Defining the relationship of salivary gland malignancies to novel cell subpopulations in human salivary glands using single nucleus RNA-sequencing.

Salivary glands have essential roles in maintaining oral health, mastication, taste and speech, by secreting saliva. Salivary glands are composed of several types of cells, and each cell type is predicted to be involved in the carcinogenesis of different types of cancers including adenoid cystic carcinoma (ACC), acinic cell carcinoma (AciCC), salivary duct carcinoma (SDC), myoepithelial carcinoma (MECA) and other histology. In our study, we performed single nucleus RNA-seq on three human salivary gland samples to clarify the gene expression profile of each complex cellular component of the salivary glands and related these expression patterns to expression found in salivary gland cancers (SGC) to infer cell of origin. By single nucleus RNA-seq, salivary gland cells were stratified into four clusters: acinar cells, ductal cells 1, ductal cells 2 and myoepithelial cells/stromal cells. The localization of each cell group was verified by IHC of each cluster marker gene, and one group of ductal cells was found to represent intercalated ductal cells labeled with HES1. Furthermore, in comparison with SGC RNA-seq data, acinar cell markers were upregulated in AciCC, but downregulated in ACC and ductal cell markers were upregulated in SDC but downregulated in MECA, suggesting that markers of origin are highly expressed in some SGC. Cell type expressions in specific SGC histology are similar to those found in normal salivary gland populations, indicating a potential etiologic relationship.

Imaging of salivary gland cancers derived from a sublingual gland herniated into the submandibular space: a report of three cases.

Sublingual gland herniation into the submandibular space through a mylohyoid muscle defect is a common anatomical variation; however, salivary gland cancers that arise from a herniated sublingual gland have not been described yet. Here, we report three patients with salivary gland cancers originating from a herniated sublingual gland. All tumors were detected as palpable submandibular masses, located anterior to the submandibular gland, medial to the mandible, and lateral to the mylohyoid muscle, with contact with the sublingual gland through a mylohyoid muscle defect. Intraoperative findings confirmed that the masses were derived from herniated sublingual glands. Pathological examination showed one case of mucoepidermoid carcinoma and two cases of adenoid cystic carcinoma. Imaging findings of the tumor location, in addition to the continuity with the sublingual gland through the mylohyoid muscle defect, are crucial for accurately diagnosing the tumor origin, which is essential for determining the appropriate clinical management.

Prognostic effects of previous cancer history on patients with major salivary gland cancer.

OBJECTIVES: To explore the prognostic effects of previous cancer history on patients with major salivary gland cancer (SGC). SUBJECTS AND METHODS: SGC patients with (sec-SGC) and without (one-SGC) a previous cancer from the SEER database were identified. Cox proportional hazards regression (CoxPH) models were used to compare the prognosis between sec-SGC and one-SGC patients. Subgroup analyses for sec-SGC patients by gender, previous cancer types, previous cancer histology, and cancer diagnosis interval (CDI) were performed. Two CoxPH models were constructed to distinguish sec-SGC patients with different prognostic risks. RESULTS: 9098 SGC patients were enrolled. Overall, sec-SGC patients (adjusted HR [aHR] = 1.26, p < 0.001), especially those with a CDI ≤ 5 years (aHR = 1.47, p < 0.001), had worse overall survival (OS) than one-SGC patients. In subgroup analysis, only sec-SGC patients with a previous head and neck cancer who were female (aHR = 2.38, p = 0.005), with a CDI ≤ 5 years (aHR = 1.65, p = 0.007) or with a previous squamous cell carcinoma (aHR = 6.52, p < 0.001) had worse OS. Our models successfully differentiated all sec-SGC patients into high-, intermediate- and low-risk groups with different prognosis. CONCLUSIONS: Sec-SGC patients with different previous cancer types, gender, CDI and previous cancer histology had varied prognosis. The models we constructed could help differentiate the prognosis of sec-SGC patients with different risks.

Chemoradiotherapy versus radiotherapy in high risk salivary gland cancer.

