Adenoid Cystic Carcinoma Patients Research Articles

Extracellular vesicles containing circMYBL1 induce CD44 in adenoid cystic carcinoma cells and pulmonary endothelial cells to promote lung metastasis.

Adenoid cystic carcinoma (ACC) is a rare malignant epithelial neoplasm that arises in secretory glands and commonly metastasizes to the lungs. MYBL1 is frequently overexpressed in ACC and has been suggested to be a driver of the disease. Here, we identified a circRNA derived from MYBL1 pre-mRNA that accompanied overexpression of MYBL1 in ACC. Overexpression of circMYBL1 was correlated with increased lung metastasis and poor overall survival in ACC patients. Ectopic circMYBL1 overexpression promoted malignant phenotypes and lung metastasis of ACC cells. Mechanistically, circMYBL1 formed a circRNA-protein complex with CCAAT enhancer binding protein beta (CEBPB), which inhibited ubiquitin-mediated degradation and promoted nuclear translocation of CEBPB. In the nucleus, circMYBL1 increased the binding of CEBPB to the CD44 promoter region and enhanced its transcription. In addition, circMYBL1 was enriched in small extracellular vesicles (sEVs) isolated from the plasma of ACC patients. Treatment with sEVs containing circMYBL1 in sEVs enhanced pro-metastatic phenotypes of ACC cells, elevated the expression of CD44 in human pulmonary microvascular endothelial cells (HPMECs), and enhanced the adhesion between HPMECs and ACC cells. Moreover, circMYBL1 encapsulated in sEVs increased the arrest of circulating ACC cells in the lung and enhanced the lung metastatic burden. This data suggests that circMYBL1 is a tumor-promoting circRNA that could serve as a potential biomarker and therapeutic target in ACC.

Clinical Outcomes in Adenoid Cystic Carcinoma of the Nasal Cavity and Paranasal Sinus: A Comparative Analysis of Treatment Modalities.

This study aimed to present the treatment patterns and outcomes for adenoid cystic carcinoma (ACC) arising in the nasal cavity and paranasal sinus. Sixty-one sinonasal ACC patients were retrospectively reviewed: 31 (50.8%) underwent surgery followed by postoperative radiation therapy (S+PORT), and 30 (49.2%) received definitive radiation therapy (D(C)RT). T4 disease was significantly more frequent in the D(C)RT group (25.8% vs. 80.0%, p < 0.001), where all T4b disease patients underwent D(C)RT. The 5-year local failure-free survival (LFFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival were 61.8% versus 37.8% (p = 0.003), 64.8% versus 38.1% (p = 0.036), 52.6% versus 19.3% (p = 0.010), and 93.2% versus 73.4% (p = 0.001) in the S+PORT and D(C)RT groups, respectively. The absolute differences in 5-year rates of LFFS, DMFS, and PFS between the two groups were smaller in the T3-4 subgroup. The univariate analysis showed that T4b disease, neurologic symptoms, longest diameter of tumor, radiological evidence of nerve involvement, and undergoing D(C)RT were associated with worse clinical outcomes, but the significance disappeared in the multivariate analysis, except for in the case of radiological evidence of nerve involvement. In conclusion, most patients with extensive disease underwent upfront D(C)RT and generally exhibited inferior clinical outcomes when compared to those with less extensive disease and who underwent S+PORT.

Prognostic value of tumor volume doubling time in lung-metastatic adenoid cystic carcinoma

ObjectivesLung metastases in adenoid cystic carcinoma (ACC) usually have indolent growth and the optimal timing to start systemic therapy is not established. We assessed ACC lung metastasis tumor growth dynamics and compared the prognostic value of time to progression (TTP) and tumor volume doubling time (TVDT). MethodsThe study included ACC patients with ≥1 pulmonary metastasis (≥5 mm) and at least 2 chest computed tomography scans. Radiology assessment was performed from the first scan showing metastasis until treatment initiation or death. Up to 5 lung nodules per patient were segmented for TVDT calculation. To assess tumor growth rate (TGR), the correlation coefficient (r) and coefficient of determination (R2) were calculated for measured lung nodules. TTP was assessed per RECIST 1.1; TVDT was calculated using the Schwartz formula. Overall survival was analyzed using the Kaplan-Meier method. ResultsThe study included 75 patients. Sixty-seven patients (89%) had lung-only metastasis on first CT scan. The TGR was overall constant (median R2 = 0.974). Median TTP and TVDT were 11.2 months and 7.5 months. Shorter TVDT (<6 months) was associated with poor overall survival (HR = 0.48; p = 0.037), but TTP was not associated with survival (HR = 1.02; p = 0.96). Cox regression showed that TVDT but not TTP significantly correlated with OS. TVDT calculated using estimated tumor volume correlated with TVDT obtained by segmentation. ConclusionMost ACC lung metastases have a constant TGR. TVDT may be a better prognostic indicator than TTP in lung-metastatic ACC. TVDT can be estimated by single longitudinal measurement in clinical practice.

