Search

Abstract Background The expression of aquaporin 4 (AQP4) and intermediate filament (IF) proteins is altered in malignant glioblastoma (GBM), yet the expression of the major IF-based cytolinker, plectin (PLEC), and its contribution to GBM migration and invasiveness, are unknown. Here, we assessed the contribution of plectin in affecting the distribution of plasmalemmal AQP4 aggregates, migratory properties, and regulation of cell volume in astrocytes. Methods In human GBM, the expression of glial fibrillary acidic protein (GFAP), AQP4 and PLEC transcripts was analyzed using publicly available datasets, and the colocalization of PLEC with AQP4 and with GFAP was determined by immunohistochemistry. We performed experiments on wild-type and plectin-deficient primary and immortalized mouse astrocytes, human astrocytes and permanent cell lines (U-251 MG and T98G) derived from a human malignant GBM. The expression of plectin isoforms in mouse astrocytes was assessed by quantitative real-time PCR. Transfection, immunolabeling and confocal microscopy were used to assess plectin-induced alterations in the distribution of the cytoskeleton, the influence of plectin and its isoforms on the abundance and size of plasmalemmal AQP4 aggregates, and the presence of plectin at the plasma membrane. The release of plectin from cells was measured by ELISA. The migration and dynamics of cell volume regulation of immortalized astrocytes were assessed by the wound-healing assay and calcein labeling, respectively. Results A positive correlation was found between plectin and AQP4 at the level of gene expression and protein localization in tumorous brain samples. Deficiency of plectin led to a decrease in the abundance and size of plasmalemmal AQP4 aggregates and altered distribution and bundling of the cytoskeleton. Astrocytes predominantly expressed P1c, P1e, and P1g plectin isoforms. The predominant plectin isoform associated with plasmalemmal AQP4 aggregates was P1c, which also affected the mobility of astrocytes most prominently. In the absence of plectin, the collective migration of astrocytes was impaired and the dynamics of cytoplasmic volume changes in peripheral cell regions decreased. Plectin’s abundance on the plasma membrane surface and its release from cells were increased in the GBM cell lines. Conclusions Plectin affects cellular properties that contribute to the pathology of GBM. The observed increase in both cell surface and released plectin levels represents a potential biomarker and therapeutic target in the diagnostics and treatment of GBMs.

Pleural mesothelioma is a devastating malignancy primarily associated with asbestos exposure. However, emerging evidence suggests that exposure to fluoro-edenite fibers, a naturally occurring mineral fiber, can also lead to the development of pleural mesothelioma. In this study, based on the hypothesis that pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP-preferring receptor (PAC1R) expressions could be dysregulated in pleural mesothelioma samples and that they could potentially act as diagnostic or prognostic biomarkers, we aimed to investigate the immunohistochemical expression of PACAP and PAC1R in pleural biopsies from patients with pleural mesothelioma exposed to fluoro-edenite fibers. A total of 12 patients were included in this study, and their biopsies were processed for immunohistochemical analysis to evaluate the expression of PACAP and its receptor. The study revealed a correlation between the overexpression of PACAP and PAC1R and shorter overall survival in patients with malignant mesothelioma. These findings suggest that PACAP and PAC1R expression levels could serve as potential prognostic biomarkers for malignant mesothelioma. Furthermore, the immunohistochemical analysis of PACAP and PAC1R may provide valuable information for clinicians to guide therapeutic decisions and identify patients with poorer prognosis.

Introduction: Alzheimer’s disease (AD) is the most common neurodegenerative disorder affecting the elderly population worldwide. Due to the multifactorial nature of the disease, involving impairment of cholinergic neurotransmission and immune system, previous attempts to find effective treatments have faced challenges.Methods: In such scenario, we attempted to investigate the effects of alpha-glyceryl-phosphoryl-choline (α-GPC), a cholinomimetic molecule, on neuroinflammation and memory outcome in the triple transgenic mouse model of AD (3xTg-AD). Mice were enrolled at 4 months of age, treated orally with α-GPC dissolved in drinking water at a concentration resulting in an average daily dose of 100 mg/kg for 8 months and sacrificed at 12 months of age. Thereafter, inflammatory markers, as well as cognitive parameters, were measured.Results: Chronic α-GPC treatment reduced accumulation of amyloid deposits and led to a substantial re-balance of the inflammatory response of resident innate immune cells, astrocytes and microglia. Specifically, fluorescent immunohistochemistry and Western blot analysis showed that α-GPC contributed to reduction of cortical and hippocampal reactive astrocytes and pro-inflammatory microglia, concurrently increasing the expression of anti-inflammatory molecules. Whereas α-GPC beneficially affect the synaptic marker synaptophysin in the hippocampus. Furthermore, we observed that α-GPC was effective in restoring cognitive dysfunction, as measured by the Novel Object Recognition test, wherein 3xTg-AD mice treated with α-GPC significantly spent more time exploring the novel object compared to 3xTg-AD untreated mice.Discussion: In conclusion, chronic treatment with α-GPC exhibited a significant anti-inflammatory activity and sustained the key function of hippocampal synapses, crucial for the maintenance of a regular cognitive status. In light of our results, we suggest that α-GPC could be exploited as a promising therapeutic approach in early phases of AD.

Myeloproliferative neoplasms (MPNs) are subdivided into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. BCR::ABL1 translocation is essential for the development and diagnosis of CML; on the other hand, the majority of Ph-negative MPNs are characterized by generally mutually exclusive mutations of Janus kinase 2 (JAK2), calreticulin (CALR), or thrombopoietin receptor/myeloproliferative leukemia (MPL). CALR mutations have been described essentially in JAK2 and MPL wild-type essential thrombocythemia and primary myelofibrosis. Rarely coexisting CALR and MPL mutations have been found in Ph-negative MPNs. BCR::ABL1 translocation and JAK2 mutations were initially considered mutually exclusive genomic events, but a discrete number of cases with the combination of these genetic alterations have been reported. The presence of BCR::ABL1 translocation with a coexisting CALR mutation is even more uncommon. Herein, starting from a routinely diagnosed case of CALR-mutated primary myelofibrosis subsequently acquiring BCR::ABL1 translocation, we performed a comprehensive review of the literature, discussing the clinicopathologic and molecular features, as well as the outcome and treatment of cases with BCR::ABL1 and CALR co-occurrence.

Background: Schwannomas are solitary neurogenic tumors originating from the myelin-producing cells of the neural sheath. Hypoglossal nerve schwannomas are exceedingly rare, particularly those extracranially originating and mimicking a submandibular salivary gland tumor. Methods: We report the case of a 31-year-old female who presented to our ENT department with a painless swelling in her left submandibular region that has persisted for approximately five months. Discussion: Due to the rarity of these tumors and their unique nature, a comprehensive diagnostic workup is imperative for accurate diagnosis. Surgical excision remains the gold standard treatment. Conclusions: Extracranial hypoglossal nerve schwannomas represent a rare clinical entity requiring a thorough diagnostic process for precise identification. The preferred treatment strategy for managing hypoglossal gland schwannomas involves complete tumor excision while preserving the facial nerve.

