytohistological and immunohistochemical characteristics of spindle-shaped mesenchymal gastrointestinal neoplams (MGNs), a group of unusual neoplastic conditions with different biological behavior. These tumors exhibit clinical pictures strictly related to the site of origin and dimensions, even if they appear generally with an intramural localization. This latter point may suggest an useful application of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), mainly followed by the cell-block procedure (CBP) in the differential diagnostic approach. First of all, we discuss the most common entity of MGNs represented by gastrointestinal stromal tumors (GISTs), analyzing the morphologic characteristics and stressing the strength of immunohistochemical algorithm for diagnostic purposes. Successively, we have reported the less common group of spindle-shaped MGNs comprehensive of those arising elsewhere the soft tissues, such as leiomyomas, leiomyosarcomas, schwannomas, inflammatory myofibroblastic tumor and intra-abdominal desmoid fibromatosis. Finally, very uncommon spindle-shaped MGNs, like clear cell, follicular dendritic cell, undifferentiated pleomorphic and radiation-induced sarcomas as well as spindle cell dedifferentiated liposarcomas, have been briefly mentioned.

Classification of human meningiomas: lights, shadows, and future perspectives.

Meningiomas represent the most common primary tumors of the central nervous system (CNS) in adulthood. They are currently classified into several histotypes and into three grades of malignancy according to the criteria of the World Health Organization (WHO) classification of tumors of the CNS. WHO histological grade is currently the most significant morphological predictor of recurrence risk of meningiomas. For this reason, it is fully taken into consideration in postsurgical therapeutic decision making in patients with meningioma. However, the main drawback of the WHO grading system system is that criteria for its assessment are rather subjective and poorly standardized. Hence, additional factors are warranted to predict recurrence risk of meningiomas, so that patients may actually receive the most appropriate therapy. In recent years, biomolecular pathogenesis of meningiomas has been partially clarified, and many efforts have been made in the identification of molecular factors associated with recurrence risk of meningioma. Here we review WHO criteria currently used for classification of meningiomas and discuss on pitfalls and limits of grading assessment. In addition we present the latest advancement in the knowledge of biomolecular alterations involved in the pathogenesis and progression of meningiomas. Similarly to what has already happened for gliomas, a novel classification integrating histology and molecular information might overcome the limits of histological classification in terms of reproducibility as well as of prognostic and predictive relevance. © 2016 Wiley Periodicals, Inc.

The micropapillary/hobnail variant of papillary thyroid carcinoma: A review of series described in the literature compared to a series from one southern Italy pathology institution.

Papillary thyroid carcinoma (PTC) has a good prognosis with a 10-yr survival greater than 90%. Recently, a micro-papillary pattern with hobnail appearance (MPHC) in PTC has been indicated as associated with poor prognosis, but this suggestion is based only on a few cases from geographical areas different from ours. Two-hundred ninety-nine consecutive PTC cases were collected between the years of 1992 and 2014 at our institution. The corresponding histologic sections (at least 6 for each case) were stained with hematoxylin and eosin and reviewed independently by two pathologists to reach a consensus on the identification and quantification of the MPHC. As done in other cohorts, parallel serial sections were stained with antisera for thyroglobulin, epithelial membrane antigen, thyroid-transcription-factor-1 and Ki 67. BRAF gene mutation at codon 600 and RET/PTC1 gene rearrangements were searched. A comparative statistical analysis was done between the present series and previously published series. Of the 295 PTC, 124 (42.5%) were follicular, 104 (35%) classic, 34 (11.5%) sclerosing, 15 (5%) tall cells, 10 (3.4%) Warthin-like, and 8 (2.7%) MPHC. Four MHPC cases (50%) harbored the BRAF V600E variant, while one was positive for RET/PTC1 rearrangement. Our rate of MPHC-PTC (2.7%) is 2X to 8X greater than those reported previously for cohorts from North America + North Italy, Korea and Mexico. MPHC prognosis appears to be better compared to other cohorts, probably due to not only to the lower rate of the vascular invasion, but also to the smaller size of the MPHC-PTC nodule.

Histologic prognostic markers in stage IIA colorectal cancer: a comparative study.

OBJECTIVE: pTNM stage IIA colorectal cancer (CRC) is not currently submitted to any adjuvant treatment due to its good prognosis. Nevertheless, a percentage of cases unexpectedly recur. The aim of this study was to assess and compare the prognostic value and inter-observer agreement of a novel histological grading system based on the counting of poorly differentiated clusters (PDC) of cancer cells and that of conventional histological grade, lymphatic, venous and perineural invasion (LVI, VI, PNI), tumour budding (TB) and tumor border configuration in stage IIA CRC. MATERIALS AND METHODS: the afore mentioned histological parameters were assessed in 82 stage IIA CRCs. Inter-observer agreement and correlation with tumour relapse were analyzed by using Fleiss-Cohen's weighted K statistics, Fisher exact test and Chi-squared test. The Mantel-Cox log-rank test was applied to assess the strength of association with disease-free interval (DFI). RESULTS: inter-observer agreement was very good/good in the assessment of PDC presence and grade, while it was moderate at best in the evaluation of the other parameters. The presence of PDC, high PDC grade, LVI and TB were significantly associated with disease progression (p < 0.0001; p = 0.0012; p = 0.0308; p = 0.0002) and shorter DFI (p = 0.0001; p < 0.0001; p = 0.0129; p = 0.0008). PDC presence (p < 0.0001) and TB (p = 0.012) were independent prognostic factors in multivariate analysis. CONCLUSIONS: our findings suggest that the assessment of PDC may be useful to stratify patients with stage IIA CRC for recurrence risk, and to identify high risk patients who could benefit from adjuvant chemotherapy.

