Potential role of the Eph/ephrin system in colorectal cancer: emerging druggable molecular targets.

The Eph/ephrin system regulates many developmental processes and adult tissue homeostasis. In colorectal cancer (CRC), it is involved in different processes including tumorigenesis, tumor angiogenesis, metastasis development, and cancer stem cell regeneration. However, conflicting data regarding Eph receptors in CRC, especially in its putative role as an oncogene or a suppressor gene, make the precise role of Eph-ephrin interaction confusing in CRC development. In this review, we provide an overview of the literature and highlight evidence that collaborates with these ambiguous roles of the Eph/ephrin system in CRC, as well as the molecular findings that represent promising therapeutic targets.

MicroRNA copy number alterations in the malignant transformation of pleomorphic adenoma to carcinoma ex pleomorphic adenoma.

OBJECTIVE: This study used array comparative genomic hybridization to assess copy number alterations (CNAs) involving miRNA genes in pleomorphic adenoma (PA), recurrent pleomorphic adenoma (RPA), residual PA, and carcinoma ex pleomorphic adenoma (CXPA). MATERIALS AND METHODS: We analyzed 13 PA, 4 RPA, 29 CXPA, and 14 residual PA using Nexus Copy Number Discovery software. The miRNAs genes affected by CNAs were evaluated based on their expression patterns and subjected to pathway enrichment analysis. RESULTS: Across the groups, we found 216 CNAs affecting 2261 miRNA genes, with 117 in PA, 59 in RPA, 846 in residual PA, and 2555 in CXPA. The chromosome 8 showed higher involvement in altered miRNAs in PAs and CXPA patients. Six miRNA genes were shared among all groups. Additionally, miR-21, miR-455-3p, miR-140, miR-320a, miR-383, miR-598, and miR-486 were prominent CNAs found and is implicated in carcinogenesis of several malignant tumors. These miRNAs regulate critical signaling pathways such as aerobic glycolysis, fatty acid biosynthesis, and cancer-related pathways. CONCLUSION: This study was the first to explore CNAs in miRNA-encoding genes in the PA-CXPA sequence. The findings suggest the involvement of numerous miRNA genes in CXPA development and progression by regulating oncogenic signaling pathways.

Hematopoietic colony-stimulating factors in head and neck cancers: Recent advances and therapeutic challenges.

Colony-stimulating factors (CSFs) are key cytokines responsible for the production, maturation, and mobilization of the granulocytic and macrophage lineages from the bone marrow, which have been gaining attention for playing pro- and/or anti-tumorigenic roles in cancer. Head and neck cancers (HNCs) represent a group of heterogeneous neoplasms with high morbidity and mortality worldwide. Treatment for HNCs is still limited even with the advancements in cancer immunotherapy. Novel treatments for patients with recurrent and metastatic HNCs are urgently needed. This article provides an in-depth review of the role of hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin-3 (IL-3; also known as multi-CSF) in the HNCs tumor microenvironment. We have reviewed current results from clinical trials using CSFs as adjuvant therapy to treat HNCs patients, and also clinical findings reported to date on the therapeutic application of CSFs toxicities arising from chemoradiotherapy.

Clinicopathological profile of sclerosing polycystic adenoma/adenosis: A systematic review.

In this systematic review, we aimed to evaluate the clinicopathological profile of sclerosing polycystic adenoma (SPA). PubMed, Scopus, EMBASE, Lilacs, Web of Science, and gray literature were searched to access cases of SPA in salivary glands. One hundred and thirty cases of SPA were found across 61 selected articles. SPA affected mainly the parotid gland of adults with a mean age of 44.6 years old, with a slight preference for females. The lesion was usually presented as a painless firm mass with a long period of evolution. Histologically, they are well-delimitated lesions composed of acinar and ductal elements with a variety of cytomorphologic features surrounded by a densely collagenized stroma. PI3K was the most common gene mutation related to SPA. SPA is a benign condition that mainly affects the parotid gland of female patients and it is usually treated by surgical resection with a good prognosis.

Evaluation of tumor load in sentinel lymph node in patients with cutaneous melanoma.

