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Abstract Long non-coding RNAs (lncRNAs) are transcripts without coding potential that are pervasively expressed from the genome and have been increasingly reported to play crucial roles in all aspects of cell biology. They have been also heavily implicated in cancer development and progression, with both oncogenic and tumor suppressor functions. In this work, we identified and characterized a novel lncRNA, TAZ-AS202, expressed from the TAZ genomic locus and exerting pro-oncogenic functions in non-small cell lung cancer. TAZ-AS202 expression is under the control of YAP/TAZ-containing transcriptional complexes. We demonstrated that TAZ-AS202 is overexpressed in lung cancer tissue, compared with surrounding lung epithelium. In lung cancer cell lines TAZ-AS202 promotes cell migration and cell invasion. TAZ-AS202 regulates the expression of a set of genes belonging to cancer-associated pathways, including WNT and EPH-Ephrin signaling. The molecular mechanism underlying TAZ-AS202 function does not involve change of TAZ expression or activity, but increases the protein level of the transcription factor E2F1, which in turn regulates the expression of a large set of target genes, including the EPHB2 receptor. Notably, the silencing of both E2F1 and EPHB2 recapitulates TAZ-AS202 silencing cellular phenotype, indicating that they are essential mediators of its activity. Overall, this work unveiled a new regulatory mechanism that, by increasing E2F1 protein, modifies the non-small cell lung cancer cells transcriptional program, leading to enhanced aggressiveness features. The TAZ-AS202/E2F1/EPHB2 axis may be the target for new therapeutic strategies.

Introduction: Mucosal melanoma is a rare neoplasm. Late diagnosis is caused by occult anatomic sites and scarcity of symptoms. Novel biological therapies have now become available. Demographic, therapeutical and survival records on mucosal melanoma are scarce. Objectives: To provide an 11-year retrospective clinical review of real-world data on mucosal melanomas managed in a tertiary referral center in Italy. Methods: We included patients with histopathological mucosal melanoma diagnosis from January 2011 to December 2021. Data were collected until last known follow up or death. Survival analysis was performed. Results: Among 33 patients, we found 9 sinonasal, 13 anorectal and 11 urogenital mucosal melanomass (median age 82, females 66.7%). Eighteen cases (54.5%) presented with metastasis (p

Abstract Background Primary effusion lymphoma is a rare, aggressive large B-cell lymphoma strictly linked to infection by Human Herpes virus 8/Kaposi sarcoma-associated herpes virus. In its classic form, it is characterized by body cavities neoplastic effusions without detectable tumor masses. It often occurs in immunocompromised patients, such as HIV-positive individuals. Primary effusion lymphoma may affect HIV-negative elderly patients from Human Herpes virus 8 endemic regions. So far, rare cases have been reported in transplanted patients. The purpose of our systematic review is to improve our understanding of this type of aggressive lymphoma in the setting of transplantation, focusing on epidemiology, clinical presentation, pathological features, differential diagnosis, treatment and outcome. The role of assessing the viral serological status in donors and recipients is also discussed. Methods We performed a systematic review adhering to the PRISMA guidelines. The literature search was conducted on PubMed/MEDLINE, Web of Science, Scopus, EMBASE and Cochrane Library, using the search terms “primary effusion lymphoma” and “post-transplant”. Results Our search identified 13 cases of post-transplant primary effusion lymphoma, predominantly in solid organ transplant recipients (6 kidney, 3 heart, 2 liver and 1 intestine), with only one case after allogenic bone marrow transplantation. Long-term immunosuppression is important in post-transplant primary effusion lymphoma commonly developing several years after transplantation. Kaposi Sarcoma occurred in association with lymphoma in 4 cases of solid organ recipients. The lymphoma showed the classical presentation with body cavity effusions in absence of tumor masses in 10 cases; 2 cases presented as solid masses, lacking effusions and one case as effusions associated with multiple organ involvement. Primary effusion lymphoma occurring in the setting of transplantation was more often Epstein Barr-virus negative. The prognosis was poor. In addition to chemotherapy, reduction of immunosuppressive treatment, was generally attempted. Conclusions Primary effusion lymphoma is a rare, but often fatal post-transplant complication. Its rarity and the difficulty in achieving the diagnosis may lead to miss this complication. Clinicians should suspect primary effusion lymphoma in transplanted patients, presenting generally with unexplained body cavity effusions, although rare cases with solid masses are described.