The interaction of programmed death-1 (PD-1) on T lymphocytes with its ligands Programmed Death Ligand 1 (PD-L1) and Programmed Death Ligand 2 (PD-L2) on tumor cells and/or tumor-associated macrophages results in inhibitory signals to the T-cell receptor pathway, consequently causing tumor immune escape. PD-L1/PD-L2 are currently used as predictive tissue biomarkers in clinical practice. Virtually PD-L1 levels expressed by tumor cells are associated with a good response to immune checkpoint blockade therapies targeting the PD-1/PD-L1 axis. These therapies restore T-cell antitumor immune response by releasing T-lymphocytes from the inhibitory effects of tumor cells. Immune checkpoint therapies have completely changed the management of patients with solid cancers. This therapeutic strategy is less used in hematological malignancies, although good results have been achieved in some settings, such as refractory/relapsed classic Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Variable results have been obtained in diffuse large B-cell lymphoma and T-cell lymphomas. Immunohistochemistry represents the main technique for assessing PD-L1 expression on tumor cells. This review aims to describe the current knowledge of PD-L1 expression in various types of lymphomas, focusing on the principal mechanisms underlying PD-L1 overexpression, its prognostic significance and practical issues concerning the evaluation of PD-L1 immunohistochemical results in lymphomas.

Myeloproliferative neoplasms (MPNs) are classified into Philadelphia (Ph) chromosome–positive chronic myeloid leukemia (CML) and Ph-negative MPNs. BCR::ABL1 translocation is the key genetic event of CML, whereas JAK2/MPL/CALR mutations are molecular aberrations of Ph-negative MPNs. Despite initially considered mutually exclusive genetic aberrations, the co-occurrence of BCR::ABL1 and JAK2 has been reported in a limited number of cases. The two genetic alterations may be identified either at the same time or JAK2 aberration may be detected in patients with a previous CML treated with tyrosine kinase inhibitors or, finally, BCR::ABL1 translocation occurs in patients with a history of JAK2-positive MPN. This combination of genomic alterations is potentially confounding with clinical manifestations often misinterpreted either as disease progression or drug resistance, therefore leading to inappropriate patient’s treatment. Our systematic review aims to improve hematologist and pathologist knowledge on this rare subset of patients. Starting from the presentation of two additional cases from our routine daily practice, we focus mainly on clinical, laboratory, and bone marrow histological findings, which may represent useful clues of BCR::ABL1 and JAK2 co-occurrence. The interaction between JAK2 and BCR::ABL1 clones during the disease course as well as therapy and outcome are presented.

Proton boron capture therapy (PBCT) in a preclinical glioblastoma model exhibits increased therapeutic effectiveness with an increased cell death and mitophagy, supporting its use as a scalable strategy to treat glioblastoma.

We aimed to analyze the association between CYP7B1 and prostate cancer, along with its association with proteins involved in cancer and metabolic processes. A retrospective analysis was performed on 390 patients with prostate cancer (PC) or benign prostatic hyperplasia (BPH). We investigated the interactions between CYP7B1 expression and proteins associated with PC and metabolic processes, followed by an analysis of the risk of biochemical recurrence based on CYP7B1 expression. Of the 139 patients with elevated CYP7B1 expression, 92.8% had prostate cancer. Overall, no increased risk of biochemical recurrence was associated with CYP7B1 expression. However, in a non-diabetic subgroup analysis, higher CYP7B1 expression indicated a higher risk of biochemical recurrence, with an HR of 1.78 (CI: 1.0–3.2, p = 0.05). PC is associated with elevated CYP7B1 expression. In a subgroup analysis of non-diabetic patients, elevated CYP7B1 expression was associated with an increased risk of biochemical recurrence, suggesting increased cancer aggressiveness.

Abstract Colorectal Cancer (CRC) is one of the most common cancers accounting for 1.8 million new cases worldwide every year. Therefore, the identification of new potential therapeutic targets represents a continuous challenge to improve survival and quality of CRC patient’s life. We performed a microarray analysis dataset consisting of colon biopsies of healthy subjects (HS) and CRC patients. These results were further confirmed in a clinical setting evaluating a series of CRC patients to assess the expression of Resistin-Like Beta (RETNLB) and to correlate it with their clinical data. Our results showed a significant reduction of RETNLB expression in CRC biopsies compared to the HS mucosa. Furthermore, such reduction was significantly associated with the TNM grade and patients’ age. Furthermore, a significantly positive correlation was found within mutated subjects for KRAS, TP53, and BRAF. In particular, patients with poor prognosis at 5 years exhibited RETNLB lower levels. In-silico analysis data were confirmed by histochemical analysis in a series of CRC patients recruited by our group. The results obtained provided that RETNLB low levels are associated with an unfavorable prognosis in CRC patients and its expression is also dependent on adjuvant therapy. Further studies are warranted in order to evaluate the molecular mechanisms underlying the role of RETNLB in CRC progression.

Mantle cell lymphoma is a B-cell malignancy, which, in its classic form, usually involves lymph nodes and extranodal sites, and, among the extranodal sites, the gastrointestinal tract and the Waldeyer’s ring are most prevalent. MCL is rarely reported in the ocular adnexa, a site more frequently affected by extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, which is a form of low-grade malignancy. The diagnosis of MCL presenting in the ocular adnexa requires special attention as its rarity in this location combined with the not uncommon CD5 negativity of the disease when occurring in the ocular adnexa, may lead the pathologist to overlook the diagnosis and misinterpret MCL as marginal zone B cell lymphoma, which has a totally different behavior. Herein, we present a case of primary bilateral conjunctival CD5-negative MCL in a patient having no other sites affected by lymphoma and we discuss possible diagnostic pitfalls.

In the original publication [...]

Since there are no morphological clues capable of making a pathologist suspect a possible mammary origin of a metastatic lesion without adequate clinical information, the histologic diagnosis of brain metastasis from BC is still based on the immunohistochemical expression of mammary gland markers such as GATA-3, ERs, PgRs and HER-2. The present retrospective study aimed to select purely morphological features capable of suggesting the mammary origin of a metastatic carcinoma in the brain. The following histological features were collected from a series of 30 cases of brain metastases from breast cancer: (i) a solid growth pattern; (ii) the presence of comedonecrosis; and (iii) glandular differentiation. Our results showed that most cases histologically exhibited a solid growth pattern with at least focal comedonecrosis, producing an overall morphology closely reminiscent of mammary high-grade ductal carcinoma in situ. Although the above-mentioned morphological parameters are not strictly specific to a mammary origin, they may have an important diagnostic utility for leading pathologists to suspect a possible breast primary tumor and to include GATA-3, ERs, PgRs and HER-2 in the immunohistochemical panel.