MYB alternative promoter activity is increased in adenoid cystic carcinoma metastases and is associated with a specific gene expression signature

ObjectiveAdenoid cystic carcinoma (ACC) is a head and neck cancer with a poor long-term prognosis that shows frequent local recurrences and distant metastases. The tumors are characterized by MYB oncogene activation and are notoriously unresponsive to systemic therapies. The biological underpinnings behind therapy resistance of disseminated ACC are largely unknown. Here, we have studied the molecular and clinical significance of MYB alternative promoter (TSS2) usage in ACC metastases. Materials and methodsMYB TSS2 activity was investigated in primary tumors and metastases from 26 ACC patients using RNA-sequencing and quantitative real-time PCR analysis. Differences in global gene expression between MYB TSS2 high and low cases were studied, and pathway analyses were performed. ResultsMYB TSS2 activity was significantly higher in ACC metastases than in primary tumors (median activity 15.1 vs 3.0, P = 0.0003). MYB TSS2 high ACC metastases showed a specific gene expression signature, including increased expression of multi-drug resistance genes and canonical MYB target genes, and suppression of the p53 and NOTCH pathways. ConclusionsCollectively, our findings indicate that elevated MYB TSS2 activity is associated with metastases, potential drug resistance, and augmented MYB-driven gene expression in ACC. Our study advocates the need for new therapies that specifically target MYB and drug resistance mechanisms in disseminated ACC.

A low systemic inflammatory response index is associated with improved survival in adenoid cystic carcinoma patients

BackgroundPredicting the long-term survival in adenoid cystic carcinoma(ACC) patients remains is challenging. Inflammatory cell-based indices are emerging as prognostic indicators of oncology. PurposeThis study aimed to determine the associations between the preoperative systemic inflammatory response index (SIRI) and, systemic immunoinflammatory index (SII), and the 10-year survival rates in patients with ACC of the head and neck (ACCHN). Study Design, Setting, SampleThis retrospective cohort study comprised ACCHNN patients treated at the Chinese People's Liberation Army General Hospital between November 2003 and December 2020. Predictor VariableThe inflammatory response, assessed using the SIRI and SII, was the predictor variable, The optimal cut-off values were based on the maximum Youden index values (sensitivity ＋ specificity－1), The patients were divided into two-group each, based on the SIRI (low, ≤ 0.15) and (high, > 0.15), and SII (low, ≤ 562.8 and high, > 562.8) values. Outcome VariableOverall survival (OS), or the number of days, weeks, or months between treatment initiation and death (or last follow-up date), was the primary outcome variable. CovariatesThe covariates were classified as demographic (age, gender, body mass index), medical (hypertension, diabetes), inflammatory (neutrophils, lymphocytes, monocytes, platelets, lymphocyte-monocyte ratio, platelet-lymphocyte ratio, neutrophil-lymphocyte ratio), and perioperative (tumor stage, lymph node metastasis, tumor size, treatment type). AnalysesDescriptive, univariate, and multivariate Cox proportional risk regression analyses were performed to determine whether the SIRI and SII were independent prognostic factors for OS. Kaplan–Meier survival curves and log-rank tests were used to determine their associations with the OS. ResultsThe study sample comprised 162 patients (mean age, 52 ± 14; males, 39.5%). The median follow-up time was 6.81 ± 0.23, and the 10-year OS rate was 7.68 ± 0.25. The low and high SIRI groups comprised 109 and 53 patients, while the low and high SII groups comprised 116 and 46 patients, respectively. SIRI was identified as a prognostic factor (P < 0.01; hazard ratio, 2.45; 95% confidence interval, 1.35–4.45). Conclusion and RelevanceThe SIRI has the advantages of reproducibility, convenience, non-invasiveness, and affordability, making it a promising prognostic inflammatory index for patients with ACCHN.