Pulmonary minute meningothelial-like nodules (MMNs) are common incidental findings in surgical specimens, consisting of tiny proliferation (usually no larger than 5–6 mm) of bland-looking meningothelial cells showing a perivenular and interstitial distribution, sharing morphologic, ultrastructural, and immunohistochemical profiles with meningiomas. The identification of multiple bilateral MMNs leading to an interstitial lung disease characterized by diffuse and micronodular/miliariform patterns radiologically allows the diagnosis of diffuse pulmonary meningotheliomatosis (DPM). Nevertheless, the lung is the most common site of metastatic primary intracranial meningioma, and differential diagnosis with DPM may be impossible without clinic–radiologic integration. Herein, we report four cases (three females; mean age, 57.5 years) fitting the criteria of DPM, all incidentally discovered and histologically evidenced on transbronchial biopsy (2) and surgical resection (2). All cases showed immunohistochemical expression of epithelial membrane antigen (EMA), progesterone receptor, and CD56. Notably, three of these patients had a proven or radiologically suspected intracranial meningioma; in two cases, it was discovered before, and in one case, after the diagnosis of DPM. An extensive literature review (44 patients with DPM) revealed similar cases with imaging studies excluding intracranial meningioma in only 9% (4 of 44 cases studied). The diagnosis of DPM requires close correlation with the clinic–radiologic data since a subset of cases coexist with or follow a previously diagnosed intracranial meningioma and, thus, may represent incidental and indolent metastatic deposits of meningioma.

Endometrial cancer (EC) is the most common malignancy of the female genital tract in Western and emerging countries. In 2012, new cancer cases numbered 319,605, and 76,160 cancer deaths were diagnosed worldwide. ECs are usually diagnosed after menopause; 70% of ECs are diagnosed at an early stage with a favorable prognosis and a 5-year overall survival rate of 77%. On the contrary, women with advanced or recurrent disease have extremely poor outcomes because they show a low response rate to conventional chemotherapy. EC is generally considered easy to treat, although it presents a 5-year mortality of 25%. Though the guidelines (GLs) recommend treatment in specialized centers by physicians specializing in gynecologic oncology, most women are managed by general gynecologists, resulting in differences and discrepancies in clinical management. In this paper we reviewed the literature with the aim of highlighting where the treatment of EC patients requires gynecologic oncologists, as suggested by the GLs. Moreover, we sought to identify the causes of the lack of GL adherence, suggesting useful changes to ensure adequate treatment for all EC patients.

Immunotherapy targeting the PD-1–PD-L1 axis yielded good results in treating different immunologically ‘‘hot’’ tumors. A phase II study revealed good therapeutic activity of pembrolizumab in selected prostatic carcinoma (PC)-patients. We performed a systematic literature review (PRISMA guidelines), which analyzes the immunohistochemical expression of PD-L1 in human PC samples and highlights the pre-analytical and interpretation variables. Interestingly, 29% acinar PCs, 7% ductal PCs, and 46% neuroendocrine carcinomas/tumors were PD-L1+ on immunohistochemistry. Different scoring methods or cut-off criteria were applied on variable specimen-types, evaluating tumors showing different clinic-pathologic features. The positivity rate of different PD-L1 antibody clones in tumor cells ranged from 3% (SP142) to 50% (ABM4E54), excluding the single case tested for RM-320. The most tested clone was E1L3N, followed by 22C3 (most used for pembrolizumab eligibility), SP263, SP142, and 28-8, which gave the positivity rates of 35%, 11–41% (depending on different scoring systems), 6%, 3%, and 15%, respectively. Other clones were tested in

Many studies have investigated the potential prognostic and predictive role of PD-L1 in prostatic carcinoma (PC). We performed a systematic literature review (PRISMA guidelines) to critically evaluate human tissue-based studies (immunohistochemistry, molecular analysis, etc.), experimental research (cell lines, mouse models), and clinical trials. Despite some controversial results and study limitations, PD-L1 expression by tumor cells may be related to clinic–pathologic features of adverse outcome, including advanced tumor stage (high pT, presence of lymph node, and distant metastases), positivity of surgical margins, high Grade Group, and castration resistance. Different PD-L1 positivity rates may be observed in matched primary PCs and various metastatic sites of the same patients. Over-fixation, type/duration of decalcification, and PD-L1 antibody clone may influence the immunohistochemical analysis of PD-L1 on bone metastases. PD-L1 seemed expressed more frequently by castration-resistant PCs (49%) as compared to hormone-sensitive PCs (17%). Some series found that PD-L1 positivity was associated with decreased time to castration resistance. Treatment with ipilimumab, cyclophosphamide/GVAX/degarelix, or degarelix alone may increase PD-L1 expression. Correlation of PD-L1 positivity with overall survival and outcomes related to tumor recurrence were rarely investigated; the few analyzed series produced conflicting results and sometimes showed limitations. Further studies are required. The testing and scoring of PD-L1 should be standardized.