OBJECTIVE: The aim of this study was to investigate the potential survival benefits associated with chemoradiotherapy (CRT) as opposed to radiotherapy (RT) in patients with resected high-risk salivary gland cancer (SGC), with a specific focus on determining whether these benefits are influenced by the number of high-risk variables. METHODS: Patients who underwent surgical treatment for high-risk SGC were retrospectively enrolled and categorized into either CRT or RT groups. The impact of adjuvant therapy on locoregional control (LRC) and overall survival (OS) was assessed using a multivariable Cox model. RESULTS: A total of 152 patients were included following propensity score-matching. In comparison to RT, CRT did not demonstrate a significant survival advantage in terms of LRC (p = 0.485, HR: 1.14, 95%CI: 0.36-4.22) and OS (p = 0.367, HR: 0.99, 95%CI: 0.17-3.87) in entire population. But among patients with T3/4 stage, high-grade tumors, and 5 or more positive lymph nodes, the addition of chemotherapy to RT significantly (p = 0.042) correlated with a 15% reduction in the risk of cancer recurrence (95%CI: 4-54%). Conversely, in other subgroups with varying combinations of high-risk variables, CRT did not provide additional survival benefits for LRC and OS compared to RT. CONCLUSION: Adjuvant chemotherapy may be considered in conjunction with RT specifically in cases where there is a presence of T3/4 stage, high-grade tumors, and 5 or more metastatic lymph nodes in high-risk SGC.

Appraisal of clinical practice guidelines for salivary gland cancer management utilizing AGREE II instrument.

OBJECTIVE: Salivary gland cancers (SGC) are rare neoplasms which comprise 1-5 % of all head and neck cancers. SGCs can be managed by resection, radiosurgery, chemotherapy, or a combination of these. Our team appraised the quality of clinical practice guidelines (CPGs) for SGC treatment and management using the Appraisal of Guidelines for Research and Evaluation (AGREE-II) instrument. DATA SOURCES: PubMed, Scopus, & EMBASE were reviewed for CPGs regarding SGC management from database inception to January 1st, 2023. REVIEW METHODS: The AGREE-II instrument was used by 4 reviewers to independently evaluate guidelines. Domain scores were generated with a satisfactory threshold being >60 % - a "high" quality CPG required >4 satisfactory domains. Intraclass correlation coefficients (ICCs) were used, via R 4.2.1., to determine inter-reviewer variability. RESULTS: Literature review identified 645 articles, with six being included after applying inclusion and exclusion criteria. Of the six included articles, one CPG was "high" quality and 5 were "low" quality. The domains with the highest scores were "Editorial Independence" (72.57 ± 36.60) and "Clarity and Presentation" (63.19 ± 26.08), while the lowest were "Rigor of Development" (34.03 ± 30.63) and "Applicability" (30.21 ± 30.46). ICC scores for each domain ranged from 0.937 to 0.983, indicating a high level of inter-rater agreement. CONCLUSION: This study found that most CPGs for the treatment and management of SGC were of "low" quality, with only one guideline being considered "high" quality based on the standard set by the AGREE-II instrument. These findings indicate that there is a high level of variability and little standardization when it comes to the quality of CPGs.

Association of salivary gland cancer with human papillomavirus infections.

PURPOSE: The link between human papillomavirus (HPV) infections and salivary gland cancer is still a subject of ongoing debate. This study aimed to explore the association between HPV infections and salivary gland cancer in a Taiwanese cohort. We hypothesize that HPV infection is associated with an increased risk of developing salivary gland cancer. METHODS: This case-control study included 416 individuals aged ≥ 20 years who had received their first diagnosis of salivary gland cancer as cases, and 2080 propensity-score-matched controls. We performed multivariate logistic regressions to evaluate the association of salivary gland cancer with HPV infections while considering sociodemographic characteristics and medical comorbidities. RESULTS: Statistical analysis showed a significant difference in the prevalence of HPV infections between patients diagnosed with salivary gland cancer and the controls, with rates of 10.8% and 6.2%, respectively (p < 0.001). The odds ratio for having prior HPV infections among patients with salivary gland cancer compared to controls was 1.885, with a 95% confidence interval of 1.315 to 2.701 after adjusting for variables such as age, sex, monthly income, geographic location, urbanization level, diabetes, hypertension, hyperlipidemia, tobacco use, and alcohol abuse/alcohol dependence syndrome. CONCLUSIONS: Our study adds to the evidence suggesting an association between HPV infections and salivary gland cancer. Individuals with a history of HPV infection have an approximately 88% higher likelihood of developing salivary gland cancer.

Oncologic outcomes of the most prevalent major salivary gland cancers: retrospective cohort study from single center.

