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Three pathological grading systems advocated by Perzin/Szanto, Spiro, and van Weert are currently used for adenoid cystic carcinoma (AdCC). In these systems, the amount or presence of the solid tumor component in AdCC specimens is an important index. However, the “solid tumor component” has not been well defined. Salivary AdCC cases (N = 195) were collected after a central pathology review. We introduced a novel criterion for solid tumor component, minAmax (minor axis maximum). The largest solid tumor nest in each AdCC case was histologically screened, the maximum oval fitting the solid nest was estimated, and the length of the minor axis of the oval (minAmax) was measured. The prognostic cutoff for the minAmax was determined using training and validation cohorts. All cases were evaluated for the four grading systems, and their prognostic impact and interobserver variability were examined. The cutoff value for the minAmax was set at 0.20 mm. Multivariate prognostic analyses showed the minAmax and van Weert systems to be independent prognostic tools for overall, disease‐free, and distant metastasis‐free survival while the Perzin/Szanto and Spiro systems were selected for overall survival but not for disease‐free or distant metastasis‐free survival. The highest hazard ratio for overall survival (11.9) was obtained with the minAmax system. The reproducibility of the minAmax system (kappa coefficient of 0.81) was scored as very good while those of the other three systems were scored as moderate. In conclusion, the minAmax is a simple, objective, and highly reproducible grading system useful for prognostic stratification for salivary AdCC. The amount or presence of the solid tumor component is an important index for histopathological grading of adenoid cystic carcinoma. However, the “solid tumor component” has not been well defined. We introduced a novel objective criterion for solid tumor component, minAmax (minor axis maximum), and showed that the minAmax is a simple, objective, and highly reproducible grading system useful for prognostic stratification for salivary adenoid cystic carcinoma.

Purpose There is no standard-of-care systemic therapy for metastatic adenoid cystic carcinoma (ACC), and its management remains challenging. This study aimed to evaluate treatment patterns and disease outcomes in patients with metastatic head and neck ACC. Methods We conducted a retrospective analysis of patients diagnosed with metastatic head and neck ACC between January 2005 and December 2023. Results A total of 51 patients were included in the study, of whom 36 (70.6%) received at least one line of systemic treatment. The median overall survival (OS) for the entire cohort was 29.21 months. Patients with lung metastases had significantly longer OS compared to those without (44.52 vs. 11.04 months, p  = 0.008). The median OS for patients who received at least one line of systemic treatment was 26.78 months. The median progression-free survival (PFS) was 7.82 months, 6.11 months, and 4.53 months for first-, second-, and third-line treatments, respectively. Disease progression was the primary reason for treatment discontinuation across all therapy lines. Conclusion There is no consensus on the optimal treatment approach for metastatic ACC, and therapeutic strategies remain heterogeneous. Patients with lung metastases had better survival outcomes than those with metastases at other sites.

SummaryBackground Deregulated Notch signaling is implicated in multiple cancers. The phase I trial (I6F-MC-JJCA) investigated the safety and anti-tumor activity of crenigacestat (LY3039478), a selective oral Notch inhibitor, in an expansion cohort of patients with adenoid cystic carcinoma (ACC) who received the dose-escalation-recommended phase 2 dose (RP2D), established previously (Massard C, et al., Annals Oncol 2018, 29:1911–17). Methods Patients with advanced or metastatic cancer, measurable disease, ECOG-PS ≤1, and baseline tumor tissue were enrolled. Primary objectives were to identify a safe RP2D, confirm this dose in expansion cohorts, and document anti-tumor activity. Secondary objectives included safety and progression-free survival (PFS). The ACC expansion cohort received the RP2D regimen of 50 mg crenigacestat thrice per week in a 28-day cycle until disease progression or other discontinuation criteria were met. Results Twenty-two patients with ACC were enrolled in the expansion cohort (median age of 60 years). Median treatment duration was 3 cycles with 6 patients remaining on treatment. There were no objective responses; 1 (5%) patient had an unconfirmed partial response. Disease control rate was 73% and 4 patients had stable disease ≥6 months. Median PFS was 5.3 months (95%CI: 2.4-NE)) for the 22 patients; and 7.7 months (95%CI: 4.0-NR) and 2.4 months (95%CI: 1.1-NE) in the subgroup of patients in second-line (n = 7) or ≥ third-line (n = 9), respectively. Frequent treatment-related-adverse events (all grades) included diarrhea, fatigue, vomiting, decreased appetite, dry mouth, and dry skin. There were no new safety signals. Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC.