Lacrimal Gland Adenocarcinoma Clinicopathologic Features and Outcomes Compared With Those of Lacrimal Gland Adenoid Cystic Carcinoma.

Lacrimal gland (LG) adenocarcinomas (ACs) are rare, with limited data. We compared clinicopathologic features and local recurrence, distant metastasis, and survival rates between LG AC and LG adenoid cystic carcinoma (ACC). The records of LG AC patients treated from 2008 to 2022 and LG ACC patients treated from 1998 to 2022 at the same center were retrospectively reviewed. The study included 20 patients with AC; 10 de-novo AC, 10 ex-pleomorphic AC; and 51 ACC patients. The median age at diagnosis was 61 years for de-novo AC, 54 years for ex-pleomorphic AC, and 45 years for ACC. All groups had male predominance. The initial T category was T2 in 50% (5/10) of de-novo ACs; 60% (6/10) of ex-pleomorphic ACs; and 59% (30/51) of ACCs. Perineural invasion was present in 33% (5/15) of ACs and 90% (45/50) of ACCs (p < 0.001). Of the 20 AC patients, 14 had eye-sparing surgery; 4 had orbital exenteration; and 2 had unresectable disease. All AC patients received postoperative radiotherapy and 15 (75%) received concurrent chemotherapy. Fourteen AC patients were tested for human growth factor receptor 2 expression, and 10 (71%) were human growth factor receptor 2 positive; 5 received human growth factor receptor 2-targeted therapy. AC and ACC had similar 5-year recurrence rates (20% and 33%, respectively, p = 0.31) and metastasis rates (20% and 34%, respectively, p = 0.30). de-novo AC, ex-pleomorphic AC, and ACC had similar 5-year disease-specific survival rates (80%, 79%, and 81%, respectively, p > 0.99). LG AC and ACC have similar baseline clinicopathologic features, except that perineural invasion is more common in ACC, and similar recurrence, metastasis, and survival rates. Human growth factor receptor 2-targeted therapy may be appropriate in some patients with LG AC.

Treatment outcomes of single-fraction stereotactic radiosurgery for adenoid cystic carcinoma: a case series of 55 patients.

This study aimed to analyze the treatment outcomes of single-fraction stereotactic radiosurgery (SRS) for adenoid cystic carcinoma patients. Retrospective analysis was conducted for 55 patients with 66 lesions. SRS intentions were categorized as definitive, adjuvant, salvage, and palliative. Tumor control was defined as local (within 50% isodose line), marginal (outside 50% isodose line), and distant (metastasis outside head/neck). The median age was 60 years (range 21-85), with 53% males. Tumor origin was head/neck for 88% and trachea/lung for 12%. 61% were recurrent lesions. Median interval from diagnosis to SRS was 14 months. Preceding surgery was performed in 30%. SRS was administered as definitive (30 lesions), adjuvant (13), salvage (19), and palliative (4). SRS was used as a boost to external beam radiation therapy (EBRT) in 39%. Concurrent chemotherapy was administered in 26%. 5-, 10-, and 15-year local control rates were 60%, 33%, and 27%, respectively; local/marginal control rates were 29%, 13%, and 10%. For recurrent lesions treated with SRS without EBRT, 5-year local control rate was 14%, and local/marginal control rate was 5%. For recurrent lesions treated with SRS and EBRT, 5-year local control rate was 100%, and local/marginal control rate was 40%. The rate of distant failure after SRS was 40%. Older age and distant metastasis before SRS were negative factors for overall survival. SRS provided a high rate of local tumor control, but marginal failure was frequent. Integrating SRS with added EBRT exhibits potential for enhancing local and local/marginal tumor control, particularly in recurrent cases.

Prognostic factors for sublingual gland carcinoma: a population-based Surveillance, Epidemiology and End Results database study

Objective To identify the clinical features and prognostic factors for sublingual gland carcinoma. Methods This was a case–control study. Patients with surgically treated sublingual gland carcinoma were retrospectively included in the Surveillance, Epidemiology and End Results database and divided into adenoid cystic carcinoma (ACC) and non-ACC groups. Primary outcome variables were disease-specific survival (DSS) and overall survival (OS). Prognostic factors for each group were analyzed using Cox models. Results We included 251 patients (115 men and 136 women). Compared with the non-ACC group, the ACC group had a larger average tumor size and received more adjuvant radiotherapy. In patients with ACC, the pathologic grade had an independent impact on DSS and OS, and patients who were undergoing adjuvant chemotherapy had worse DSS than those who were not receiving chemotherapy. In the non-ACC group, pathologic grade IV, lymph node metastasis, and adjuvant chemotherapy were associated with poor DSS and OS, and tumor extension predicted worsening DSS. Conclusions In sublingual gland carcinoma, the pathologic grade and adjuvant chemotherapy were the most important prognostic factors, whereas lymph node metastasis had a negative impact in non-ACC patients but not in ACC patients.