Abstract Therapy of uveal melanoma aims to preserve the eye and its function and to avoid metastatic dissemination. The treatment choice is difficult and must keep into account several factors; the therapeutic strategy of uveal melanoma should therefore be personalized, sometimes requiring to combine different treatment techniques. Nowadays globe-sparing radiotherapy techniques are often preferred to enucleation. Plaque brachytherapy, the most commonly used eye-preserving therapy, is suitable for small- and medium-sized uveal melanomas. Proton beam radiotherapy is indicated for tumours with noticeable size, challenging shape and location, but is more expensive and less available than brachytherapy. Enucleation is currently restricted to advanced tumours, uveal melanomas with orbital or optic nerve involvement, blind and painful eyes because of treatment-related complications (neovascular glaucoma, chronic inflammatory processes). The effect of proton beam therapy on neoplastic tissue is related to direct cytotoxic action of the radiations, impairment of neoplastic vascular supply and immunologic response. Complications after radiotherapy are frequent and numerous and mainly related to tumour thickness, radiation dose and distance between the tumour and optic nerve. The purpose of this pictorial review is to provide the radiologists with awareness about diagnostic methods and therapeutic options of uveal melanoma. In the present second section, we discuss the therapeutic management of uveal melanoma, describing the main ocular-conserving radiotherapic techniques. We subsequently present an overview of the effects of radiations on neoplastic tissue. Lastly, we review ocular complications following radiotherapy that should be evaluated by radiologists during follow-up MRI examinations.

Abstract Uveal melanoma is a malignant neoplasm that derives from pigmented melanocytes of the uvea and involves, in order of decreasing prevalence, the choroid, ciliary body and iris. Its prognosis is related to histopathologic and genetic features, tumor size and location, extraocular extension. The diagnosis is fundamentally based on clinical evaluation (ophthalmoscopy, biomicroscopy) and ultrasonography. MRI is useful in case of untransparent lens or subretinal effusion. Moreover, MRI has a significant role to confirm the diagnosis, in the evaluation of the local extent of the disease with implications for treatment planning, and in the follow-up after radiotherapy treatment. Uveal melanoma can show different morphologic features (lentiform, dome or mushroom shape) and often determines retinal detachment. MR appearance of uveal melanoma mainly depends on the melanin content. Uveal melanoma typically displays high signal intensity on T1-weighted images and low signal intensity on T2-weighted images. Nevertheless, imaging appearance may be variable based on the degree of pigmentation and the presence of areas of necrosis or cavitation. Differential diagnosis includes other uveal lesions. The radiologists and in particular MRI play a significant role in the clinical management of uveal melanoma. The purpose of this pictorial review is to provide the radiologists with awareness about diagnostic methods and therapeutic options of uveal melanoma. In the present first section we summarize the MR anatomy of the eye and describe ophthalmological and radiological imaging techniques to diagnose uveal melanomas, with emphasis on the role of MR imaging. Additionally, we review MR imaging appearance of uveal melanomas.

The tumor microenvironment (TME) plays a pivotal role in establishing malignancy, and it is associated with high glycolytic metabolism and lactate release through monocarboxylate transporters (MCTs). Several lines of evidence suggest that lactate also serves as a signaling molecule through its receptor hydroxycarboxylic acid receptor 1 (HCAR1/GPR81), thus functioning as a paracrine and autocrine signaling molecule. The aim of the present study was to investigate the role of lactate in glioblastoma (GBM) progression and metabolic reprogramming in an in vitro and in vivo model. The cell proliferation, migration, and clonogenicity were tested in vitro in three different human GBM cell lines. The expressions of MCT1, MCT4, and HCAR1 were evaluated both in vitro and in a zebrafish GBM model. The results were further validated in patient-derived GBM biopsies. Our results showed that lactate significantly increased the cell proliferation, migration, and colony formation capacity of GBM cells, both in vitro and in vivo. We also showed that lactate increased the expressions of MCT1 and HCAR1. Moreover, lactate modulated the epithelial–mesenchymal transition protein markers E-cadherin and β-catenin. Interestingly, lactate induced mitochondrial mass and the OXPHOS gene, suggesting improved mitochondrial fitness. Similar effects were observed after treatment with 3,5-dihydroxybenzoic acid, a known agonist of HCAR1. Consistently, the GBM zebrafish model exhibited an altered metabolism and increased expressions of MCT1 and HCAR1, leading to high levels of extracellular lactate and, thus, supporting tumor cell proliferation. Our data from human GBM biopsies also showed that, in high proliferative GBM biopsies, Ki67-positive cells expressed significantly higher levels of MCT1 compared to low proliferative GBM cells. In conclusion, our data suggest that lactate and its transporter and receptor play a major role in GBM proliferation and migration, thus representing a potential target for new therapeutic strategies to counteract tumor progression and recurrence.

The management of patients with Central Nervous System (CNS) malignancies relies on the appropriate classification of these tumors. Recently, the World Health Organization (WHO) has published new criteria underlining the importance of an accurate molecular characterization of CNS malignancies, in order to integrate the information generated by histology. Next generation sequencing (NGS) allows single step sequencing of multiple genes, generating a comprehensive and specific mutational profile of the tumor tissue. We developed a custom NGS-based multi-gene panel (Glio-DNA panel) for the identification of the correct glioma oncotype and the detection of its essential molecular aberrations. Specifically, the Glio-DNA panel targets specific genetic and chromosomal alterations involving ATRX chromatin remodeler (ATRX), cyclin dependent kinase inhibitor 2A (CDKN2A), isocitrate dehydrogenase (NADP+) 1 (IDH1) and the telomerase reverse transcriptase (TERT) promoter while also recognizing the co-deletion of 1p/19q, loss of chromosome 10 and gain of chromosome 7. Furthermore, the Glio-DNA panel also evaluates the methylation level of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter that predicts temozolomide efficacy. As knowledge of the mutational landscape of each glioma is mandatory to define a personalized therapeutic strategy, the Glio-DNA panel also identifies alterations involving “druggable” or “actionable” genes. To test the specificity of our panel, we used two reference mutated DNAs verifying that NGS allele frequency measurement was highly accurate and sensitive. Subsequently, we performed a comparative analysis between conventional techniques - such as immunohistochemistry or fluorescence in situ hybridization - and NGS on 60 diffuse glioma samples that had been previously characterized. The comparison between conventional testing and NGS showed high concordance, suggesting that the Glio-DNA panel may replace multiple time-consuming tests. Finally, the identification of alterations involving different actionable genes matches glioma patients with potential targeted therapies available through clinical trials. In conclusion, our analysis demonstrates NGS efficacy in simultaneously detecting different genetic alterations useful for the diagnosis, prognosis and treatment of adult patients with diffuse glioma.

Abstract Background Primary squamous cell carcinoma of the liver is a very rare cancer requiring a complete diagnostic investigation, as it presents some differences from other primary hepatic malignancies. We describe the case of an elderly patient with primitive squamous cell carcinoma of the liver treated by percutaneous microwave ablation and transarterial chemoembolization. Case presentation Although the pathogenesis remains uncertain, a possible transformation of the biliary epithelium caused by chronic inflammation or metaplasia and subsequent malignant transformation of preexisting benign hepatic cysts has been suggested. A critical review of the existing literature was performed by focusing on the pathogenesis, clinical presentation, and the suggested therapeutic strategies. Conclusion A multidisciplinary approach is needed to face rare hepatic malignancies where there are no clear guidelines.