BACKGROUND: The preoperative diagnosis of salivary gland cancer (SGC) is crucial for the application of appropriate treatment, particularly involving the extension of the resection. METHODS: Retrospective search of medical database identified 116 patients treated surgically with malignant tumors of salivary gland between 2010 and 2020. Analysis included the demographical data, clinical course, type of surgical and adjuvant treatment, histology type and margin status, perivascular invasion (LVI), perineural invasion (PNI), metastatic lymph nodes (LN). Facial nerve function, recurrence-free and overall survival were evaluated. Adequate statistics were used for data analysis. RESULTS: The final cohort included 63 SGC patients, with adenoid cystic carcinoma the most common pathological type (27%, n = 17), followed by adenocarcinoma (17.4% n = 11). T1 and T2 patients accounted for majority cases (n = 46). The lymph node metastases were confirmed with the histopathology in 31.7% (n = 20). Distant metastases were observed in 4.8% of cases (n = 3). 38% (n = 24) of SGC were treated selectively with surgery, 49.2% (n = 31) had postoperative radiotherapy and 15.9% (n = 10)-radio-chemotherapy. The final facial nerve function was impaired in 38% of patients. Mean overall survival (OS) for all patients was 108.7 (± 132.1) months, and was the most favorable for acinar cell carcinoma (118.9 ± 45.4) and the poorest for squamous cell carcinoma (44 ± 32). Cox regression analysis of disease-free survival and OS identified significant association only with patients' age over 65 years, the hazard ratio of 7.955 and 6.486, respectively. CONCLUSIONS: The efficacy of treatment modalities for SGC should be verified with regard to the histopathological type, but also the patients' age should be taken into account.

Novel Epigenetic Modifiers of Histones Presenting Potent Inhibitory Effects on Adenoid Cystic Carcinoma Stemness and Invasive Properties.

Adenoid cystic carcinoma (ACC) is a rare neoplasm known for its indolent clinical course, risk of perineural invasion, and late onset of distant metastasis. Due to the scarcity of samples and the tumor's rarity, progress in developing effective treatments has been historically limited. To tackle this issue, a high-throughput screening of epigenetic drugs was conducted to identify compounds capable of disrupting the invasive properties of the tumor and its cancer stem cells (CSCs). ACC cells were screened for changes in tumor viability, chromatin decondensation, Snail inhibition along tumor migration, and disruption of cancer stem cells. Seven compounds showed potential clinical interest, and further validation showed that Scriptaid emerged as a promising candidate for treating ACC invasion. Scriptaid demonstrated a favorable cellular toxicity index, effectively inhibited Snail expression, induced hyperacetylation of histone, reduced cell migration, and effectively disrupted tumorspheres. Additionally, LMK235 displayed encouraging results in four out of five validation assays, further highlighting its potential in combating tumor invasion in ACC. By targeting the invasive properties of the tumor and CSCs, Scriptaid and LMK235 hold promise as potential treatments for ACC, with the potential to improve patient outcomes and pave the way for further research in this critical area.

Near-Infrared Photoimmunotherapy Using a Protein Mimetic for EGFR-Positive Salivary Gland Cancer.

Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer therapy based on a monoclonal antibody (mAb) conjugated to a photosensitizer (IR700Dye). The conjugate can be activated by near-infrared light irradiation, causing necrotic cell death with high selectivity. In this study, we investigated NIR-PIT using a small protein mimetic (6-7 kDa, Affibody) which has more rapid clearance and better tissue penetration than mAbs for epidermal growth factor receptor (EGFR)-positive salivary gland cancer (SGC). The level of EGFR expression was examined in vitro using immunocytochemistry and Western blotting. Cell viability was analyzed using the alamarBlue assay. In vivo, the volume of EGFR-positive tumors treated with NIR-PIT using the EGFR Affibody-IR700Dye conjugate was followed for 43 days. It was found that NIR-PIT using the EGFR Affibody-IR700Dye conjugate induced the selective destruction of EGFR-positive SGC cells and restricted the progression of EGFR-positive tumors. We expect that NIR-PIT using the EGFR Affibody-IR700Dye conjugate can efficiently treat EGFR-positive SGC and preserve normal salivary function.

miR-183-5p overexpression orchestrates collective invasion in salivary adenoid cystic carcinoma through the FAT1/YAP1 signaling pathway.