INTRODUCTION: cutaneous melanoma (MC) is a malignant neoplasm derived from melanocytic cells with an aggressive behavior. It is usually associated with the multifactorial interaction of genetic susceptibility and environmental exposure, usually ultraviolet radiation. Despite advances in treatment, the disease remains relentless with poor prognosis. Sentinel lymph node (SLN) biopsy is a technique used to screen patients in need of lymph node dissection. OBJECTIVES: to correlate the tumor burden in the SLN with the mortality of patients undergoing SLN biopsy. METHODOLOGY: the medical records and histological slides of patients with MC who underwent SLN biopsy treated at HC-Unicamp from 2001 to 2021 were retrospectively analyzed. The positive SLN were measured according to the size of the tumor infiltration area, for analysis of the depth of invasion (DI), closest proximity to the capsule (CPC) and tumor burden (TB). For statistical analysis, associations between variables were analyzed using Fishers exact test, with post Bonferroni test and Wilcoxon test. RESULTS: 105 records of patients who underwent SLN biopsy of MC were identified. Of these, nine (8.6%) had positive SLN and 81 (77.1%) had negative SLN. The performed lymphadenectomies resulted in 55.6% (n=5) affected, 22.2% (n=2) without disease and 22.2% (n=2) were not performed. Mean CPC, TB, and DI were 0.14mm, 32.10mm and 2.33mm, respectively. Patients with T2 and T3 tumors were more likely to show the SLN affected (p=0.022). No patient with positive SLN died during follow-up. CONCLUSION: patients who presented T3 staging are the ones who most presented positive SLN.

Heterogeneity and versatility of the extracellular matrix during the transition from pleomorphic adenoma to carcinoma ex pleomorphic adenoma: cumulative findings from basic research and new insights.

Pleomorphic adenoma (PA) is the most common salivary gland tumor, accounting for 50%-60% of these neoplasms. If untreated, 6.2% of PA may undergo malignant transformation to carcinoma ex-pleomorphic adenoma (CXPA). CXPA is a rare and aggressive malignant tumor, whose prevalence represents approximately 3%-6% of all salivary gland tumors. Although the pathogenesis of the PA-CXPA transition remains unclear, CXPA development requires the participation of cellular components and the tumor microenvironment for its progression. The extracellular matrix (ECM) comprises a heterogeneous and versatile network of macromolecules synthesized and secreted by embryonic cells. In the PA-CXPA sequence, ECM is formed by a variety of components including collagen, elastin, fibronectin, laminins, glycosaminoglycans, proteoglycans, and other glycoproteins, mainly secreted by epithelial cells, myoepithelial cells, cancer-associated fibroblasts, immune cells, and endothelial cells. Like in other tumors including breast cancer, ECM changes play an important role in the PA-CXPA sequence. This review summarizes what is currently known about the role of ECM during CXPA development.

Clinicopathological and survival profile of patients with salivary gland myoepithelial carcinoma: A systematic review.

OBJECTIVES: In this systematic review, we aimed to evaluate the clinicopathological and prognosis data of patients with salivary gland myoepithelial carcinoma. MATERIALS AND METHODS: MEDLINE/PubMed, Scopus, and Embase search was performed with the keywords "myoepithelial carcinoma" "malignant myoepithelioma," and "salivary glands." Primary salivary glands myoepithelial carcinoma that fulfilled the World Health Organization diagnostic criteria were included. The Joanna Briggs Institute tool was used to assess the risk of bias. RESULTS: Forty-three studies (71 patients) met the inclusion criteria. The patients showed a mean age of 56.4 ± 19.6 years with no sex predilection. The parotid was the most affected gland (49.3%). The tumor presented as an asymptomatic (65.1%) mass (84%). The most common histological findings were the presence of clear tumor cells (39.7%) and multinodular growth patterns (60.7%). Multivariate analysis showed plasmacytoid cell type (p = 0.010) and solid growth pattern (p = 0.003) were related to decreased disease-free survival. Surgery alone was the most used treatment (53.5%). Patients with a combination of treatments showed a longer disease-free survival (p = 0.049). The 2-year and 5-year overall survival rates were 67.5% and 46.1%, respectively. CONCLUSION: Salivary gland myoepithelial carcinoma showed no sex predilection, with a higher incidence in the parotid gland. Cell type, growth pattern, and treatment type may be related to a lower disease-free survival. Overall, salivary gland myoepithelial carcinoma presented low recurrence and metastasis rates. Registration and protocol: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist and registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42022311512).

