Cellular liquid biopsy provides unique chances for disease monitoring, preclinical model generation and therapy adjustment in rare salivary gland cancer patients.

While cell-free liquid biopsy (cfLB) approaches provide simple and inexpensive disease monitoring, cell-based liquid biopsy (cLB) may enable additional molecular genetic assessment of systemic disease heterogeneity and preclinical model development. We investigated 71 blood samples of 62 patients with various advanced cancer types and subjected enriched circulating tumor cells (CTCs) to organoid culture conditions. CTC-derived tumoroid models were characterized by DNA/RNA sequencing and immunohistochemistry, as well as functional drug testing. Results were linked to molecular features of primary tumors, metastases, and CTCs; CTC enumeration was linked to disease progression. Of 52 samples with positive CTC counts (≥1) from eight different cancer types, only CTCs from two salivary gland cancer (SGC) patients formed tumoroid cultures (P = 0.0005). Longitudinal CTC enumeration of one SGC patient closely reflected disease progression during treatment and revealed metastatic relapse earlier than clinical imaging. Multiomics analysis and functional in vitro drug testing identified potential resistance mechanisms and drug vulnerabilities. We conclude that cLB might add a functional dimension (to the genetic approaches) in the personalized management of rare, difficult-to-treat cancers such as SGC.

Systemic treatments in recurrent or metastatic salivary gland cancer: a systematic review.

BACKGROUND: Salivary gland cancers are infrequent and pose a challenge owing to their histological diversity and varied clinical behavior, making the selection of optimal systemic treatments for advanced or recurrent stages difficult. This systematic review aims to assess overall survival outcomes and systemic treatment responses across four types of salivary cancers. METHODS: A PubMed and Google Scholar search identified studies involving initially advanced or relapsed cases undergoing systemic treatment. Studies with clear, individualized data on treatment responses and outcomes were selected based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Of the 723 studies screened, 44 met our inclusion criteria. RESULTS: A total of 426 cases of recurrent/metastatic salivary gland cancer, mostly salivary duct carcinoma (SDC; n = 219) and adenoid cyst carcinoma (ACC; n = 167), were included. Histomolecular markers were heavily associated with histology, with HER2 overexpression and androgen receptor nuclear expression typically found in SDC and adenocarcinoma not otherwise specified cases and KIT overexpression only in ACC. The response rates were associated with specific receptor blockage, with trastuzumab plus chemotherapy, and bicalutamide being the most effective (overall response rate 80% and 42.8%, respectively). Moreover, the response to treatment positively influenced overall survival (responders 38 versus non-responders 18.7 median months; P < 0.001). In this retrospective analysis of a particular cohort, survival outcomes per histology types showed that anti-human epidermal growth factor receptor 2 therapy was more effective for SDC, while chemotherapy was more effective for ACC. CONCLUSION: Systemic treatments contribute to the survival of patients with salivary gland cancer at relapsed or newly advanced stages. The response to treatment is heavily influenced by histological subtype and treatment specificity.

The impact of digital inequities on salivary gland cancer disparities in the United States.

INTRODUCTION: Technology and internet access have become increasingly integrated into healthcare as the primary platform for health-related information and provider-patient communication. Disparities in access to digital resources exist in the United States and have been shown to impact health outcomes in various head and neck malignancies. Our objective is to evaluate the associations of digital inequity on health outcomes in patients with salivary gland cancer (SGC). METHODS: The Digital Inequity Index (DII) was developed using 17 census-tract level variables obtained from the American Community Survey and Federal Communications Commission. Variables were categorized as digital infrastructure or sociodemographic (e.g., non-digital) and scored based on relative rankings across all US counties. Scores were assigned to patients from the Surveillance-Epidemiology-End Results (SEER) database diagnosed with SGC between 2013 and 2017 based on county-of-residence. Regressions were performed between DII score and outcomes of surveillance time, survival time, tumor stage at time of diagnosis, and treatment modality. RESULTS: Among 9306 SGC-patients, increased digital inequity was associated with advanced-staging at presentation (OR: 1.04, 95% CI: 1.01-1.07, p = 0.033), increased odds of chemotherapy receipt (OR: 1.05, CI: 1.01-1.10, p = 0.010), and decreased odds of surgical intervention (OR: 0.94, 95% CI: 0.91-0.98, p = 0.003) after accounting for traditional sociodemographic factors. Increased digital inequity was also associated with decreased surveillance time and survival periods. CONCLUSIONS: Digital inequity significantly and independently associates with negative health and treatment outcomes in SGC patients, highlighting the importance of directed efforts to address these seldom-investigated drivers of health disparities.