In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapy-resistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ T-cells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and RB deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223).

Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC) displays a complex genetic and epigenetic regulation of cell-growth pathways and tumor progression. We performed a systematic literature review (following PRISMA guidelines) focused on the epigenetic regulation of PD-L1 expression in PC. In PC cell lines, CpG island methylation of the CD274 promoter negatively regulated PD-L1 expression. Histone modifiers also influence the PD-L1 transcription rate: the deletion or silencing of the histone modifiers MLL3/MML1 can positively regulate PD-L1 expression. Epigenetic drugs (EDs) may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. EDs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) downregulated PD-L1, while EDs favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression. miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer biochemical recurrence-free survival; they also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to the methylation of PD-L1 promoter in a large series. miR-570, miR-34a and miR-513 may also be involved in epigenetic regulation.

The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients’ serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.

The adoption of neoadjuvant chemotherapy (NACT) for breast cancer (BC) is increasing. The need to repeat the biomarkers on a residual tumor after NACT is still a matter of debate. We verified estrogen receptors (ER), progesterone receptors (PR), Ki67 and human epidermal growth factor receptor 2 (HER2) status changes impact in a retrospective monocentric series of 265 BCs undergoing NACT. All biomarkers changed with an overall tendency toward a reduced expression. Changes in PR and Ki67 were statistically significant (p = 0.001). Ki67 changed in 114/265 (43.0%) cases, PR in 44/265 (16.6%), ER in 31/265 (11.7%) and HER2 in 26/265 (9.8%). Overall, intrinsic subtype changed in 72/265 (27.2%) cases after NACT, and 10/265 (3.8%) cases switched to a different adjuvant therapy accordingly. Luminal subtypes changed most frequently (66/175; 31.7%) but with less impact on therapy (5/175; 2.8%). Only 3 of 58 triple-negative BCs (5.2%) changed their intrinsic subtype, but all of them switched treatment. No correlation was found between intrinsic subtype changes and clinicopathological features. To conclude, biomarkers changes with prognostic implications occurred in all BC intrinsic subtypes, albeit they impacted therapy mostly in HER2 negative and/or hormone receptors negative BCs. Biomarkers retesting after NACT is important to improve both tailored adjuvant therapies and prognostication of patients.

Lung cancer is the leading cause of cancer-related human death. It is a heterogeneous disease, classified in two main histotypes, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), which is further subdivided into squamous-cell carcinoma (SCC) and adenocarcinoma (AD) subtypes. Despite the introduction of innovative therapeutics, mainly designed to specifically treat AD patients, the prognosis of lung cancer remains poor. In particular, available treatments for SCLC and SCC patients are currently limited to platinum-based chemotherapy and immune checkpoint inhibitors. In this work, we used an integrative approach to identify novel vulnerabilities in lung cancer. First, we compared the data from a CRISPR/Cas9 dependency screening performed in our laboratory with Cancer Dependency Map Project data, essentiality comprising information on 73 lung cancer cell lines. Next, to identify relevant therapeutic targets, we integrated dependency data with pharmacological data and TCGA gene expression information. Through this analysis, we identified CSNK1A1, KDM2A, and LTB4R2 as relevant druggable essentiality genes in lung cancer. We validated the antiproliferative effect of genetic or pharmacological inhibition of these genes in two lung cancer cell lines. Overall, our results identified new vulnerabilities associated with different lung cancer histotypes, laying the basis for the development of new therapeutic strategies.

Normal breast tissue undergoes great variations during a woman’s life as a consequence of the different hormonal stimulation. The purpose of the present study was to examine the hormonal receptor expression variations according to age, menstrual cycle, menopausal state and body mass index. To this purpose, 49 tissue samples of normal breast tissue, obtained during surgery performed for benign and malignant conditions, were immunostained with Estrogen (ER), Progesterone (PR) and Androgen receptors (AR). In addition, Ki67 and Gross Cystic Disease Fluid Protein were studied. The data obtained revealed a great variability of hormone receptor expression. ER and AR generally increased in older and post-menopausal women, while young women presented a higher proliferative rate, evaluated with Ki67. PR increase was observed in women with BMI higher than 25. The different hormonal receptor expression could favor the development of breast cancer.