It has been reported that in-frame FGFR3-TACC3 fusions confer to glioblastomas, IDH-wild type (GBMs, IDHwt) some unusual morphologic features, including monomorphous rounded cells with ovoid nuclei, nuclear palisading, endocrinoid network of “chicken-wire” vessels, microcalcifications and desmoplastic stroma, whose observation may predict the molecular profile of the tumor. We herein present a case of recurrent GBMs, IDHwt, exhibiting some of the above-mentioned morphological features and a molecularly-proven FGFR3-TACC3 fusion. A 56-year-old man presented to our hospital for a recurrent GBM, IDHwt, surgically treated at another center. Histologically, the tumor, in addition to the conventional GBM morphology, exhibited the following peculiar morphologic features: (1) monomorphous neoplastic cells with rounded nuclei and scant pale cytoplasm; (2) thin capillary-like vessels with “chicken-wire” pattern; (3) nuclear palisading; (4) formation of vague perivascular pseudorosettes; (5) spindled tumor cells embedded in a loose, myxoid background. Based on this unusual morphology, molecular analyses were performed and an FGFR3 exon17-TACC3 exon 10 fusion was found. The present case contributes to widening the morphologic spectrum of FGFR3-TACC3-fused GBM, IDHwt and emphasizes that pathologists, in the presence of a GBM, IDHwt with unconventional morphology, should promptly search for this fusion gene.

Although malignant melanoma (MM) most frequently tends to metastasize to the regional lymph nodes, liver, lung and brain, several unusual sites of metastasis have been described in the literature. Among these, the metastatic involvement of gallbladder or uterus represents an exceptional event, usually associated with diffuse metastatic disease or observed as an autopsy finding. In this paper, we present two unusual cases of isolated MM metastasis to these anatomic sites, arising in a 71-year-old man and a 54-year-old woman, for whom no information on previous malignancies was known at the time of the histological examination. The clinico-pathologic features are described, emphasizing that MM metastasis must be included in the differential diagnosis when dealing with patients with a previous diagnosis of MM and onset of a novel mass/lesion even at unusual sites.

The central nervous system represents a complex environment in which glioblastoma adapts skillfully, unleashing a series of mechanisms suitable for its efficient development and diffusion. In particular, changes in gene expression and mutational events that fall within the domain of epigenetics interact complexly with metabolic reprogramming and stress responses enacted in the tumor microenvironment, which in turn fuel genomic instability by providing substrates for DNA modifications. The aim of this review is to analyze this complex interaction that consolidates several conditions that confer a state of immunosuppression and immunoevasion, making glioblastoma capable of escaping attack and elimination by immune cells and therefore invincible against current therapies. The progressive knowledge of the cellular mechanisms that underlie the resistance of the glioblastoma represents, in fact, the only weapon to unmask its weak points to be exploited to plan successful therapeutic strategies.

The extent of resection beyond the enhancing core (EC) in glioblastoma IDH-wild type (GBM, IDHwt) is one of the most debated topics in neuro-oncology. Indeed, it has been demonstrated that local disease recurrence often arises in peritumoral areas and that radiologically-defined FLAIR hyperintensity areas of GBM IDHwt are often visible beyond the conventional EC. Therefore, the need to extend the surgical resection also to the FLAIR hyperintensity areas is a matter of debate. Since little is known about the histological composition of FLAIR hyperintensity regions, in this study we aimed to provide a comprehensive description of the histological features of EC and FLAIR hyperintensity regions sampled intraoperatively using neuronavigation and 5-aminolevulinic acid (5-ALA) fluorescence, in 33 patients with GBM, IDHwt. Assessing a total 109 histological samples, we found that FLAIR areas consisted in: (i) fragments of white matter focally to diffusely infiltrated by tumor cells in 76% of cases; (ii) a mixture of white matter with reactive astrogliosis and grey matter with perineuronal satellitosis in 15% and (iii) tumor tissue in 9%. A deeper knowledge of the histology of FLAIR hyperintensity areas in GBM, IDH-wt may serve to better guide neurosurgeons on the choice of the most appropriate surgical approach in patients with this neoplasm.

Palmoplantar psoriasis (PP) is a relatively uncommon variant of psoriasis that affects palms and soles, and that frequently shares both clinical and histologic features with chronic eczema, hyperkeratotic hand dermatitis and allergic contact dermatitis. The present study aims to characterize the histologic features of PP on a series of 21 cases. The following morphological features and their distribution were included: parakeratosis, dilated vessels in papillary dermis, psoriasiform acanthosis with elongation of rete ridges, perivascular lymphocytic infiltrate, decrease/loss of granular layer, Munro’s microabscesses, spongiform pustules of Kogoj, spongiosis and lymphocytic exocytosis. The main diagnostic clues and histologic differential diagnoses are also discussed.

Uveal melanoma (UM), the most common primary intraocular cancer in adults, is among the tumors with poorer prognosis. Recently, the role of the oncometabolite lactate has become attractive due to its role as hydroxycarboxylic acid receptor 1 (HCAR1) activator, as an epigenetic modulator inducing lysine residues lactylation and, of course, as a glycolysis end-product, bridging the gap between glycolysis and oxidative phosphorylation. The aim of the present study was to dissect in UM cell line (92.1) the role of lactate as either a metabolite or a signaling molecule, using the known modulators of HCAR1 and of lactate transporters. Our results show that lactate (20 mM) resulted in a significant decrease in cell proliferation and migration, acting and switching cell metabolism toward oxidative phosphorylation. These results were coupled with increased euchromatin content and quiescence in UM cells. We further showed, in a clinical setting, that an increase in lactate transporters MCT4 and HCAR1 is associated with a spindle-shape histological type in UM. In conclusion, our results suggest that lactate metabolism may serve as a prognostic marker of UM progression and may be exploited as a potential therapeutic target.