A randomized phase II trial on the addition of dutasteride to combined androgen blockade therapy versus combined androgen blockade therapy alone in patients with advanced or metastatic salivary duct carcinoma - the DUCT study protocol.

BACKGROUND: Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer, frequently associated with incurable recurrences and distant metastases (R/M). Proliferation of SDC relies on androgen receptor (AR) signalling, prompting the use of combined androgen blockade (CAB, i.e., luteinizing hormone-releasing hormone agonist and/or AR antagonists) to R/M SDC patients. However, only a subset of patients benefits from such treatments. We have shown that response to CAB is associated with steroid 5α-reductase 1 (SRD5A1) mRNA expression. SRD5A1 catalyses the intracellular conversion of testosterone into the more potent AR-agonist dihydrotestosterone. This conversion can be inhibited by dutasteride, a potent SRD5A1-inhibitor, which is currently prescribed for benign prostatic hyperplasia. We hypothesize that repurposing dutasteride to target AR signalling in SDC could enhance therapeutic response and clinical outcome in SDC patients. METHODS: This prospective, open-label, randomized controlled phase II clinical trial, is designed to investigate whether dutasteride as an adjunct drug to CAB improves response rate and clinical outcome in patients with AR-positive R/M SDC. Patients are divided in two cohorts based on their prior systemic treatments. In cohort A, CAB-naïve patients (n = 74) will be randomly assigned to either a control arm (Arm 1) receiving CAB (goserelin 10.8 mg/3m and bicalutamide 50 mg/OD) or an experimental arm (Arm 2) where dutasteride (0.5 mg/OD) is added to the CAB regimen. In cohort B, patients with disease progression after adjuvant or first-line palliative CAB therapy (max. n = 24) will receive goserelin, bicalutamide, and dutasteride to assess whether the addition of dutasteride can overcome therapy resistance. The primary endpoints are the objective response rate and duration of response. Secondary endpoints are progression-free survival, overall survival, clinical benefit rate, quality of life, and safety. Translational research will be performed to explore molecular target expression differences and their correlation with clinical outcome. DISCUSSION: The DUCT study addresses an unmet medical need by investigating the repurposing of dutasteride to enhance treatment response and improve clinical outcome for patients with R/M SDC, especially those with limited alternative treatment options, such as HER2-negative cases. By repurposing a registered low-cost drug, this trial's findings could be readily applied into clinical practice. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT05513365. Date of registration: August 24, 2022. PROTOCOL VERSION: Current protocol version 4.0, February 21, 2024.

The Clinical Utilisation and Duration of Treatment with HER2-Directed Therapies in HER2-Positive Recurrent or Metastatic Salivary Gland Cancers.