Oral Teratoma with Hairy Polyp-Like Features: A Brief Report of a Rare Presentation.

We present a 21-day-old female child presenting with a large oral epithelialized tumor implanted at the rhinopharynx and ethmoid plate through a cleft palate, associated with feeding and respiratory difficulties. The histopathological exam showed mature central adipose tissue, hair follicles, sebaceous glands, and neurovascular structures, lined by keratinized stratified squamous epithelium. Proliferative cartilaginous, glandular, lymphatic, bony, and immature myxoid tissue was seen at the posterior region and insertion. Despite the characterization of the tumor as a teratoma containing structures derived from the three embryonic leaflets, the anterior portion presented a microscopic bigeminal pattern fully compatible with hairy polyp.

Immunopathological insights into villitis of unknown etiology on the basis of transplant immunology.

Villitis of unknown etiology (VUE) is an inflammatory disease characterized by the infiltration of maternal CD8 +T cells into the placental villi. Although the pathogenesis of VUE is still debated, dysregulation of the immune system appears to be an important factor in the development of the disease. Interaction of maternal T cells with the fetal antigens seems to be the trigger for the VUE onset. In this context, graft vs host disease (GVHD) and allographic rejection seem to share similarities in the VUE immunopathological mechanism, especially those related to immunoregulation. In this review, we compared the immunological characteristics of VUE with allograft rejection, and GVHD favoring a better knowledge of VUE pathogenesis that may contribute to VUE therapeutics strategies in the future.

Discovery proteomics reveals potential protein signature associated with malignant phenotype acquisition in pleomorphic adenoma.

OBJECTIVE: To analyze the proteomic profile of salivary pleomorphic adenoma (PA) and carcinoma ex pleomorphic adenoma (CXPA) samples and correlate them with the malignant transformation of the PA. MATERIALS AND METHODS: Thirty samples (10 PA, 16 CXPA, and 4 residual PA) were microdissected and submitted to liquid chromatography-tandem mass spectrometry (LC-MS/MS). The proteomic data and protein identification were analyzed through LC-MS/MS spectra using the MaxQuant software. RESULTS: The proteomic analysis identified and quantified a total of 240 proteins in which 135 were found in PA, residual PA, and CXPA. The shared proteins were divided into six subgroups, and the proteins that showed statistically significant differences (p > 0.05) and fold-change > or <2.5 in one subgroup to another subgroup were included. Seven proteins (Apolipoprotein A-I-APOA1, haptoglobin-HP, protein of the synaptonemal complex 1-SYCP1, anion transport protein of band 3-SLC4A1, subunit µ1 of AP-1 complex-AP1M1, beta subunit of hemoglobin-HBB, and dermcidin-DCD) were classified as potential protein signatures, being HP, AP1M1, and HBB with higher abundance for PA to residual PA, APOA1 with higher abundance for PA to CXPA, SLC4A1 with lower abundance in the PA to CXPA, SYCP1with lower abundance for residual PA to CXPA, and DCD with higher abundance in the CXPA with epithelial differentiation to myoepithelial differentiation. CONCLUSIONS: In this work, we demonstrated the comparative proteomic profiling of PA, residual PA, and CXPA, and seven were proposed as protein signatures, some of which may be associated with the malignant phenotype acquisition.