The involvement of non-coding RNAs (ncRNAs) in glioblastoma multiforme (GBM) pathogenesis and progression has been ascertained but their cross-talk within GBM cells remains elusive. We previously demonstrated the role of circSMARCA5 as a tumor suppressor (TS) in GBM. In this paper, we explore the involvement of circSMARCA5 in the control of microRNA (miRNA) expression in GBM. By using TaqMan® low-density arrays, the expression of 748 miRNAs was assayed in U87MG overexpressing circSMARCA5. Differentially expressed (DE) miRNAs were validated through single TaqMan® assays in: (i) U87MG overexpressing circSMARCA5; (ii) four additional GBM cell lines (A172; CAS-1; SNB-19; U251MG); (iii) thirty-eight GBM biopsies; (iv) twenty biopsies of unaffected brain parenchyma (UC). Validated targets of DE miRNAs were selected from the databases TarBase and miRTarbase, and the literature; their expression was inferred from the GBM TCGA dataset. Expression was assayed in U87MG overexpressing circSMARCA5, GBM cell lines, and biopsies through real-time PCR. TS miRNAs 126-3p and 515-5p were upregulated following circSMARCA5 overexpression in U87MG and their expression was positively correlated with that of circSMARCA5 (r-values = 0.49 and 0.50, p-values = 9 × 10−5 and 7 × 10−5, respectively) in GBM biopsies. Among targets, IGFBP2 (target of miR-126-3p) and NRAS (target of miR-515-5p) mRNAs were positively correlated (r-value = 0.46, p-value = 0.00027), while their expression was negatively correlated with that of circSMARCA5 (r-values = −0.58 and −0.30, p-values = 0 and 0.019, respectively), miR-126-3p (r-value = −0.36, p-value = 0.0066), and miR-515-5p (r-value = −0.34, p-value = 0.010), respectively. Our data identified a new GBM subnetwork controlled by circSMARCA5, which regulates downstream miRNAs 126-3p and 515-5p, and their mRNA targets IGFBP2 and NRAS.

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. To date, the main strategies to counteract its progression consist of focal radiation on the tumor site and ocular enucleation. Furthermore, many UM patients develop liver metastasis within 10 years following diagnosis, eventually resulting in a poorer prognosis for those patients. Dissecting the molecular mechanism involved in UM progression may lead to identify novel prognostic markers with significative clinical applications. The aim of the present study was to evaluate the role of Heme Oxygenase 1 (HO-1) in regulating UM progression. UM cell lines (92.1) were treated with Hemin (CONC e time), a strong inducer of HO-1, and VP13/47, a selective inhibitor of its enzymatic activity. Interestingly, our results showed an enhanced 92.1 cellular proliferation and wound healing ability following an HO-1 increase, overall unveiling the role played by this protein in tumor progression. Similar results were obtained following treatment with two different CO releasing molecules (CORM-3 and CORM-A1). These results were further confirmed in a clinical setting using our UM cohort. Our results demonstrated an increased median HO-1 expression in metastasizing UM when compared to nonmetastasizing patients. Overall, our results showed that HO-1 derived CO plays a major role in UM progression and HO-1 protein expression may serve as a potential prognostic and therapeutical factor in UM patients.

Pediatric thymomas are extremely rare and slow-growing malignant tumors. The recent publication of the first Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) Tumor–Node–Metastasis (TNM) stage classification and updated treatment guidelines for thymomas has prompted us to perform a review of the literature on pediatric thymomas. A search of English-language articles in the PubMed, Cochrane, Web of Science, and Embase databases was conducted. Additional articles were identified through reference lists of retrieved publications. Thirty-two articles involving 82 pediatric thymomas were included. Males comprised 60% of patients, and 13% manifested myasthenia gravis (MG). Histotype B1 (45%) and stage I (52% Masaoka–Koga and 71% UICC/AJCC TNM) were the most frequent. Of note is the possibility that the lack of cases with mixed histologies in the reviewed publications might be related to a sampling issue, as it is well known that the more sections are available for review, the more likely it is that the majority of these neoplasms will show mixed histologies. Both staging systems showed a gradual increase in the percentage of cases, with more advanced stages of disease moving from type A to B3 thymomas. Complete surgical resection (R0) was the main therapeutic approach in Masaoka–Koga stage I (89%) and UICC/AJCC TNM stage I (70%) thymomas. Advanced stages of disease and incomplete surgical resection were most often associated with recurrence and death. An association between stage and outcome, and completeness of resection and outcome, was found. Interestingly, though an association between histotype and staging was found, this does not take into account the possibility of mixed histologies which would reduce the clinical impact of histologic subtyping over staging.

Hemoglobin and iron overload is considered the major contributor to intracerebral hemorrhage (ICH)-induced brain injury. Accumulation of iron in the brain leads to microglia activation, inflammation and cell loss. Current available treatments for iron overload-mediated disorders are characterized by severe adverse effects, making such conditions an unmet clinical need. We assessed the potential of α-lipoic acid (ALA) as an iron chelator, antioxidant and anti-inflammatory agent in both in vitro and in vivo models of iron overload. ALA was found to revert iron-overload-induced toxicity in HMC3 microglia cell line, preventing cell apoptosis, reactive oxygen species generation and reducing glutathione depletion. Furthermore, ALA regulated gene expression of iron-related markers and inflammatory cytokines, such as IL-6, IL-1β and TNF. Iron toxicity also affects mitochondria fitness and biogenesis, impairments which were prevented by ALA pre-treatment in vitro. Immunocytochemistry assay showed that, although iron treatment caused inflammatory activation of microglia, ALA treatment resulted in increased ARG1 expression, suggesting it promoted an anti-inflammatory phenotype. We also assessed the effects of ALA in an in vivo zebrafish model of iron overload, showing that ALA treatment was able to reduce iron accumulation in the brain and reduced iron-mediated oxidative stress and inflammation. Our data support ALA as a novel approach for iron-overload-induced brain damage.

The introduction of novel, non-invasive techniques capable of improving the diagnostic accuracy and sensibility of both inflammatory and neoplastic cutaneous diseases has always been one of the most practical objectives of dermatological research [...]

Background and Objectives: Eosinophilic angiocentric fibrosis (EAF) is an indolent but sometimes locally destructive lesion with a predilection for the sinonasal tract. Although it was first described in 1983, its etiology remains unknown. Some authors initially attributed EAF to trauma, hypersensitivity, and/or surgical manipulation, while it has been recently suggested to include EAF within the spectrum of IgG4-related systemic diseases. Materials and Methods: We report an uncommon case of idiopathic EAF in a 76-year-old male who developed two bilateral tumefactive masses in the nasal cavities. Results: As the histological examination showed a subepithelial proliferation of fibroblasts along with sclero-hyaline fibrosis around small-sized vessels (an “onion skin-like” pattern) and an eosinophils-rich inflammatory infiltrate, a diagnosis of EAF was rendered. The differential diagnosis included granuloma faciale, Wegener’s granulomatosis, and Churg–Strauss syndrome. Conclusions: Pathologists should be aware of the possibility that this lesion can be part of the wide spectrum of IgG4-related systemic diseases by performing IgG4 investigations to assess adherence to IgG4-related systemic disease criteria.

Peripheral nerve sheath tumors encompass a wide spectrum of lesions with different biological behavior, including both benign and malignant neoplasms as well as the recent diagnostic category, i.e., “atypical neurofibromatous neoplasm with uncertain biologic potential” to be used only for NF1 patients. Neurofibromas and schwannomas are benign Schwann-cell-derived peripheral nerve sheath tumors arising as isolated lesions or within the context of classical neurofibromatosis or schwannomatoses. Multiple tumors are a hallmark of neurofibromatosis type 1(NF1) and related forms, NF2-related-schwannomatosis (formerly NF2) or SMARCB1/LZTR1-related schwannomatoses. Perineuriomas are benign, mostly sporadic, peripheral nerve sheath tumors that show morphological, immunohistochemical, and ultrastructural features reminiscent of perineurial differentiation. Hybrid tumors exist, with the most common lesions represented by a variable mixture of neurofibromas, schwannomas, and perineuriomas. Conversely, malignant peripheral nerve sheath tumors are soft tissue sarcomas that may arise from a peripheral nerve or a pre-existing neurofibroma, and in about 50% of cases, these tumors are associated with NF1. The present review emphasizes the main clinicopathologic features of each pathological entity, focusing on the diagnostic clues and unusual morphological variants.