Salivary gland cancers (SGC) are rare tumours with limited availability of systemic therapies. Some SGC subtypes overexpress HER2, and this represents a potential therapeutic target, but the evidence base is limited. This study sought to analyse real-world data on the efficacy of HER2-directed therapies in SGC. This is a retrospective observational study using anonymised data from commercial compassionate-use access registrations and a privately funded pharmacy prescribing register. Treatment duration was defined as the time from drug initiation to treatment discontinuation. Kaplan-Meier analysis of treatment duration was performed using R for Windows (v4.3.2). A case report is also provided of an exceptional responder. Eighteen patients were identified who received HER2-directed therapies for HER2-positive recurrent/metastatic SGC, and complete data on treatment duration was available for 15/18. Histology was salivary duct carcinoma in 13/18 patients, adenocarcinoma NOS in 4/18, and carcinoma ex pleomorphic adenoma in 1/18. The median treatment duration was 8.3 months (95% CI: 6.41-not reached), and the range was 1.0-47.0 months. Choice of HER2-directed therapy varied, with ado-trastuzumab emtasine being the most common (9/18). At the time of analysis, HER2-directed therapy was ongoing for 9/15, discontinued due to disease progression for 4/15, discontinued due to toxicity for 1/15, and 1/15 was discontinued for an unspecified reason. An exceptional responder experienced a complete response with a treatment duration of 47.0 months. These real-world data are comparable to the median PFS observed with HER2-directed therapies in phase II trials and support the use of HER2-directed therapies in this group.

Lutetium-177-PSMA therapy for recurrent/metastatic salivary gland cancer: a prospective pilot study.

There is an urgent need for novel systemic therapies for recurrent/systemic salivary gland cancer, as current treatment options are scarce. [68Ga]Ga-PSMA-11 PET/CT revealed relevant uptake of prostate-specific membrane antigen (PSMA) in adenoid cystic carcinoma (AdCC) and salivary duct carcinoma (SDC). Therefore, we assessed the safety, feasibility, efficacy and radiation dosimetry of [177Lu]Lu-PSMA-I&T treatment in AdCC and SDC patients in a prospective pilot study. Methods: This single-center, single-arm study intended to include 10 recurrent/metastatic AdCC patients and five recurrent/metastatic SDC patients. AdCC patients could only participate in case of progressive and/or symptomatic disease. Patients required ≥ 1 lesion ≥ 1.5 cm with an SUVmax on [68Ga]Ga-PSMA-11 PET/CT above liver SUVmean. Patients were planned to receive four cycles ~ 7.4 GBq [177Lu]Lu-PSMA-I&T. In case of progressive disease per RECIST 1.1 at mid-treatment evaluation after two cycles, treatment was discontinued. Safety was the primary endpoint. Secondary endpoints included objective response rate (ORR), tumor- and organ-absorbed radiation doses and progression-free survival. Results: After screening, 10 out of 15 (67%) AdCC and two out of 10 (20%) SDC patients were eligible. Two patients (17%) demonstrated grade 3 treatment-related toxicity: lymphocytopenia (8%) and hyponatremia (8%). No dose-limiting toxicities occurred. In the AdCC cohort, six patients (60%) completed the four treatment cycles. Due to progressive disease, treatment was discontinued after two cycles in three patients (30%) and after one cycle in one patient (10%). No objective responses were observed (ORR: 0%). Three AdCC patients (30%) showed stable disease ≥ 6 months (7, 17 and 23 months). None of the two SDC patients completed the treatment: one patient deteriorated after the first cycle, while the other had progressive disease after two cycles. The high screen failure rate due to insufficient PSMA uptake resulted in premature closure of the SDC cohort. Dosimetry revealed low tumor-absorbed doses (median 0.07 Gy/GBq, range 0.001-0.63 Gy/GBq). Conclusions: [177Lu]Lu-PSMA-I&T in AdCC and SDC patients was safe and generally well-tolerated. However, efficacy was limited, likely due to low tumor-absorbed doses. For SDC, [177Lu]Lu-PSMA-I&T appears unfeasible due to insufficient PSMA uptake.

Different characteristics of the tumor immune microenvironment among subtypes of salivary gland cancer.