Atypical teratoid rhabdoid tumor involving the nasal cavities and anterior skull base.

Rhabdoid tumors are a spectrum of neoplasias composed of cells which show rhabdoid morphology but are devoid of skeletal muscle differentiation. These tumors are characterized by inactivation of the INI1/SMARCB1 gene and they have been described in virtually every anatomical site, including the central nervous system (CNS) and sinonasal tract. Rhabdoid tumor of the CNS was named atypical teratoid rhabdoid tumor (ATRT) and it mainly affects children under the age of 3 years with supra- or infra-tentorial location.Herein we report the first case of ATRT infiltrating the nasal cavities and skull base in an adolescent. Due to its unusual location, differential diagnosis was challenging and included several other entities such as sinonasal carcinoma or meningioma. Awareness that ATRT may infiltrate the nasal tract and knowledge of its clinico-pathological, immunohistochemical and biomolecular features are essential for its distinction from other rhabdoid tumors which more frequently involve this anatomical site and for appropriate therapeutic management.

Morphological and Cellular Features of Innate Immune Reaction in Helicobacter pylori Gastritis: A Brief Review.

Innate and adaptive immunity are both involved in acute and chronic inflammatory processes. The main cellular players in the innate immune system are macrophages, mast cells, dendritic cells, neutrophils, eosinophils, and natural killer (NK), which offer antigen-independent defense against infection. Helicobacter pylori (H. pylori) infection presents peculiar characteristics in gastric mucosa infrequently occurring in other organs; its gastric colonization determines a causal role in both gastric carcinomas and mucosa-associated lymphoid tissue lymphoma. In contrast, an active role for Epstein-Barr virus (EBV) has been identified only in 9% of gastric carcinomas. The aim of the present review is to discuss the role of cellular morphological effectors in innate immunity during H. pylori infection and gastric carcinogenesis.

HER2 Analysis in Sporadic Thyroid Cancer of Follicular Cell Origin.

The Epidermal Growth Factor Receoptor (EGFR) family member human epidermal growth factor receptor 2 (HER2) is overexpressed in many human epithelial malignancies, representing a molecular target for specific anti-neoplastic drugs. Few data are available on HER2 status in differentiated thyroid cancer (DTC). The present study was aimed to investigate HER2 status in sporadic cancers of follicular cell origin to better clarify the role of this receptor in the stratification of thyroid cancer. By immunohistochemistry and fluorescence in-situ hybridization, HER2 expression was investigated in formalin-fixed paraffin-embedded surgical specimens from 90 DTC patients, 45 follicular (FTC) and 45 papillary (PTC) histotypes. No HER2 immunostaining was recorded in background thyroid tissue. By contrast, overall HER2 overexpression was found in 20/45 (44%) FTC and 8/45 (18%) PTC, with a significant difference between the two histotypes (p = 0.046). Five of the six patients who developed metastatic disease during a median nine-year follow-up had a HER2-positive tumor. Therefore, we suggest that HER2 expression may represent an additional aid to identify a subset of patients who are characterized by a worse prognosis and are potentially eligible for targeted therapy.

p-CREB expression in human meningiomas: correlation with angiogenesis and recurrence risk.

Despite total surgical resection, a percentage of meningiomas do unexpectedly recur. At present the prediction of recurrence risk and the management of recurrent tumours represent major issues in the patients affected by meningiomas. The present study aims at investigating the prognostic value of the expression of the phosphorylated transcription factor cyclic AMP responsive element binding protein (p-CREB) in a series of meningiomas of different histotype and grade. While no p-CREB expression was found in specimens of normal leptomeninges, 71 % of meningiomas in our cohort expressed p-CREB. In addition, nuclear expression of p-CREB was present in the endothelia of tumor vessels in all of the meningiomas, but not in the vessels of the non-neoplastic meninges. High expression of p-CREB was significantly more frequent in meningiomas showing atypical, chordoid or microcystic histotype (P = 0.0003), high histological grade (P < 0.0001), high Ki-67 labeling index (P = 0.0001), high microvessel density counts (P < 0.0001) and high vascular endothelial growth factor expression (P = 0.0113). In addition, high p-CREB expression was significantly associated with the development of recurrences (P = 0.0031) and it was a significant negative, albeit not independent, prognostic factor for disease free survival in patients with meningiomas submitted to complete surgical removal (P = 0.0019). In conclusion, we showed that p-CREB is expressed in human meningiomas and that it represents a significant predictor of recurrence risk in these tumors. Due to its high expression in more aggressive tumors and in the tumor vessels, it may represent a novel therapeutic target in meningiomas.