The invasion of cancer cells into interstitial tissues in a cohesive unit is termed collective invasion, and it is important for the invasion and metastasis of salivary adenoid cystic carcinoma (SACC). However, the underlying mechanisms regulating SACC collective invasion are still poorly understood. Here, we found that SACC tissues exhibited remarkable FAT1 downregulation and YAP1 upregulation at the invasive front, which was closely associated with collective invasion and distant metastasis. Decreasing FAT1 expression significantly activated the YAP1 signaling pathway and promoted collective invasion. Moreover, miR-183-5p was identified as the candidate regulator of FAT1 by bioinformatic analysis and an online database algorithm. A dual luciferase reporter experiment further confirmed that miR-183-5p directly targeted the FAT1 3'-UTR to reduce FAT1 expression. Increasing or decreasing miR-183-5p expression promoted or attenuated collective invasion, which was reversed by YAP1 siRNA or FAT1 siRNA, respectively. In addition, knocking down miR-183-5p reduced tumor burden and attenuated collective invasion in vivo. Together, these results suggest that the miR-183-5p/FAT1/YAP1 signaling pathway is a critical driver of SACC collective invasion, revealing a novel therapeutic target.

Minor Salivary Gland Cancer of the Head and Neck: A Review of Epidemiologic Aspects, Prognostic Factors, and Outcomes.

PURPOSE OF REVIEW: Minor salivary gland carcinomas (MiSGC) of the head and neck are a group of rare cancers with significant heterogeneity in histological types and with variable clinical behavior. This study aims to clarify the incidence, epidemiology, predictive factors, and outcome-based survival in a large cohort of patients treated at the Brazilian National Cancer Institute (BNCI) over a 20-year period by comparing and associating the results of current articles on the world stage. RECENT FINDINGS: The difficulty in developing an algorithm of treatment is due to the low number of cases when evaluated in a single institution and the variety of histological subtypes that have different behaviors and different treatments according to each anatomical location. We reviewed the experience of tertiary centers for the treatment of head and neck cancer and epidemiological studies from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute of the USA. The lack of consensus on the management of MiSGC requires further knowledge about the biological behaviors of these tumors, as the identification of predictive factor of failure and survival to adequate treatment intensity. The growing collaboration of different centers publishing their experience allows us to unify these samples to reach concrete conclusions about these tumors.

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).

Pre-treatment quality of life in patients with salivary gland cancer in comparison with those of head and neck cancer patients.

INTRODUCTION: Salivary gland cancer (SGC) is a rare malignant tumor arising from the salivary glands, with a variety of clinical and biological behaviors different from head and neck cancer (HNC). Because of the rarity of SGC, there are limited data on pre-treatment quality of life (QoL). Therefore, we evaluated the pre-treatment QoL in SGC patients by stage and compared it with that of HNC patients. METHODS: From a prospective registry of HNC patients (2016-2020), we selected 225 patients with SGC, and 912 patients with oral cavity (OC) and oropharyngeal cancer (OPC) who were diagnosed in the same period as the HNC control group. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and HNC-Specific Module (H&N35) were used to assess QoL. RESULTS: SGC patients had a statistically better baseline QoL (69.8 vs. 64.0), emotional (82.1 vs. 78.8), cognitive (92.0 vs. 88.7), and social function (86.3 vs. 80.5), and fewer symptoms than HNC patients. The estimated average QoL differences between SGC patient diagnosed at stages I and IV was -12.9. Especially, advanced-stage of tumors was associated with much lower role functioning and emotional functioning scores in SGC patients, compared to those in HNC patients, among females and of younger age. DISCUSSION: Although the overall QoL score was higher in SGC patients than in HNC patients, specific domains were significantly affected in SGC patients according to the tumor stage. Females and those of younger age were more affected by severity of disease in SGC. STUDY REGISTRATION: ClinicalTrials.gov Identifier NCT02546895.

Seasonality of head and neck cancers.

PURPOSE: The purpose of this study is to investigate if the season of diagnosis is associated with patient, tumor, and treatment characteristics within head and neck cancer. MATERIALS AND METHODS: 1406 patients with a diagnosis of head and neck cancer (HNC) were identified from a HNC database (1996-2019). Patients were classified as receiving a diagnosis in the winter, spring, summer, or fall by calendar definition. Proportions and chi-squared analysis compared patient, tumor, and treatment factors for all diagnoses. Data was subdivided and analyzed based on the primary site. RESULTS: From this cohort, 23 %, 27 %, 25 %, and 25 % of HNC patients were diagnosed in winter, spring, summer, and fall respectively with no statistically significant difference between seasons of diagnosis. When subdivided by primary site, oral cavity cancer was significantly more likely to be diagnosed in spring, salivary gland cancer was more likely to be diagnosed in winter and summer (p = 0.03 and p = 0.01 respectively). No other demographic, clinicopathologic, or management characteristics were associated with the season of diagnosis (p > 0.05 for all). CONCLUSIONS: Diagnosis of head and neck cancer does not follow a seasonal pattern. Diagnosis of oral cavity and salivary gland cancer showed a seasonal pattern. The majority of patient, tumor and management characteristics were not associated with the.