AIM: Although immune checkpoint inhibitors (ICPi) for salivary gland cancer (SGC) have been investigated in clinical trials, details of the tumor immune microenvironment (TIME) remain unclear. This research aimed to elucidate the TIME of SGC and its relationship with tumor mutation burden (TMB) and to explore the rationale for the applicability of ICPi. MATERIALS AND METHODS: We selected five pathological types, namely adenoid cystic carcinoma (ACC); adenocarcinoma, not otherwise specified (ANOS); salivary duct carcinoma (SDC); and low/high-grade mucoepidermoid carcinoma (MEClow/high). We investigated the TIME and TMB of each pathological type. TIME was evaluated by multiplexed fluorescent immunohistochemistry. TMB was measured by next-generation sequencing. RESULTS: ACC and MEChigh showed the lowest and highest infiltration of immune effector and suppressor cells in both tumor and stroma. ANOS, SDC, and MEClow showed modest infiltration of immune effector cells in tumors. Correlation analysis showed a positive correlation between CD3+CD8+ T cells in tumor and TMB (r = 0.647). CD3+CD8+ T cells in tumors showed a positive correlation with programmed cell death-ligand 1 expression in tumor cells (r = 0.513) and a weak positive correlation with CD3+CD4+Foxp3+ cells in tumors (r = 0.399). However, no correlation was observed between CD3+CD8+ T cells and CD204+ cells in tumors (r = -0.049). CONCLUSION: The TIME of ACC was the so-called immune desert type, which may explain the mechanisms of the poor response to ICPi in previous clinical trials. On the other hand, MEChigh was the immune-inflamed type, and this may support the rationale of ICPi for this pathological subtype.

Improving the response to lenvatinib in partial responders using a Constrained-Disorder-Principle-based second-generation artificial intelligence-therapeutic regimen: a proof-of-concept open-labeled clinical trial.

Introduction: The main obstacle in treating cancer patients is drug resistance. Lenvatinib treatment poses challenges due to loss of response and the common dose-limiting adverse events (AEs). The Constrained-disorder-principle (CDP)-based second-generation artificial intelligence (AI) systems introduce variability into treatment regimens and offer a potential strategy for enhancing treatment efficacy. This proof-of-concept clinical trial aimed to assess the impact of a personalized algorithm-controlled therapeutic regimen on lenvatinib effectiveness and tolerability. Methods: A 14-week open-label, non-randomized trial was conducted with five cancer patients receiving lenvatinib-an AI-assisted application tailored to a personalized therapeutic regimen for each patient, which the treating physician approved. The study assessed changes in tumor response through FDG-PET-CT and tumor markers and quality of life via the EORTC QLQ-THY34 questionnaire, AEs, and laboratory evaluations. The app monitored treatment adherence. Results: At 14 weeks of follow-up, the disease control rate (including the following outcomes: complete response, partial response, stable disease) was 80%. The FDG-PET-CT scan-based RECIST v1.1 and PERCIST criteria showed partial response in 40% of patients and stable disease in an additional 40% of patients. One patient experienced a progressing disease. Of the participants with thyroid cancer, 75% showed a reduction in thyroglobulin levels, and 60% of all the participants showed a decrease in neutrophil-to-lymphocyte ratio during treatment. Improvement in the median social support score among patients utilizing the system supports an ancillary benefit of the intervention. No grade 4 AEs or functional deteriorations were recorded. Summary: The results of this proof-of-concept open-labeled clinical trial suggest that the CDP-based second-generation AI system-generated personalized therapeutic recommendations may improve the response to lenvatinib with manageable AEs. Prospective controlled studies are needed to determine the efficacy of this approach.

Unique Cohorts of Salivary Gland Cancer Cells as an in-vitro Model of Circulating Tumor Cells.

Introduction: The characterization of circulating tumor cells (CTC) and circulating tumor microemboli (CTM) has emerged as both a challenge to the standard view of metastasis, and as a valuable means for understanding genotypic and phenotypic variability shown even within the same cancer type. However, in the case of salivary gland neoplasms, limited data are available for the role that CTCs and CTMs play in metastasis and secondary tumor formation.ru.AQ1 In response to this, we propose that similarities between in vitro clusters of cultured salivary gland cancer cells may act as a surrogate model for in vivo CTCs and CTMs isolated from patients. Materials and Methods: Using techniques in immunofluorescence, immunoblotting, and 2-dimensional migration, we isolated and characterized a group of cohort cells from a commercially available cell line (HTB-41). Results: Here, cells exhibited a hybrid phenotype with simultaneous expression of both epithelial and mesenchymal markers (E-cadherin, vimentin, and α-SMA). Cohort cells also exhibited increased migration in comparison to parental cells. Conclusion: Data suggest that these isolated cell clusters may fucntion as a potential in vitro model of CTCs and CTMs.