AimsAdenoid cystic carcinoma (AdCC) originates from salivary-type like glands in the head and neck, lung, and breast. AdCC shows chromosomal translocation, resulting in MYB::NFIB fusion and overexpression of MYB. Recently, NOTCH1 pathway alteration has been recognised in a subset of patients with salivary gland AdCC and has been shown to be associated with poor survival. In this study, we investigated the correlation of NOTCH1 pathway alteration with the clinical outcome of patients with primary breast AdCC by examining NOTCH1 immunoreactivity in attempts to better predict clinical outcomes.MethodsWe identified 25 cases of breast AdCC, reviewed the clinical outcome and performed immunohistochemical (IHC) staining for NOTCH1 on FFPE sections.ResultsIHC evaluation of NOTCH1 expression in 25 cases of primary breast AdCCs revealed a positive correlation between NOTCH1 expression and primary tumour size. All cases with NOTCH1 expression were greater than 15 mm in size at presentation but only 50% of NOTCH1 negative tumours were greater than 15 mm. We demonstrated a positive correlation between NOTCH1 positive AdCCs and recurrence/metastases. 63.6% of NOTCH1 positive AdCCs had either metastases or recurrence. On the contrary, only 21.5% of NOTCH1 negative AdCCs had recurrence or metastases. AdCCs with NOTCH1 positivity correlated with inferior relapse free survival (median 33 vs 129 months).ConclusionsOur study demonstrates that in patients with breast AdCC, overexpression of NOTCH1 ≥20% is associated with larger tumour size and aggressive clinical outcomes. Importantly, NOTCH1 inhibitors may have potential therapeutic effect in patients with breast AdCC.

Triple-negative breast carcinomas constitute a wide spectrum of lesions, mostly being highly aggressive. Nevertheless, some special histologic subtypes can have low malignant potential. The purpose of the present paper is to review diagnostic criteria and prognostic parameters of breast neoplasms of special histotypes. Specifically, adenoid cystic carcinoma, adenomyoepithelioma, acinic cell carcinoma, mucoepidermoid carcinoma, tall cell carcinoma with reverse polarity, and secretory carcinoma will be discussed. For each tumour, definition and morphological and molecular features, together with prognostic parameters, will be presented. Paradigmatic cases will be illustrated.

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.

Background Adenoid cystic carcinoma (ACC) is a rare, malignant neoplasm of the salivary glands that, despite its slow growth, exhibits aggressive behavior, including perineural invasion, high recurrence rates, and distant metastasis. The lack of effective systemic therapies, combined with the resistance of cancer stem cells (CSCs) to standard treatments, highlights the urgent need for novel therapeutic strategies. Methods In this study, we employed a high-throughput screening approach to evaluate a library of 157 histone modification drugs (HMDs) using the UM-HACC-2 A cell line. Two complementary in vitro models were used: traditional two-dimensional culture representing the bulk non‑CSC tumor population and three‑dimensional tumorspheres that enrich for CSCs. Automated liquid handling, high‑content imaging (ImageXpress), and image analysis (MetaXpress) enabled precise quantification of cell viability and tumorsphere characteristics following treatment with HMDs. Results Screening identified 14 candidate compounds that induced statistically significant cell death in non‑CSCs and 11 compounds that were effective against tumorspheres. Key epigenetic targets included histone deacetylases, histone methyltransferases, EZH2, c‑RET, and EGFR. Notably, ITF2357 (Givinostat) induced 84% cell death in non-CSC populations ( p  < 0.0001), while the histone methyltransferase inhibitors, UNC0631 and LLY-507, elicited cell death rates of 82.5% ( p  < 0.0001) and 82.3% ( p  < 0.0001), respectively. In the CSC model, GSK343, an EZH2 inhibitor, induced 35.2% cell death ( p  < 0.0001). Furthermore, combination assays, pairing HMD hits from CSC and non‑CSC screenings, revealed synergistic effects that significantly enhanced tumor cell death compared to monotherapy. Conclusion These findings demonstrate that CSCs and non‑CSCs respond differently to epigenetic modulation, suggesting that personalized combination therapies targeting both subpopulations may be necessary to improve treatment outcomes for ACC. Although these targeted therapies are still in the early stages of investigation, our study provides a promising pre-clinical foundation for the development of effective, personalized therapeutic strategies for this challenging malignancy.