In dermatopathological daily practice, vertical histopathology sections are classically used to analyze skin biopsies. Conversely, horizontal histopathological sections are currently used for the diagnosis of some types of alopecia. In the last years the morphological findings obtained by horizontal histopathology have been correlated to those obtained by in vivo reflectance confocal microscopy which provides the same “point of view” of the skin. This review paper emphasizes the strong matching and correlation between reflectance confocal microscopy images and horizontal histopathology in cutaneous neoplasms, further demonstrating the strong reliability of this innovative, non-invasive technique in the management of skin tumors.

Long non-coding RNAs (lncRNAs) are the most heterogeneous class of non-protein-coding RNAs involved in a broad spectrum of molecular mechanisms controlling genome function, including the generation of complex networks of RNA-RNA competitive interactions. Accordingly, their dysregulation contributes to the onset of many tumors, including colorectal cancer (CRC). Through a combination of in silico approaches (statistical screening of expression datasets) and in vitro analyses (enforced expression, artificial inhibition, or activation of pathways), we identified LINC00483 as a potential tumor suppressor lncRNA in CRC. LINC00483 was downregulated in CRC biopsies and metastases and its decreased levels were associated with severe clinical features. Inhibition of the MAPK pathway and cell cycle arrest by starvation induced an upregulation of LINC00483, while the epithelial to mesenchymal transition activation by TGFβ-1 and IL-6 caused its down-modulation. Moreover, enforced expression of LINC00483 provoked a slowing down of cell migration rate without affecting cell proliferation. Since LINC00483 was predominantly cytoplasmic, we hypothesized a “miRNA sponge” role for it. Accordingly, we computationally reconstructed the LINC00483/miRNA/mRNA axes and evaluated the expression of mRNAs in different experimental conditions inducing LINC00483 alteration. By this approach, we identified a set of mRNAs sharing the miRNA response elements with LINC00483 and modulated in accordance with it. Moreover, we found that LINC00483 is potentially under negative control of transcription factor HNF4α. In conclusion, we propose that LINC00483 is a tumor suppressor in CRC that, through an RNA-RNA network, may control cell migration and participate in proliferation signaling.

BackgroundDilated and tortuous vessels within elongated dermal papillae represent a histopathological clue of psoriasis. However, the number of dilated capillaries (capillary density) in psoriasis remains undefined as the results from the available studies differ significantly.ObjectivesTo evaluate the capillary density in psoriasis using dermoscopy and horizontal histopathological sections (HHS), two techniques that share the horizontal view of the skin, and to compare the results with the existing data.MethodsTwenty adult patients with stable plaque psoriasis were enrolled and, in each patient, a target area of the examined plaque, previously engraved by gently rotating a 5-mm biopsy punch device, underwent dermoscopy and biopsy for HHS. In all examined fields, capillary density was evaluated in a centered 4-mm diameter area, counting the number of red dots at dermoscopy and of dermal papillae at HHS.ResultsA total of 20 target lesions located on the trunk, arms and tights were evaluated. The mean capillary density resulting from dermoscopy was 43.02±6.60/mm 2 whereas that from HHS was 50.30±9.05/mm 2. These data showed a statistically significant difference (p = 0.006), with a strong correlation at Pearson's test (r = 0.88).ConclusionsOur results when compared with those from the existing literature showed some differences. The peculiarity of our work is represented by the precise measurement and correlation of the capillary density using two different methods, as the preliminary skin engraving allowed a perfect match between the area undergoing dermoscopy and that of skin sampling for HHS. Compared to dermoscopy in which deep-located vessels might have gone undetected, HHS seems to reflect more precisely and reliably the real capillary density showing an average of 50 capillaries/mm 2 that in a common 5x5 cm psoriatic patch corresponds to an average of 125.000 capillaries. These results highlight the extraordinary potential of psoriatic skin to develop such a complex and intricate vascular network.

The ossifying variant and the granular cell variant are rare subtypes of cutaneous fibrous histiocytoma (CFH), characterized by islands of mature metaplastic bone tissue rimmed by multinucleated osteoclast-like giant cells and by large-sized cells with granular cytoplasm and mildly hyperchromatic nuclei with inconspicuous nucleoli, respectively. We herein present two cases of these unusual CFH variants in a 37-year-old woman and in a 38-year-old man, respectively. The main differential diagnoses, including both benign and malignant lesions, are also discussed.

Uveal melanoma (UM) is the most common primary intraocular tumor in adults and usually has a very poor prognosis. Histologically, UMs have been classified in epithelioid cell type, spindle cell type, and mixed cell type. Balloon cells are large pale cells that contain small, hyperchromatic, central nuclei with vesiculated, clear, and lipid-rich cytoplasm. A balloon cell morphology is infrequently observed in naevi and even less frequently in malignant melanomas of the skin, conjunctiva, ciliary body and choroid. In this regard, UMs that exhibit balloon cell features are generally those previously treated with proton beam irradiation and then enucleated, rather than those that directly underwent primary surgery. To the best of our knowledge, very few cases of primary UM showing extensive balloon cell morphology have been reported in scientific literature to date. We herein present an unusual case of primary UM with diffuse balloon cell changes in a 69-year-old woman.

Uveal melanoma, in spite of its rarity, represents the most common primitive intraocular malignant neoplasm of the adults; it affects choroid, ciliary bodied and iris and remains clinically silent for a long time, being accidentally discovered by routine ophthalmic exams. Prognosis of uveal melanoma is poor and frequently characterized by liver metastases, within 10–15 years from diagnosis. Autophagy is a multi-step catabolic process by which cells remove damaged organelles and proteins and recycle nutrients. It has been hypothesized that in early stages of tumorigenesis autophagy has a tumor suppressor role while, in more advanced stages, it may represent a survival mechanism of neoplastic cells in response to stress. Several proteins related to autophagy cascade have been investigated in numerous subtypes of human cancer, with overall controversal results. In this paper we studied the immunohistochemical expression of 3 autophagy related proteins (Beclin-1, p62 and ATG7) in a cohort of 85 primary uveal melanoma treated by primary enucleation (39 with metastasis and 46 non metastatic) and correlated their expression with clinico-pathological parameters and blood vascular microvessel density, in order to investigate the potential prognostic role of autophagy in this rare neoplasm. We found that high immunohistochemical levels of Beclin-1 correlated with a lower risk of metastasis and higher disease-free survival times, indicating a positive prognostic role for Beclin-1 in uveal melanoma. No statistically significative differences regarding the expression of ATG7 and p62 between metastatic and non metastatic patients was detected.

Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite sharing the name and similar morphological features with cutaneous melanoma (CM), it is an entirely different neoplasia with a particular genetic background and clinical behavior. CDKN2A is a gene located at chromosome 9p21, encoding for P16INK4a and P14(ARF) proteins, whose role as a tumor suppressor has been clearly defined in many malignant tumors. CDKN2A frequently presents germline mutations in familial CM and epigenetic downregulation in a considerable percentage of sporadic CM. It has been hypothesized that CDKN2A alterations are early events in CM development, playing a central role in the malignant transformation of melanocytes. Alterations of the CDKN2A gene reduce the expression of P16INK4a in most CM subtypes. Immunohistochemical evaluation of P16INK4a is currently used, in association with Ki67 and HMB45, in pathology practice to discriminate between dysplastic nevi and melanoma. On the other hand, CKDN2A is rarely mutated in UM, and the immunohistochemical expression of P16INK4a has only been reported in small case series. We tested P16INK4a expression on paraffin-embedded tissue sections from 9 tissue microarrays (TMAs), built with 2 mm cores derived from 133 uveal melanoma FFPE blocks, collected from 1990 to 2018, and from selected paraffin-blocks of 3 UM liver metastases. The immunohistochemical expression of P16INK4a was assessed with a visual evaluation by light microscopy and then with a digital approach. Both approaches, with an acceptable concordance rate, revealed P16INK4a expression in a large proportion of UM cases and all liver metastases, opening new possibilities of using it in the differential diagnosis between cutaneous and uveal melanoma metastases in cases of unknown primary tumor or patients with two different primary melanomas.

MacroH2A1 has two splice isoforms, macroH2A1.1 and macroH2A1.2, that have been studied in several form of cancer. In the literature there are not many scientific papers dealing with the role of macroH2A1 in breast cancer. Breast cancer is the most frequent form of malignancy in females. It tend to metastasize to the bone in ~70% of patients. Despite treatment, new bone metastases will still occur in 30–50% of cases with advanced disease. Overall 5-year survival after the diagnosis of bone metastasis is ~20%. Osteoclasts and osteoblasts of the bone microenvironment are engaged by soluble factors released by neoplastic cells, resulting in bone matrix breakdown. This malfunction enhances the proliferation of the cancer cells, creating a vicious cycle. We investigated immunohistochemical expression of macroH2A1 in primitive breast cancer, focusing on the comparison of metastatic and non-metastatic cases. Furthermore, the immunohistochemical expression of macroH2A1 has been evaluated both in all cases of nodal metastases and in distant metastases. Our data demonstrated that macroH2A1 expression was higher expressed in metastatic breast cancer (77%) vs. non-metastatic breast cancer (32%). Also in analyzed metastases cases, a high macroH2A1 expression was detected: 85 and 80% in nodal and distant metastases cases, respectively. These results supported the fact that macroH2A1 is more highly expressed in breast cancer with worst prognosis.

Horizontal histopathological sections (HHSs) have been reported to show a strong correlation with images obtained via in vivo reflectance confocal microscopy (RCM), as both reflect the same horizontal plane of the skin. Although vertical histopathology remains the diagnostic gold standard for most neoplastic and inflammatory skin diseases, HHSs represent a useful tool to validate the RCM features of some inflammatory disorders, including psoriasis, discoid lupus erythematosus, and eczema. The aim of the present review is to summarize the state of the art on the existing correlations between HHS and RCM in this field and to emphasize that RCM may represent a useful diagnostic tool to discriminate between diseases with similar clinical presentations.

Background: SFRS1 is a member of the splicing factor protein family. Through a specific sequence of alteration, SRSF1 can move from the cytoplasm to the nucleus where it can work autonomously as a splicing activator, or as a silencer when interacting with other regulators. Alternative splicing (AS) is a fundamental biological process that ensures protein diversity. In fact, different proteins, produced by alternative splicing, can gain different and even antagonistic biological functions. Methods: Our review is based on English articles published in the MEDLINE/PubMed medical library between 2000 and 2021. We retrieved articles that were specifically related to SRSF1 and cancers, and we excluded other reviews and meta-analyses. We included in vitro studies, animal studies and clinical studies, evaluated using the Medical Education Research Study Quality Instrument (MERSQI) and the Newcastle–Ottawa Scale-Education (NOSE). Result: SRSF1 is related to various genes and plays a role in cell cycle, ubiquitin-mediated proteolysis, nucleotide excision repair, p53 pathway, apoptosis, DNA replication and RNA degradation. In most cases, SRSF1 carries out its cancer-related function via abnormal alternative splicing (AS). However, according to the most recent literature, SRSF1 may also be involved in mRNA translation and cancer chemoresistance or radio-sensitivity. Conclusion: Our results showed that SRSF1 plays a key clinical role in tumorigenesis and tumor progression in several types of cancer (such as Prostate, Lung, Breast, Colon, Glioblastoma), through various mechanisms of action and different cellular pathways. This review could be a starting point for several studies regarding the biology of and therapies for cancer.

Background and Objectives: Basal cell carcinomas (BCCs) are the most frequent skin tumors; although they usually exhibit a good prognosis, it has been reported that there is a 2–8% rate of local recurrence of surgically-excised BCCs, even in the presence of tumor-free surgical margins. Several histological and clinical risk factors have been associated with a higher risk of local relapse; however, the exact pathogenetic mechanisms that regulate the local recurrence of these tumors are still to be elucidated. The serine and arginine-rich splicing factor 1 (SRSF1) is an RNA-binding protein whose oncogenic function has been described in numerous forms of human cancers, including brain, lung, and prostate tumors. We evaluated the correlation between SRSF1 immunoexpression and the local recurrence of BCCs. Materials and Methods: Fifty-two cases of surgically excised BCCs with free-tumor margins (10 high-risk and 42 low-risk variants), for which follow-up data were available, were selected. Local recurrence occurred in only 5 cases. Results: We found high and low immunoexpressions of SRSF1 in 18 and 34 cases, respectively. A statistically significant association between high SRSF1 immunoexpression and the local recurrence of BCC was found (p = 0.0433). Conclusions: Our immunohistochemical results suggest an active role of SRSF1 in inducing a local recurrence of BCCs; however, further studies on a larger series are needed to validate our findings.