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.

An autopsy case of pulmonary tumor thrombotic microangiopathy that developed during chemotherapy for salivary duct carcinoma of the parotid gland.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rapidly progressive cancer-related disease with a dismal clinical course. The patient in this report was a 43-year-old man with metastatic salivary duct carcinoma arising from the parotid gland. Combined androgen blockade therapy was administered started as first-line treatment, but failed after 5 months, followed by docetaxel plus carboplatin therapy as second-line treatment, which failed after 3 months. Genomic profiling revealed a BRAF V600E mutation, and combined BRAF and MEK inhibitor therapy was started as third-line treatment. The cancer remained stable during the first 10 months of third-line treatment, but treatment was subsequently discontinued due to the onset of symptoms of fatigue, myalgia and arthritis. Twenty days after the onset of these symptoms and interruption of third-line treatment, the patient was urgently admitted to hospital with respiratory distress and severe thrombocytopenia. CT images at the time of admission led our radiologist to the possibility of PTTM, but the patient died the day after admission and autopsy findings indicated that PTTM was the cause of death. This report describes a very informative case of PTTM with sequential imaging and detailed autopsy findings were available and provides a literature review.

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.

Recurrence after primary salivary gland carcinoma: Frequency, survival, and risk factors.

BACKGROUND: Primary salivary gland carcinomas (SGC) are rare neoplasms that present therapeutic challenges especially in recurrent tumors. The aim of this study was to investigate the incidence and distribution of tumor recurrence, associated risk factors, and survival. METHODS: This analysis includes data from 318 patients treated for SGC between 1992 and 2020. Survival analysis was performed using the Kaplan-Meier method. Univariate and multivariate analyses were used to identify risk factors associated with recurrence. RESULTS: 21.7% of the patients developed recurrent disease after a mean of 38.2 months. In multivariate analysis, positive-resection margins, vascular invasion, and tumor localization in the submandibular gland and small salivary glands were independent factors for recurrence. The 5-year overall survival was 67%, the 5-year disease-free survival was 54%. CONCLUSION: Tumor recurrence in SGC occurred in one out of five patients. In highly aggressive entities and patients with risk factors, treatment intensification should be considered.

The Current Position of Postoperative Radiotherapy for Salivary Gland Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Because of the rarity, heterogeneous histology, and diverse anatomical sites of salivary gland cancer (SGC), there are a limited number of clinical studies on its management. This study reports the cumulative evidence of postoperative radiotherapy (PORT) for SGC of the head and neck. METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases between 7th and 10th November 2023. RESULTS: A total of 2962 patients from 26 studies between 2007 and 2023 were included in this meta-analysis. The median RT dose was 64 Gy (range: 56-66 Gy). The median proportions of high-grade, pathological tumor stage 3 or 4 and pathological lymph node involvement were 42% (0-100%), 40% (0-77%), and 31% (0-75%). The pooled locoregional control rates at 3, 5, and 10 years were 92% (95% confidence interval [CI], 89-94%), 89% (95% CI, 86-93%), and 84% (95% CI, 73-92%), respectively. The pooled disease-free survival (DFS) rates at 3, 5, and 10 years were 77% (95% CI, 70-83%), 67% (95% CI, 60-74%), and 61% (95% CI, 55-67%), respectively. The pooled overall survival rates at 3, 5, and 10 years were 84% (95% CI, 79-88%), 75% (95% CI, 72-79%), and 68% (95% CI, 62-74%), respectively. Severe late toxicity ≥ grade 3 occurred in 7% (95% CI, 3-14%). CONCLUSION: PORT showed favorable long-term efficacy and safety in SGC, especially for patients with high-grade histology. Considering that DFS continued to decrease, further clinical trials exploring treatment intensification are warranted.