Prognostic Significance of Primary Tumor Surgery in Adenoid Cystic Carcinoma Patients With Distant Metastases at Diagnosis: A Population-Based Database Analysis in Head and Neck Region.

Purpose: Adenoid cystic carcinoma (ACC) is an aggressive cancer that often leads to poor prognosis, especially when it has metastasized. The prognostic significance of primary tumor surgery (PTS) for ACC with distant metastasis (DM) at the time of diagnosis has not been extensively studied. Methods: Using data from the surveillance, epidemiology, and end results (SEER) database from 2010 to 2019, we identified patients with ACC in head and neck region and synchronous DM. We evaluated the effect of PTS on different patterns of metastasis using Kaplan-Meier analysis, log-rank tests, and multivariate Cox regression analysis to assess the therapeutic benefit of PTS in the overall cohort and various subgroups. Results: Of the 192 identified patients with synchronous metastatic ACC of head and neck, 91 (47.4%) underwent PTS. Patients who received PTS had significantly better survival than nonsurgical patients (median overall survival: 19 vs 43 months, P = .006). Cox regression analysis also showed that PTS was associated with improved survival (HR = .46, 95% CI: 0.42-0.88; P = .028). In sub-analyses, except for patients with liver metastases [overall survival (OS), P = .107, cancer-specific survival (CSS), P = .153], PTS consistently conferred significant survival benefits in patients with bone metastases (OS, P = .041, CSS, P = .065) and lung metastases (OS, P = .016, CSS, P = .027). PTS also led to better survival in patients who did not receive radiotherapy (median OS: 13 vs 52 months, P = .007). Conclusion: Our study suggests that PTS in metastatic ACC patients of head and neck improved overall and CSS, particularly in those with bone or lung metastases and those who did not receive radiotherapy. However, further prospective studies are needed to confirm these findings, and the indications for PTS in metastatic ACC should be carefully evaluated by a multidisciplinary board.

Cell-type-specific tumour sensitivity identified with a bromodomain targeting PROTAC in adenoid cystic carcinoma.

Salivary gland adenoid cystic carcinoma (ACC) is a rare malignancy with limited treatment options. The development of novel therapies is hindered by a lack of preclinical models. We have generated ACC patient-derived xenograft (PDX) lines that retain the physical and genetic properties of the original tumours, including the presence of the common MYB::NFIB or MYBL1::NFIB translocations. We have developed the conditions for the generation of both 2D and 3D tumour organoid patient-derived ACC models that retain MYB expression and can be used for drug studies. Using these models, we show in vitro and in vivo sensitivity of ACC cells to the bromodomain degrader, dBET6. Molecular studies show a decrease in BRD4 and MYB protein levels and target gene expression with treatment. The most prominent effect of dBET6 on tumours in vivo was a change in the relative composition of ACC cell types expressing either myoepithelial or ductal markers. We show that dBET6 inhibits the progenitor function of ACC cells, particularly in the myoepithelial marker-expressing population, revealing a cell-type-specific sensitivity. These studies uncover a novel mechanistic effect of bromodomain inhibitors on tumours and highlight the need to impact both cell-type populations for more effective treatments in ACC patients. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

A Comparative Population-Based Study of Tracheal and Lung Adenoid Cystic Carcinoma