Evaluation of tumor load in sentinel lymph node in patients with cutaneous melanoma / Avaliação da carga do tumor em linfonodo sentinela nos doentes portadores de melanoma cutâneo

ABSTRACT Introduction: cutaneous melanoma (MC) is a malignant neoplasm derived from melanocytic cells with an aggressive behavior. It is usually associated with the multifactorial interaction of genetic susceptibility and environmental exposure, usually ultraviolet radiation. Despite advances in treatment, the disease remains relentless with poor prognosis. Sentinel lymph node (SLN) biopsy is a technique used to screen patients in need of lymph node dissection. Objectives: to correlate the tumor burden in the SLN with the mortality of patients undergoing SLN biopsy. Methodology: the medical records and histological slides of patients with MC who underwent SLN biopsy treated at HC-Unicamp from 2001 to 2021 were retrospectively analyzed. The positive SLN were measured according to the size of the tumor infiltration area, for analysis of the depth of invasion (DI), closest proximity to the capsule (CPC) and tumor burden (TB). For statistical analysis, associations between variables were analyzed using Fishers exact test, with post Bonferroni test and Wilcoxon test. Results: 105 records of patients who underwent SLN biopsy of MC were identified. Of these, nine (8.6%) had positive SLN and 81 (77.1%) had negative SLN. The performed lymphadenectomies resulted in 55.6% (n=5) affected, 22.2% (n=2) without disease and 22.2% (n=2) were not performed. Mean CPC, TB, and DI were 0.14mm, 32.10mm and 2.33mm, respectively. Patients with T2 and T3 tumors were more likely to show the SLN affected (p=0.022). No patient with positive SLN died during follow-up. Conclusion: patients who presented T3 staging are the ones who most presented positive SLN.

RESUMO Introdução: o melanoma cutâneo (MC) é uma neoplasia maligna de comportamento agressivo, derivada das células melanocíticas, geralmente causado pela associação de interação da suscetibilidade genética e a exposição ambiental. A biópsia do linfonodo sentinela (LNS) é um procedimento utilizado para rastreamento de doentes com necessidade ou não de linfadenectomia, diminuindo a exposição do paciente a cirurgias maiores. Objetivos: correlacionar a carga do tumor no LNS com a mortalidade de pacientes com MC. Métodos: foram examinados retrospectivamente prontuários e lâminas histológicas de doentes com MC submetidos a biópsia de LNS atendidos no HC-Unicamp entre o período compreendido de 2001 a 2021. Os LNS positivos foram mensurados quanto ao tamanho da área de infiltração do tumor, para análise da profundidade de invasão (PI), menor proximidade com a cápsula (MPC) e carga do tumor (CT). As associações entre as variáveis foram analisadas pelo teste Exato de Fisher, com pós teste de Bonferroni e Wilcoxon. Resultados: foram identificados 105 pacientes com biópsia de LNS, sendo nove (8,6%) casos com LNS positivo. A média de MDC, CT e PI foram 0,14 mm, 32,10 mm, e 2,33 mm, respectivamente. Doentes com tumores T2 e T3 apresentaram maior chance de acometimento do LNS (p=0,022). Nenhum paciente com LNS positivo foi a óbito durante o acompanhamento. Conclusão: doentes que apresentaram tumores maiores (T2 e T3) apresentaram maior chance de linfonodos sentinelas positivos. Além do tamanho do tumor, a presença de maior carga do tumor demonstrou que os mesmos podem ser beneficiados pela biópsia de LNS.

Head and neck squamous cell carcinoma: Exploring frontiers of combinatorial approaches with tyrosine kinase inhibitors and immune checkpoint therapy.

Squamous cell carcinomas (SCC) are the most common malignant tumors that arise in the head and neck. Despite advances in the management of affected patients, the mortality burden of these tumors is increasing every year. The discovery of a vast genetic landscape has revealed new opportunities for therapeutic intervention of head and neck SCC (HNSCC). Molecular alterations of tyrosine kinases are involved in the pathogenesis of cancer and may help keep cancer cells from growing. Currently, many drugs inhibit this enzyme family and are being studied by the pharmaceutical industry opening the room to expand the use and efficacy of this therapeutic modality alone or using combinatorial approaches including checkpoint inhibitors for treatment. In this paper, we explored the role of tyrosine kinases inhibitors of HNSCC, and clinical trials related to these molecules, expecting to provide references for HNSCC therapy.

Tumor microenvironment in salivary gland carcinomas: An orchestrated state of chaos.