Background: The category of the “stromal tumors of the lower female genital tract” encompasses a wide spectrum of lesions with variable heterogeneity, which can be nosologically classified on the basis of their morphologic and immunohistochemical profiles as deep (aggressive) angiomyxoma (DAM), cellular angiofibroma (CAF), angiomyofibroblastoma (AMFB) or myofibroblastoma (MFB). Despite the differential diagnosis between these entities being usually straightforward, their increasingly recognized unusual morphological variants, along with the overlapping morphological and immunohistochemical features among these tumours, may raise serious differential diagnostic problems. Methods and Results: The data presented in the present paper have been retrieved from the entire published literature on the PubMed website about DAM, CAF, AFMB and MFB from 1984 to 2021. The selected articles are mainly represented by small-series, and, more rarely, single-case reports with unusual clinicopathologic features. The present review focuses on the diagnostic clues of the stromal tumours of the lower female genital tract to achieve a correct classification. The main clinicopathologic features of each single entity, emphasizing their differential diagnostic clues, are discussed and summarized in tables. Representative illustrations, including the unusual morphological variants, of each single tumour are also provided. Conclusion: Awareness by pathologists of the wide morphological and immunohistochemical spectrum exhibited by these tumours is crucial to achieve correct diagnoses and to avoid confusion with reactive conditions or other benign or malignant entities.

Pediatric small round blue cell tumors (SRBCTs) are a heterogeneous group of neoplasms with overlapping morphological appearance. Accordingly, their diagnosis is one of the most difficult in the field of surgical pathology. The most common tumors include rhabdomyosarcoma, Ewing’s sarcoma, neuroblastoma, lymphoblastic lymphoma and Wilms’ tumor (the blastemal component). Over time their diagnosis has become more difficult due to the increasing use of small biopsies. However, the advent of immunohistochemistry has improved the quality of diagnosis in most cases by the application of an adequate panel of immunomarkers. Recently, WT1 and Cyclin D1 have been shown to be useful in the differential diagnosis of SRBCTs on surgically-resected specimens, showing a diffuse cytoplasmic positivity of the former in all RMSs and a diffuse nuclear staining of the latter in both EWS and NB. The aim of the present study was to investigate the expression of WT1 and Cyclin D1 on small biopsies from a series of 105 pediatric SRBCTs to evaluate their diagnostic utility. Both immunomarkers were differentially expressed, with a diffuse and strong cytoplasmic staining for WT1 limited to all cases of RMS, and a diffuse nuclear staining for cyclin D1 restricted to all cases of EWS and NB. Notably, the expression of WT1 and cyclin D1 was also retained in those cases in which the conventional tumor markers (myogenin, desmin and MyoD1 for RMS; CD99 for EWS; NB84 for NB) were focally expressed or more rarely absent. The present study shows that WT1 and Cyclin D1 are helpful immunomarkers exploitable in the differential diagnosis of pediatric SRBCTs on small biopsies, suggesting their applicability in routine practice.

Interest in the role of dietary patterns has been consistently emerging in recent years due to much research that has documented the impact of metabolism on erectile dysfunction (ED) and/or benign prostatic hyperplasia (BPH). We conducted a non-systematic review of English articles published from 1964 to September 2021. The search terms were: (“dietary patterns” OR “diet”) AND/OR (“erectile dysfunction”) AND/OR (“benign prostatic hyperplasia”). In the present review, we have highlighted how the association between dietary patterns and two of the most frequent pathologies in urology, namely erectile dysfunction and benign prostatic hyperplasia, is present in the literature. The data suggested that a diet that is more adherent to the Mediterranean diet or that emphasizes the presence of vegetables, fruits, nuts, legumes, and fish or other sources of long-chain (n-3) fats, in addition to reduced content of red meat, may have a beneficial role on erectile function. At the same time, the same beneficial effects can be transferred to BPH as a result of the indirect regulatory effects on prostatic growth and smooth muscle tone, thus determining an improvement in symptoms. Certainly, in-depth studies and translational medicine are needed to confirm these encouraging data.

Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts different effects in various human cancer. In glioblastoma (GBM), PACAP has been shown to interfere with the hypoxic micro-environment through the modulation of hypoxia-inducible factors via PI3K/AKT and MAPK/ERK pathways inhibition. Considering that hypoxic tumor micro-environment is strictly linked to angiogenesis and Epithelial–Mesenchymal transition (EMT), in the present study, we have investigated the ability of PACAP to regulate these events. Results have demonstrated that PACAP and its related receptor, PAC1R, are expressed in hypoxic area of human GBM colocalizing either in epithelial or mesenchymal cells. By using an in vitro model of GBM cells, we have observed that PACAP interferes with hypoxic/angiogenic pathway by reducing vascular-endothelial growth factor (VEGF) release and inhibiting formation of vessel-like structures in H5V endothelial cells cultured with GBM-conditioned medium. Moreover, PACAP treatment decreased the expression of mesenchymal markers such as vimentin, matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) as well as CD44 in GBM cells by affecting their invasiveness. In conclusion, our study provides new insights regarding the multimodal role of PACAP in GBM malignancy.

Uveal melanoma (UM) is the most frequent primary ocular malignancy of adults; it exhibits an almost invariably poor prognosis with onset of liver metastases within 10–15 years after the diagnosis. Serine and arginine-rich splicing factor 1 (SRSF1) is an RNA-binding protein with proto-oncogene functions, including stimulation of angiogenesis, cell migration and cell growth; regarding the complex regulation of tumor angiogenesis, it has been suggested that SRSF1 regulates the alternative splicing of vascular endothelial growth factor-α, promoting the formation of its pro-angiogenic isoform. The immunohistochemical expression of SRSF1 on a series of 85 primary UMs, including 39 metastasizing and 46 non-metastasizing cases, was investigated; to clarify the potential pathogenetic role of SRSF1 in this tumor and its effect on angiogenesis, we correlated our immunohistochemical findings with the clinico-pathological features, the prognostic data and blood vascular microvessel density (MVD) findings of the cases from our series. Cases with higher immunohistochemical expression of SRSF1 also had higher MVD, higher metastatic potential and shorter metastasis-free survival; conversely, cases with lower SRSF1 immunoexpression showed lower MVD, lower metastatic risk and longer metastasis-free survival times. Our results suggested that SRSF1 has a negative prognostic role and a pro-angiogenic function in UM.

Background: In the present study, we evaluated the prognostic value of TILs as well their relation with clinicopathological factors in patients affected by HER-2 positive breast cancer. Methods: We evaluated 47 patients with a histologically confirmed diagnosis of invasive breast carcinoma showing an immunohistochemically confirmed (score 3+) amplification of the c-erbB-2 gene for the presence of TILs and categorized in three predefined groups of low (0–10% immune cells in stromal tissue within the tumor), intermediate (11–40%), and high TILs (>40%). Results: Low, intermediate and high TILs were found in 17/47 (36%), 23/47 (49%) and 7/47(15%) cases, respectively. It was found that 6/47 cases treated with adjuvant chemotherapy plus trastuzumab underwent progression of the disease; none of these cases exhibited high TILs. It was found that 12/47 patients with a prognostically unfavorable stage of III and IV showed low and intermediate levels of TILs, while high TILs were never observed. A significant association between intermediate/high-levels of TILs, elevated KI 67 index and hormone receptors nuclear staining was observed. High concordance in TILs distribution was observed between preoperative breast biopsies and surgical samples. Conclusions: We observed a positive correlation between the TILs and the response to both adjuvant and neoadjuvant treatments in HER-2 positive BC. High TILs were also related to increased KI-67 index and to the expression of hormone receptors.