Adenoid cystic carcinoma of the salivary glands: a pilot study of potential therapeutic targets and characterization of the immunological tumor environment and angiogenesis.

BACKGROUND: Adenoid cystic carcinoma (ACC) is a rare type of cancer commonly occurring in salivary glands. It is characterized by slow but infiltrative growth, nerve infiltration and overall poor prognosis, with late recurrence and distant metastasis. The treatment of ACC is still limited to surgery and/or (adjuvant) radiotherapy. Till now no promising systemic therapy option exists. However, various studies deliver promising results after treatment with anti-angiogenetic agents, such as anti-EGFR-antibody Cetuximab or Tyrosinkinase inhibitor Lenvatinib. METHODS: By using of immunohistological methods we analyzed and compared the macrophage and lymphocyte populations, vascularization, and PD-L1-status in 12 ACC of the salivary glands. RESULTS: All cases showed a significant elevation of macrophages with M2 polarization and a higher vascularization in ACC compared to normal salivary gland tissue. The CD4/CD8 quotient was heterogenous. ACC does not show relevant PD-L1 expression. CONCLUSIONS: The predominant M2 polarization of macrophages in ACC could be responsible for elevated vascularization, as already been proved in other cancer types, that M2 macrophages promote angiogenesis.

Rearrangement of KMT2A Characterizes a Subset of Pediatric Parotid Mucoepidermoid Carcinomas Arising Metachronous to Acute Lymphoblastic Leukemia.

Introduction: Metachronous mucoepidermoid carcinomas (MMEC) may occur in association with childhood leukemias and lymphomas. We compared molecular abnormalities of MMEC in patients with ALL with the abnormalities found in primary mucoepidermoid carcinomas (MECs) in pediatric cases and young adults. Materials and methods: Immunohistochemical stains for p63 and SOX10, molecular alterations in MAML2 and KMT2A genes detected by FISH and/or next-generation sequencing were studied in 12 pediatric MMECs secondary to ALL and six primary MECs in pediatric patients and young adults. Follow-up information of patients in both groups was obtained. Results: KMT2A rearrangements were detected in pediatric MMECs, and they were associated with remarkable histomorphological changes, including deposits of abundant stromal collagen and intratumoral lymphoid proliferations. No KMT2A rearrangements were found in primary MECs. The prognosis of MMEC in patients with ALL, especially in KMT2A-rearranged cases, was worse than in primary MECs. Kruskal-Wallis test showed a statistically significant difference in overall survival between KMT2A-rearranged MMECs and KMT2A-intact MMECs in cases with ALL (p = 0.027). Conclusion: KMT2A-rearranged MMECs in ALL patients may have inherently more aggressive behavior, even when the histomorphology of MMEC suggests a low-grade malignancy.

Patterns of care analysis for salivary gland cancer: a survey within the German Society of Radiation Oncology (DEGRO) and recommendations for daily practice.

BACKGROUND: Salivary gland cancer (SGC) is rare and a heterogeneous type of cancer. Prospective randomized trials are lacking. No guideline focusing on standard procedures of radiotherapy (RT) in the treatment of SGC exists. Therefore, we surveyed the members of the German Society of Radiation Oncology (DEGRO) to gain information about current therapeutic strategies of SGC. METHODS: An anonymous questionnaire was designed and made available on the online platform umfrageonline.com. The corresponding link was sent to all DEGRO members who provided their user data for contact purposes. Alternatively, a PDF printout version was sent. Frequency distributions of responses for each question were calculated. The data were also analyzed by type of institution. RESULTS: Sixty-seven responses were received, including answers from 21 university departments, 22 non-university institutions, and 24 radiation oncology practices. Six participants reported that their departments (practice: n = 5, non-university hospital: n = 1) did not treat SGC, and therefore the questionnaire was not completed. Concerning radiation techniques, target volume definition, and concomitant chemotherapy, treatment strategies varied greatly among the participants. Comparing university vs. non-university institutions, university hospitals treat significantly more patients with SGC per year and initiated more molecular pathological diagnostics. CONCLUSION: SGC represents a major challenge for clinicians, as reflected by the inhomogeneous survey results regarding diagnostics, RT approaches, and systemic therapy. Future prospective, multicenter clinical trials are warranted to improve and homogenize treatment of SGC and to individualize treatment according to histologic subtypes and risk factors.