Thoracic adenoid cystic carcinoma (ACC) is very rare, and its clinicopathological characteristics, treatment and prognosis have not been fully elucidated. Previous studies did not differentiate between tracheal and lung lesions. We identified tracheal ACC (TACC) and lung and bronchus ACC (LACC) patients from our cancer center (from 2005 to 2022) and the Surveillance, Epidemiology, and End Results (SEER) database (from 2000 to 2009). Incidence was calculated and trends were quantified. Significant prognostic factors for overall survival (OS) were reviewed and analyzed by using Cox proportional hazards regression. Then, two nomograms predicting OS of TACC and LACC were constructed based on the SEER database and validated externally by using the separate cohort. There was an upward trend from 2000 to 2019 for LACC while a downward trend from 2000 to 2009 was shown for TACC. Totally, 55 TACC and 25 LACC were included in our cohort, 121 TACC and 162 LACC included in the SEER cohort. There were larger tumor sizes, more lymph nodes and distant metastases for LACC patients than TACC patients. The proportion of patients receiving radiotherapy were higher for TACC than LACC. More patients with TACC received surgery and perioperative radiotherapy than those with LACC. Patients with LACC had significantly worse OS than patients with TACC (SEER cohort: 93.7 mons vs. 127.0 mons, p = 0.001, our cohort: 72.2 months vs. 130.8months, p = 0.061). Age, lymph node metastasis, distant metastasis and radiation and/or surgery were identified as independent prognostic factors for OS of TACC. Laterality, distant metastasis and surgery were identified for LACC. The discrimination of the nomogram revealed good prognostic accuracy and clinical applicability as indicated by C-index values of 0.753 and 0.833 for the training cohort and the external validation cohort for TACC, and 0.739 and 0.786 for LACC. TACC and LACC are different in incidence, clinical features, prognosis. Compared with LACC, radiotherapy combined with surgery is more important for TACC. Two nomograms were established for TACC and LACC respectively to help physicians make more individualized survival predictions and clinical decisions.

Abstract PO-071: Pseudonormal morphology of adenoid cystic carcinoma cells subverts the antitumor reactivity of immune cells

Abstract Objectives: Adenoid cystic carcinoma (ACC) is a rare salivary gland cancer most frequently arising in the head and neck region. The ACC microenvironment exhibits low immunogenicity (low tumor infiltrating lymphocytes and dendritic cells). This scenario favours immune evasion and partially explains poor prognosis because of the activation of immune inhibitory proteins. Gipie is a hook-related protein, that is involved in protein trafficking. Gipie (HkRP3, encoded by CCDC88B) is associated with T cell maturation and inflammatory functions and target cell killing in natural killer (NK) cells. Gipie is present in ACC patient samples and cells. Therefore, we investigated proliferation, apoptosis, and morphologic changes caused by Gipie in oral and salivary gland cancer cells in presence of immune cells. Methods: We assayed UM-HACC-2A (adenoid cystic carcinoma), A-253 (mucoepidermoid carcinoma, MEC), SCC4, SCC9, SCC25, CAL27 (oral squamous cell carcinoma, OSCC), OKF6 (normal oral) cells cocultured with, NK-92 (natural killer), and Jurkat, Clone E6-1 (acute T cell leukemia) cells, to construct multiple salivary gland and oral cancer-immune cell co-culture models. Gipie silenced cancer cells (silencing maintained for 48 hours) in the cancer immune coculture models were compared with their unaltered subsets. Cancer-immune cells interactions were maintained for 16 hours. Overall three hundred thirty-six (336) co-culture models were used to determine apoptosis, immune activation, morphology, transmigration, and protein expression. Additionally, we performed targeted mass spectrometry analysis to identify changes in protein profiles. Results: ACC cells exhibited Pseudonormal morphology after interacting with immune cells in the 3D coculture model. Gipie-silenced ACC cells in coculture model transformed to “lymphoblast-like” morphology. Gipie-silenced ACC cells in co-culture model (n = 24) showed significant increase of apoptotic cells compared to unaltered ACC cells, lowering of T regulatory cells (FoxP3+/IL-2Rα+/CD25+) (n = 24), and increase of activated NK cells (NKp30+/IFN-γ+) (n = 24) with significantly higher release of granzyme (n = 12) and perforin (n = 12). Increased activation of immune cells (transmigration and fluorescence intensity) via 3D-z-stack images were observed in Gipie-silenced subsets (n = 24). MEC cells responses were significantly less compared to ACC in co-culture models followed by silencing of Gipie, while OSCC and OKF6 cell responses were negligible, under identical conditions. Conclusions: The presence of Gipie confers pseudonormal morphology to ACC cells thereby reducing immune attack. Thus, trafficking proteins may impact ACC cancer-immune cell interaction during conventional chemotherapy or monoclonal immunotherapy. Citation Format: Rajdeep Chakraborty, Charbel Darido, Giuseppe Palmisano, Arthur Chien, Aidan Tay, Thiri Zaw, Shoba Ranganathan. Pseudonormal morphology of adenoid cystic carcinoma cells subverts the antitumor reactivity of immune cells [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-071.

Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers.