Molecular characterization of the salivary adenoid cystic carcinoma immune landscape by anatomic subsites.

Adenoid cystic carcinoma (AdCC) is a slow-growing salivary gland malignancy that relapses frequently. AdCCs of the submandibular gland exhibit unique differences in prognosis and treatment response to adjuvant radiotherapy compared to other sites, yet the role of tumor anatomic subsite on gene expression and tumor immune microenvironment (TIME) composition remains unclear. We used 87 samples, including 48 samples (27 AdCC and 21 normal salivary gland tissue samples) from 4 publicly available AdCC RNA sequencing datasets, a validation set of 33 minor gland AdCCs, and 39 samples from an in-house cohort (30 AdCC and 9 normal salivary gland samples). RNA sequencing data were used for single sample gene set enrichment analysis and TIME deconvolution. Quantitative PCR and multiplex immunofluorescence were performed on the in-house cohort. Wilcoxon rank-sum, nonparametric equality-of-medians tests and linear regression models were used to evaluate tumor subsite differences. AdCCs of different anatomic subsites including parotid, submandibular, sublingual, and minor salivary glands differed with respect to expression of several key tumorigenic pathways. Among the three major salivary glands, the reactive oxygen species (ROS)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway signature was significantly underexpressed in AdCC of submandibular compared to parotid and sublingual glands while this association was not observed among normal glands. Additionally, the NRF2 pathway, whose expression was associated with favorable overall survival, was overexpressed in AdCCs of parotid gland compared to minor and submandibular glands. The TIME deconvolution identified differences in CD4+ T cell populations between AdCC of major and minor glands and natural killer (NK) cells among AdCC of minor, submandibular, and parotid glands while plasma cells were enriched in normal submandibular glands compared to other normal gland controls. Our data reveal key molecular differences in AdCC of different anatomic subsites. The ROS and NRF2 pathways are underexpressed in submandibular and minor AdCCs compared to parotid gland AdCCs, and NRF2 pathway expression is associated with favorable overall survival. The CD4+ T, NK, and plasma cell populations also vary by tumor subsites, suggesting that the observed submandibular AdCC tumor-intrinsic pathway differences may be responsible for influencing the TIME composition and survival differences.

Impact of childhood/adolescent cancer history on prognosis in parotid mucoepidermoid carcinoma.

Our goal was to assess the impact of childhood/adolescent cancer history on overall survival (OS) and disease-specific survival (DSS) in patients with parotid mucoepidermoid carcinoma (MEC). Patients who underwent surgical treatment for primary parotid MEC and those with a second malignancy of parotid MEC were retrospectively identified from the Surveillance, Epidemiology, and End Results (SEER) database. The primary outcome variables were OS and DSS. The hazard ratios (HRs) of these survival rates associated with cancer history were analysed using Cox regression models. In total, 2681 patients were included, 263 of whom had a second malignancy. The 10-year OS rates in the primary (72%) and second malignancy groups (59%) were significantly different. Cox regression confirmed that a history of cancer tended to decrease OS (p = 0.062, HR: 1.28, 95% confidence interval: 0.99 to 1.64). Subgroup analyses showed that a history of solid tumour as opposed to haematological cancer predicted worse OS, with central nervous system tumours exhibiting a more significant influence than others (p = 0.030 vs p = 0.088). Cancer history was not related to DSS. A history of childhood/adolescent cancer negatively influenced the prognosis of patients with parotid MEC, and this effect was primarily driven by a history of solid malignancy.

Timing of postoperative radiation therapy for major salivary gland cancers.