The expression profiles of CD47 in the tumor microenvironment of salivary gland cancers: a next step in histology-driven immunotherapy.

BACKGROUND: Salivary gland carcinomas (SGC) are extremely rare malignancies with only limited treatment options for the metastatic phase of the disease. Treatment with anti-CD47 antibodies could represent a potent therapy for SGCs by promoting the phagocytic clearance of tumor cells through various mechanisms. However, the efficacy of anti-CD47 therapy is largely dependent on the expression of CD47 within the tumor microenvironment (TME). MATERIALS AND METHODS: In 43 patients with SGC, we were the first to investigate the CD47 expression in both tumor cells and tumor-infiltrating immune cells (TIIC) in the center and periphery of primary tumors. We also correlated the data with the clinicopathological variables of the patients and offered novel insights into the potential effectiveness of anti-CD47 therapy in SGCs. RESULTS: We observed that the CD47+ tumor cells are outnumbered by CD47+ TIICs in mucoepidermoid carcinoma. In the tumor center, the proportion of CD47+ tumor cells was comparable to the proportion of CD47+ TIICs in most histological subtypes. In low-grade tumors, significantly higher expression of CD47 was observed in TIICs in the periphery of the tumor as compared to the center of the tumor. CONCLUSION: The reason for a high expression of 'don't eat me' signals in TIICs in the tumor periphery is unclear. However, we hypothesize that in the tumor periphery, upregulation of CD47 in TIICs could be a mechanism to protect newly recruited leukocytes from macrophage-mediated phagocytosis, while also allowing the removal of old or exhausted leukocytes in the tumor center.

Cephaeline is an inductor of histone H3 acetylation and inhibitor of mucoepidermoid carcinoma cancer stem cells.

AIM: To evaluate the potential use of Cephaeline as a therapeutic strategy to manage mucoepidermoid carcinomas (MEC) of the salivary glands. MATERIAL AND METHODS: UM-HMC-1, UM-HMC-2, and UM-HMC-3A MEC cell lines were used to establish the effects of Cephaeline over tumor viability determined by MTT assay. In vitro wound healing scratch assays were performed to address cellular migration while immunofluorescence staining for histone H3 lysine 9 (H3k9ac) was used to identify the acetylation status of tumor cells upon Cephaeline administration. The presence of cancer stem cells was evaluated by the identification of ALDH enzymatic activity by flow cytometry and through functional assays using in vitro tumorsphere formation. RESULTS: A single administration of Cephaeline resulted in reduced viability of MEC cells along with the halt on tumor growth and cellular migration potential. Administration of Cephaeline resulted in chromatin histone acetylation as judged by the increased levels of H3K9ac and disruption of tumorspheres formation. Interestingly, ALDH levels were increased in UM-HMC-1 and UM-HMC-3A cell lines, while UM-HMC-2 showed a reduced enzymatic activity. CONCLUSION: Cephaeline has shown anti-cancer properties in all MEC cell lines tested by regulating tumor cells' viability, migration, proliferation, and disrupting the ability of cancer cells to generate tumorspheres.

Metastatic Adenoid Cystic Carcinoma: Genomic Landscape and Emerging Treatments.

OPINION STATEMENT: Adenoid cystic carcinoma (ACC) is a heterogeneous cancer that commonly develops in the salivary glands. Approximately 40 to 50% of patients with ACC develop recurrence and/or metastasis. Although most patients with ACC have slow-growing disease, a subset experiences aggressive disease with early visceral and/or bone metastasis. Thus far, there is no consensus on the best time to start palliative treatment in patients with indolent disease. The only systemic therapies available for recurrent or metastatic ACC are cytotoxic agents and multikinase inhibitors targeting vascular endothelial growth factor receptor, and both types of therapy have modest activity. Studies integrating proteomics, genomics, and clinical data have revealed distinct molecular ACC subtypes, ACC-I and ACC-II, with ACC-I generally associated with more aggressive disease biology. ACC-I tumors were enriched for NOTCH1-activating mutation and upregulation of MYC and MYC targets, while ACC-II tumors exhibited upregulation of TP63 and receptor tyrosine kinases. These findings highlight the importance of patient selection for surveillance and targeted therapy development in ACC. In recent clinical trials of targeted therapy in ACC, patients are being selected according to tumor molecular profile (e.g., presence of NOTCH-activating mutations), which represents a major advance in the field. Ongoing collaborative research focusing on the development of novel therapeutic strategies for ACC patients based on disease biology will increase the drug armamentarium and improve survival outcomes for these patients in dire need.