Ovarian carcinomas represent a heterogeneous group of neoplasms consisting of separate entities with distinct risk factors, precursor lesions, pathogenesis, patterns of spread, molecular profiles, clinical course, response to chemotherapy, and outcomes. The histologic subtype and the related molecular features are essential for individualized clinical decision-making. The fifth edition of the World Health Organization classification of tumors of the female genital tract divides ovarian carcinomas into at least five main and distinct types of ovarian carcinomas: high-grade serous carcinoma, low-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, and mucinous carcinoma. Molecular pathology has improved the knowledge of genomic landscape of ovarian carcinomas identifying peculiar alterations for every histologic subtype. It is well-known that high-grade and low-grade serous carcinomas are separate entities with entirely different morphologic and molecular characteristics. TP53 and BRCA mutations are typical of high-grade serous carcinoma, whereas BRAF and KRAS mutations frequently occur in low-grade serous carcinoma. Endometrioid and clear cell carcinomas are frequently associated with endometriosis. Endometrioid tumors are characterized by β-catenin alterations, microsatellite instability, and PTEN and POLE mutations, while ARID1A mutations occur in both endometrioid and clear cell carcinomas. Mucinous carcinomas are uncommon tumors associated with copy-number loss of CDKN2A and KRAS alterations and metastasis from other sites should always be considered in the differential diagnosis.

According to our systematic literature review (PRISMA guidelines), only 37 vulvar squamous cell carcinomas (VSCCs) were diagnosed during pregnancy (age range: 17–41 years). The tumor size range was 0.3–15 cm. The treatment was performed after (14/37, 38%), before (10/37, 27%), or before-and-after delivery (11/37, 30%). We found that 21/37 (57%) cases were stage I, 2 II (5%), 11 III (30%), and 3 IVB (8%). HPV-related features (condylomas/warts; HPV infection; high-grade squamous intraepithelial lesion) were reported in 11/37 (30%) cases. We also found that 9/37 (24%) patients had inflammatory conditions (lichen sclerosus/planus, psoriasis, chronic dermatitis). The time-to-recurrence/progression (12/37, 32%) ranged from 0 to 36 (mean 9) months. Eight women died of disease (22%) 2.5–48 months after diagnosis, 2 (5%) were alive with disease, and 23 (62%) were disease-free at the end of follow-up. Pregnant patients must be followed-up. Even if they are small, newly arising vulvar lesions should be biopsied, especially in women with risk factors (HPV, dermatosis, etc.). The treatment of VSCCs diagnosed in late third trimester might be delayed until postpartum. Elective cesarean section may prevent vulvar wound dehiscence. In the few reported cases, pregnancy/fetal outcomes seemed to not be affected by invasive treatments during pregnancy. However, clinicians must be careful; larger cohorts should define the best treatment. Definite guidelines are lacking, so a multidisciplinary approach and discussion with patients are mandatory.

Primary pulmonary B-cell lymphomas (PP-BCLs) comprise a group of extranodal non-Hodgkin lymphomas of B-cell origin, which primarily affect the lung without evidence of extrapulmonary disease at the time of diagnosis and up to 3 months afterwards. Primary lymphoid proliferations of the lung are most often of B-cell lineage, and include three major entities with different clinical, morphological, and molecular features: primary pulmonary marginal zone lymphoma of mucosa-associated lymphoid tissue (PP-MZL, or MALT lymphoma), primary pulmonary diffuse large B cell lymphoma (PP-DLBCL), and lymphomatoid granulomatosis (LYG). Less common entities include primary effusion B-cell lymphoma (PEL) and intravascular large B cell lymphoma (IVLBCL). A proper workup requires a multidisciplinary approach, including radiologists, pneumologists, thoracic surgeons, pathologists, hemato-oncologists, and radiation oncologists, in order to achieve a correct diagnosis and risk assessment. Aim of this review is to analyze and outline the clinical and pathological features of the most frequent PP-BCLs, and to critically analyze the major issues in their diagnosis and management.

The term “ovarian carcinoma” encompasses at least five different malignant neoplasms: high-grade serous carcinoma, low-grade serous carcinoma, endometrioid carcinoma, mucinous carcinoma, and clear cell carcinoma. These five histotypes demonstrated distinctive histological, molecular, and clinical features. The rise of novel target therapies and of a tailored oncological approach has demanded an integrated multidisciplinary approach in the setting of ovarian carcinoma. The need to implement a molecular-based classification in the worldwide diagnostic and therapeutic setting of ovarian cancer demanded a search for easy-to-use and cost-effective molecular-surrogate biomarkers, relying particularly on immunohistochemical analysis. The present review focuses on the role of immunohistochemistry as a surrogate of molecular analysis in the everyday diagnostic approach to ovarian carcinomas.