Adenoid cystic carcinoma (ACC) is a MYB-driven head and neck malignancy with high rates of local recurrence and distant metastasis and poor long-term survival. New effective targeted therapies and clinically useful biomarkers for patient stratification are needed to improve ACC patient survival. Here, we present an integrated copy number and transcriptomic analysis of ACC to identify novel driver genes and prognostic biomarkers. A total of 598 ACCs were studied. Clinical follow-up was available from 366 patients, the largest cohort analyzed to date. Copy number losses of 1p36 (70/492; 14%) and of the tumor suppressor gene PARK2 (6q26) (85/343; 25%) were prognostic biomarkers; patients with concurrent losses (n = 20) had significantly shorter overall survival (OS) than those with one or no deletions (p < 0.0001). Deletion of 1p36 independently predicted short OS in multivariate analysis (p = 0.02). Two pro-apoptotic genes, TP73 and KIF1B, were identified as putative 1p36 tumor suppressor genes whose reduced expression was associated with poor survival and increased resistance to apoptosis. PARK2 expression was markedly reduced in tumors with 6q deletions, and PARK2 knockdown increased spherogenesis and decreased apoptosis, indicating that PARK2 is a tumor suppressor in ACC. Moreover, analysis of the global gene expression pattern in 30 ACCs revealed a transcriptomic signature associated with short OS, multiple copy number alterations including 1p36 deletions, and reduced expression of TP73. Taken together, the results indicate that TP73 and PARK2 are novel putative tumor suppressor genes and potential prognostic biomarkers in ACC. Our studies provide new important insights into the pathogenesis of ACC. The results have important implications for biomarker-driven stratification of patients in clinical trials. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Identification of MicroRNA Expression Profiles Related to the Aggressiveness of Salivary Gland Adenoid Cystic Carcinomas.

Adenoid cystic carcinoma (ACC) has been reported as the second most common carcinoma of the salivary glands. Few studies have associated miRNA expression with ACC aggressiveness. In this study, we evaluated the miRNA profile of formalin-fixed, paraffin-embedded (FFPE) samples of salivary gland ACC patients using the NanoString platform. We studied the miRNA expression levels associated with the solid growth pattern, the more aggressive histologic feature of ACCs, compared with the tubular and cribriform growth patterns. Moreover, the perineural invasion status, a common clinicopathological feature of the disease that is frequently associated with the clinical progression of ACC, was investigated. The miRNAs showing significant differences between the study groups were selected for target prediction and functional enrichment, which included associations with the disease according to dedicated databases. We observed decreased expression of miR-181d, miR-23b, miR-455, miR-154-5p, and miR-409 in the solid growth pattern compared with tubular and cribriform growth patterns. In contrast, miR-29c, miR-140, miR-195, miR-24, miR-143, and miR-21 were overexpressed in patients with perineural invasion. Several target genes of the miRNAs identified have been associated with molecular processes involved in cell proliferation, apoptosis, and tumor progression. Together, these findings allowed the characterization of miRNAs potentially associated with aggressiveness in salivary gland adenoid cystic carcinoma. Our results highlight important new miRNA expression profiles involved in ACC carcinogenesis that could be associated with the aggressive behavior of this tumor type.

Clinical and genomic characterisation of adenoid cystic carcinoma of the head and neck, lung, and breast.