BACKGROUND: The impact of timing of PORT initiation for major salivary gland cancers on survival is unknown. We aim to examine the impact of PORT timeliness on overall survival (OS) of patients with major salivary gland cancers. METHODS: This was a cross-sectional analysis using data from the National Cancer Database (2004-2017) and included patients with major salivary gland cancer treated with surgery and PORT. RESULTS: In total, 5701 patients were included (3133 [55%] male, 4644 [82%] white, mean age 59 ± 16 years). For the overall cohort, PORT >6 weeks was not associated with decreased OS (1.00 aHR, 95% CI 0.89-1.11). When specifically examining patients with mucoepidermoid carcinoma, PORT >6 weeks was associated with a decreased OS (1.27 aHR, 95% CI 1.01-1.58). CONCLUSIONS: Overall, this analysis did not demonstrate a survival benefit for initiating PORT within 6 weeks for patients with salivary gland malignancies. Subset analysis did support initiating PORT within 6 weeks after resection for patients with mucoepidermoid carcinomas. This was not demonstrated in other major salivary gland cancer histologies.

Adenoid Cystic carcinoma of minor salivary glands (AdCCmSG): a multidisciplinary update.

INTRODUCTION: Adenoid cystic carcinoma of minor salivary glands (AdCCmSG) represents a 'rarity in the rarity,' posing a clinical challenge in lack of standardized, evidence-based recommendations. At present, AdCCmSG management is mostly translated from major salivary gland cancers (MSGCs). Ideally, AdCCmSG diagnostic-therapeutic workup should be discussed and carried out within a multidisciplinary, high-expertise setting, including pathologists, surgeons, radiation oncologists and medical oncologists. AREAS COVERED: The present review provides an overview of epidemiology and pathologic classification. Moreover, the most recent, clinically relevant updates in the treatment of AdCCmSG (Pubmed searches, specific guidelines) are critically discussed, aiming to a better understanding of this rare pathologic entity, potentially optimizing the care process, and offering a starting point for reflection on future therapeutic developments. EXPERT OPINION: The management of rare cancers is often hindered by limited data and clinical trials, lack of evidence-based guidelines, and hardly represented disease heterogeneity, which cannot be successfully tackled with a 'one-size-fits-all' approach. Our goal is to address these potential pitfalls, providing an easy-to-use, updated, multidisciplinary collection of expert opinions concerning AdCCmSG management as of today's clinical practice. We will also cover the most promising future perspectives, based on the potential therapeutic targets highlighted within AdCCmSG's molecular background.

Interleukin-10 induces TNF-driven apoptosis and ROS production in salivary gland cancer cells.

Treatment resistance after chemo-/immunotherapy occurs in patients with head and neck squamous cell cancers (HNSCs), including salivary gland cancers (SGCs). Interleukin-10 (IL-10), a cytokine with pro- and anti-cancer effects, has an unclear impact on HNSC/SGC cells. We show that HNSC patients exhibiting high expression of IL-10 and its receptor IL-10Rα experience have prolonged overall survival. Immunoreactive IL-10 was low in ductal cells of human SGC biopsies. Human (A253) and murine WR21-SGC cells expressed IL-10Rß, but only A253 cells expressed IL-10 and IL-10Rα. The addition of recombinant IL-10 impaired SGC cell proliferation and induced apoptosis in vitro. N-acetylcysteine restored IL-10-induced reactive oxygen species (ROS) production but did not prevent IL-10-mediated viability loss. Mechanistically, recIL-10 delayed cell cycle progression from G0/G1 to the S phase with cyclin D downregulation and upregulation of NF-kB. IL-10 increased tumor necrosis factor-α (TNF-α) in A253 and WR21 and FasL in WR21 cells. Neutralizing antibodies against TNF-α and NF-kB inhibition restored SGC proliferation after IL-10 treatment, emphasizing the critical role of TNF-α and NF-kB in IL-10-mediated anti-tumor effects. These findings underscore the potential of IL-10 to impede SGC cell growth through apoptosis induction, unraveling potential therapeutic targets for intervention in salivary gland carcinomas.