Salivary gland carcinomas (SGC) are rare tumors of heterogeneous morphology and many histological subtypes. Like other tumors, the SGC mass consists of a varied population of malignant cells and a diverse array of immune cells, cancer-associated fibroblasts, cytokines, chemokines, extracellular matrix proteins, and metalloproteinases, collectively known as the tumor microenvironment (TME). This chaotic network serves as an important physical mediator of cancer cell growth. In this review, we provided current insights into the TME of some of the most common SGC. Here, we highlighted the histological heterogeneity of these tumors, delineated the nature/intensity of inflammatory infiltrates, and the mechanisms involved in immunological escaping related to each SGC subtype.

Protein markers of primary salivary gland tumors: A systematic review of proteomic profiling studies.

OBJECTIVE: To integrate all the available data published in the English literature regarding the protein diagnostic and/or prognostic markers in salivary gland tumors identified by mass spectrometry (MS)-based discovery proteomics. DESIGN: An extensive search was carried out using MEDLINE/PubMed, EMBASE, Web of Science, and Scopus databases. Manual searching in Google Scholar and assessment of the reference list of the included articles also was performed. The risk of bias was assessed by the Joanna Briggs Institute Critical Appraisal tool for the specific type of study. RESULTS: A total of 1092 articles were initially retrieved within which 6 were used for data extraction, resulting in 145 cases of salivary gland tumors. The data was composted by eleven salivary gland tumor types. In total, 2136 proteins were detected by MS-based discovery proteomics in salivary gland tumors. Ninety-one proteins were proposed as potential diagnostic and/or prognostic markers. Of these, some have been identified in one or more studies, whereas fifteen were in common across studies and a total of seventy-six were non-repeat proteins. CONCLUSION: In summary, we compiled data about the proteomic profile of potential diagnostic and/or prognostic protein markers of the salivary gland tumors detected by MS-based discovery proteomics. The proteins ANXA1, ANXA5, CAPG, CRYAB, FGB, GNB2L1, IGHG1, PPIA, S100A9, and SOD1 were proposed as the most common potential diagnostic markers of salivary gland tumors.

Salivary gland cancer in the setting of tumor microenvironment: Translational routes for therapy.

Salivary gland carcinomas (SGC) are aggressive cancers that arise in minor and major salivary glands. Given the complexity and the multiple subtypes of this class of tumors, diagnosis and, treatment may be challenging for clinicians. Recently the tumor microenvironment, composed mainly of immune and stromal cells are been a target for treatment. Accumulating evidence indicates that cancer immunotherapies have made a significant impact on oncologic patients, however immunotherapeutic attempts in SGC have been shown limited improvement. Advances in the models that best translate aggressive SGC are needed for the development of clinical protocols grouping immunotherapies and other classes of drugs that will promote better responses in patients with advanced SGC stages. In this review, we introduced different experimental models for SGC with a focus on tumor microenvironment highlighting potential therapy applications for each model.

Spindle cell carcinoma of the lip: An immunohistochemical study of a challenging case.

INTRODUCTION: Spindle cell carcinoma (SpCC) or sarcomatoid carcinoma, is a rare variant of squamous cell carcinoma (SCC) that has a variable proportion of carcinomatous and sarcomatous components. Here, we reported an immunohistochemical study of a spindle cell carcinoma with a challenging morphological diagnosis. CASE REPORT: A 50-year-old woman with a previous history of nodular melanoma was referred for evaluation of a painful papule in the lower lip. After surgical resection, neoplastic cells showed focal positivity for CK-14, αSMA, p63, and confirmed the strong positivity for S100 and vimentin. Tumor cells were negative for HMB-45, Melan A, SOX-10, AE1/AE3, 34ßE12, CK5-6, CAM5.2, EMA, desmin, calponin, CD10, CD34, and CD68. With these findings, a diagnosis of SpCC was rendered. The patient presented lung and dorsal metastases after 12 months and after 3 years of follow-up, the patient died. CONCLUSION: In summary, a careful correlation of microscopy and immunohistochemical characteristics is required for the proper diagnosis of this lesion.