6094 Background: Adenoid cystic carcinoma (ACC) arises most commonly within the major salivary glands and other exocrine glands. ACC is typically a slow growing disease with high rates of recurrence many years after diagnosis. To inform post-operative surveillance and to provide comparator data for non-randomised studies, we sought to perform clinical and genomic characterisation of a cohort of 450 ACC patients, comparing outcomes between salivary ACC and other primary sites. Methods: 450 patients with ACC underwent clinical review at 4 UK NHS institutions. Electronic records were reviewed to extract clinical and demographic data. In 225 patients, DNA-based next-generation sequencing was performed to identify alterations in the most frequently altered genes in ACC (NOTCH1, ARID1A, KDM6A, SETD2, or TP53). Kaplan-Meier survival analyses calculated the time to first confirmed recurrence (TTFR) and overall survival from diagnosis (OS-diag) and from first confirmed recurrence (OS-rec). Results: Of 450 ACC patients, the primary site was most frequently the major salivary gland (44.7%; 201/450) comprising parotid (86), submandibular (96), sublingual (9) and salivary NOS (12). Other primary sites were sinonasal (99/450; 22.0%), upper aerodigestive (69/450; 15.3%), tracheobronchial (46/450; 10.2%), breast (16/450; 3.6%), skin (10/450; 2.2%), lacrimal (7/450; 1.6%), and other (2/450; 0.4%). Complete survival data were available in 440 patients. Recurrent/metastatic disease was confirmed in 69.8% (314/450). For these patients, the median TTFR was 4.5 yrs and for those with recurrence, the median OS from recurrence (OS-rec) was 4.8 yrs. The median TTFR in major salivary ACC was 5.8 yrs (95% CI 4.3 – 7.0). In comparison, the shortest median TTFR was seen in tracheobronchial (2.9 yrs, 95% CI 1.6 – 6.8; p = 0.019) and sinonasal ACC (3.8 yrs, 95% CI 2.9 – 5.0; p = 0.004). Breast ACC showed a differing survival pattern compared with major salivary ACC. Although the OS-diag in these two groups was not significantly different (9.75 yrs and 11.3 yrs respectively, p = ns), breast ACC showed a significantly increased TTFR (9.8 versus 4.4 yrs, p = 0.067), and a significantly reduced OS-rec (0.75 versus 4.8 yrs, p = &lt; 0.001). KDM6A mutation was seen more frequently in primary sites outside the major salivary glands (p = 0.005). However, there was no relationship between primary tumour site and mutations in NOTCH1, ARID1A, SETD2 or TP53. Conclusions: In this real-world multi-centre UK study, tracheobronchial and sinonasal ACC have significantly shorter TTFR than major salivary ACC. This study suggests that breast ACC has a similar OS from diagnosis to major salivary ACC, but has an increased TTFR and shorter OS following recurrence. This may have implications for follow-up protocols after primary treatment of breast ACC, and initiation of systemic therapy following recurrence.

Spatial Immunoprofiling of Adenoid Cystic Carcinoma Reveals B7-H4 Is a Therapeutic Target for Aggressive Tumors.

Adenoid cystic carcinoma (ACC) is a heterogeneous malignancy, and no effective systemic therapy exists for metastatic disease. We previously described two prognostic ACC molecular subtypes with distinct therapeutic vulnerabilities, ACC-I and ACC-II. In this study, we explored the ACC tumor microenvironment (TME) using RNA-sequencing and spatial biology to identify potential therapeutic targets. Tumor samples from 62 ACC patients with available RNA-sequencing data that had been collected as part of previous studies were stained with a panel of 28 validated metal-tagged antibodies. Imaging mass cytometry (IMC) was performed using the Fluidigm Helios CyTOF instrument and analyzed with Visiopharm software. The B7-H4 antibody-drug conjugate AZD8205 was tested in ACC patient-derived xenografts (PDX). RNA deconvolution revealed that most ACCs are immunologically "cold," with approximately 30% being "hot." ACC-I tumors with a poor prognosis harbored a higher density of immune cells; however, spatial analysis by IMC revealed that ACC-I immune cells were significantly restricted to the stroma, characterizing an immune-excluded TME. ACC-I tumors overexpressed the immune checkpoint B7-H4, and the degree of immune exclusion was directly correlated with B7-H4 expression levels, an independent predictor of poor survival. Two ACC-I/B7-H4-high PDXs obtained 90% complete responses to a single dose of AZD8205, but none were observed with isotype-conjugated payload or in an ACC-II/B7-H4 low PDX. Spatial analysis revealed that ACC subtypes have distinct TMEs, with enrichment of ACC-I immune cells that are restricted to the stroma. B7-H4 is highly expressed in poor-prognosis ACC-I subtype and is a potential therapeutic target.

Transcriptomic insights into adenoid cystic carcinoma via RNA sequencing.

Background: The aim of this study was to investigate the underlying mechanisms of adenoid cystic carcinoma (ACC) at the transcriptome level. Materials and methods: We obtained paired tumor and normal salivary gland tissues from 15 ACC patients, which were prepared for RNA sequencing. Results: Gene enrichment analysis revealed that the upregulated pathways were mainly involved in axonogenesis, and the downregulated pathways were mainly related to leukocyte migration, the adaptive immune response, lymphocyte-mediated immunity, and the humoral immune response. T-cells, B-cells and NK cells showed low infiltration in ACC tissues. In addition to the gene fusions MYB-NFIB and MYBL1-NFIB, a new gene fusion, TVP23C-CDRT4, was also detected in 3 ACC tissues. PRAME was significantly upregulated in ACC tissues, while antigen-presenting human leukocyte antigen (HLA) genes were downregulated. Conclusion: We found a new gene fusion, TVP23C-CDRT4, that was highly expressed in ACC. PRAME may be an attractive target for ACC immunotherapy.