Objective Nasopharyngeal adenoid cystic carcinoma (NACC) is a rare malignancy with special biological features. Controversies exist regarding the treatment approach and prognostic factors in the IMRT era. This study aimed to evaluate the long-term outcomes and management approaches in NACC. Methods Fifty patients with NACC at our institution between 2010 and 2020 were reviewed. Sixteen patients received primary radiotherapy (RT), and 34 patients underwent primary surgery. Results Between January 2010 and October 2020, a total of 50 patients with pathologically proven NACC were included in our analysis. The median follow-up time was 58.5 months (range: 6.0–151.0 months). The 5-year overall survival rate (OS) and progression-free survival rate (PFS) were 83.9% and 67.5%, respectively. The 5-year OS rates of patients whose primary treatment was surgery and RT were 90.0% and 67.3%, respectively (log-rank P  = 0.028). The 5-year PFS rates of patients whose primary treatment was surgery or RT were 80.8% and 40.7%, respectively (log-rank P  = 0.024). Multivariate analyses showed that nerve invasion and the pattern of primary treatment were independent factors associated with PFS. Conclusions Due to the relative insensitivity to radiation , primary surgery seemed to provide a better chance of disease control and improved survival in NACC. Meanwhile, postoperative radiotherapy should be performed for advanced stage or residual tumours. Cranial nerve invasion and treatment pattern might be important factors affecting the prognosis of patients with NACC.

PurposeAdenoid cystic carcinoma (AdCC) is generally slow growing but has highly metastatic potential to distant organs. Several factors and biomarkers are associated with metastasis and treatment outcomes, although further definition is needed. Therefore, this study aimed to evaluate the risk factors for survival and distant metastasis in patients with head and neck AdCC.MethodsThis study included 125 patients with previously untreated AdCC who underwent primary surgery with or without radiotherapy in our tertiary referral centre. Univariate and multivariate Cox proportional hazard regression analyses were used to identify risk factors associated with overall survival (OS), cause-specific survival (CSS), disease-free survival (DFS), and distant metastasis-free survival (DMFS). Factors associated with OS in patients with distant metastasis were separately analysed.ResultsDuring a median follow-up of 9.8 years (range 3.0–22.6 years), 58 patients (46.4%) had distant metastasis and 29 (23.2%) died of disease. Multivariate analyses showed that lymphovascular invasion, lymph node metastasis, and distant metastasis were independent factors of OS and CSS outcomes (all P < 0.05). The T classification and extranodal extension were independent factors of DFS and DMFS outcomes (P < 0.05). After patients presented with distant metastasis, the median survival was 5.8 years. Multivariate analyses showed that extranodal extension and regional recurrence were independent factors of survival after occurrence of distant metastasis (P < 0.05).ConclusionSeveral clinicopathological factors can predict distant metastasis and survival of patients with AdCC treated with primary surgery. This may promote post-treatment surveillance in patients with AdCC.

Objectives To investigate the role of hypoxia in vasculogenic mimicry (VM) of salivary adenoid cystic carcinoma (SACC) and the underlying mechanism involved. Materials and methods Firstly, wound healing, transwell invasion, immunofluorescence and tube formation assays were performed to measure the effect of hypoxia on migration, invasion, EMT and VM of SACC cells, respectively. Then, immunofluorescence and RT‐PCR were used to detect the effect of hypoxia on VE‐cadherin and VEGFA expression. And pro‐vasculogenic mimicry effect of VEGFA was investigated by confocal laser scanning microscopy and Western blot. Moreover, the levels of E‐cadherin, N‐cadherin, Vimentin, CD44 and ALDH1 were determined by Western blot and immunofluorescence in SACC cells treated by exogenous VEGFA or bevacizumab. Finally, CD31/ PAS staining was performed to observe VM and immunohistochemistry was used to determine the levels of VEGFA and HIF‐1α in 95 SACC patients. The relationships between VM and clinicopathological variables, VEGFA or HIF‐1α level were analysed. Results Hypoxia promoted cell migration, invasion, EMT and VM formation, and enhanced VE‐cadherin and VEGFA expression in SACC cells. Further, exogenous VEGFA markedly increased the levels of N‐cadherin, Vimentin, CD44 and ALDH1, and inhibited the expression of E‐cadherin, while the VEGFA inhibitor reversed these changes. In addition, VM channels existed in 25 of 95 SACC samples, and there was a strong positive correlation between VM and clinic stage, distant metastases, VEGFA and HIF‐1α expression. Conclusions VEGFA played an important role in hypoxia‐induced VM through regulating EMT and stemness, which may eventually fuel the migration and invasion of SACC.