Malignant sublingual gland tumors: A single-center retrospective analysis of 79 patients.

To analyze and summarize the clinicopathological features, risk factors for cervical nodal metastasis, and prognostic factors of malignant sublingual gland tumors (MSLGT). Patients diagnosed with MSLGT were retrospectively reviewed from January 2005 to December 2017 at Shanghai Ninth Hospital. The clinicopathological features were summarized, and the correlations between clinicopathological parameters, cervical nodal metastasis, and local-regional recurrence were evaluated using the Chi-square test. Kaplan-Meier method and Cox regression analysis were performed to assess the survival and independent prognostic factors. Seventy-nine patients were included, and the 5-year overall survival and disease-free survival rates was 85.7% and 71.7%, respectively. Gender and clinical tumor stage were risk factors for cervical nodal metastasis. Tumor size and pathological lymph node (LN) stage were independent prognostic factors for adenoid cystic carcinoma (ACC) of the sublingual gland; while age, pathological LN stage, and distant metastasis were prognostic factors for patients with non-ACC of the sublingual gland. Patients with higher clinical stage were more likely to undergo tumor recurrence. Malignant sublingual gland tumors are rare, and neck dissection should be performed in male MSLGT patients with higher clinical stage. Among patients with both ACC and non-ACC MSLGT patients, pN+ indicate a poor prognosis.

Expression of Lymphoma-2 Gene and NF-κB in Human Adenoid Cystic Carcinoma Tissue and Its Relation with Disease Prognosis

Background: Adenoid cystic carcinoma (ACC) is a common tumor of the head and neck. It is characterized by slow growth, strong invasiveness, easy recurrence and distant organ metastasis. Bcl-2 and NF-κB are indicated to relate to tumor growth, proliferation and apoptosis. This study aims to analyze the relationship between Bcl-2, NF-κB and ACC. Methods: With ELISA method to detect Bcl-2 and NF-κB expression in the blood of patients with ACC, patients with benign adenoma and healthy controls, and the expression of Bcl-2 and NF-κB in tissues was detected by immunohistochemistry, and their relationship with ACC was analyzed. relevance. Relationships between clinicopathological features. Results: The levels of Bcl-2 (4.16±1.34 ng/ml) and NF-κB (4.47 ± 1.37 ng/ml) as well as positive rates of Bcl-2 and NF-κB (87.5% and 85%) were significantly elevated in the ACC group (P &lt;0.05). Bcl-2 was positively correlated with NF-κB (P &lt;0.05). Of note, Bcl-2 and NF-κB expressions were correlated with the incidence frequency, histological type, clinical stage, lymph node metastasis and distant metastasis of ACC patients (P &lt; 0.05) as the distant metastasis is an independent risk factor. Conclusion: In summary, Bcl-2 and NF-κB expression in ACC patients is associated with the clinicopathological features of ACC.

Dominant Gene Expression Profiles Define Adenoid Cystic Carcinoma (ACC) from Different Tissues: Validation of a Gene Signature Classifier for Poor Survival in Salivary Gland ACC.

Adenoid cystic carcinoma (ACC) is an aggressive malignancy that most often arises in salivary or lacrimal glands but can also occur in other tissues. We used optimized RNA-sequencing to analyze the transcriptomes of 113 ACC tumor samples from salivary gland, lacrimal gland, breast or skin. ACC tumors from different organs displayed remarkedly similar transcription profiles, and most harbored translocations in the MYB or MYBL1 genes, which encode oncogenic transcription factors that may induce dramatic genetic and epigenetic changes leading to a dominant 'ACC phenotype'. Further analysis of the 56 salivary gland ACC tumors led to the identification of three distinct groups of patients, based on gene expression profiles, including one group with worse survival. We tested whether this new cohort could be used to validate a biomarker developed previously with a different set of 68 ACC tumor samples. Indeed, a 49-gene classifier developed with the earlier cohort correctly identified 98% of the poor survival patients from the new set, and a 14-gene classifier was almost as accurate. These validated biomarkers form a platform to identify and stratify high-risk ACC patients into clinical trials of targeted therapies for sustained clinical response.