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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., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

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., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

Background: Salivary gland cancers (SGC)-social determinants of health (SDoH) investigations are limited by narrow scopes of SGC-types and SDoH. This Social Vulnerability Index (SVI)-study hypothesized that socioeconomic status (SES) most contributed to SDoH-associated SGC-disparities., Methods: Retrospective cohort of 24 775 SGCs assessed SES, minority-language status (ML), household composition (HH), housing-transportation (HT), and composite-SDoH measured by the SVI via regressions with surveillance and survival length, late-staging presentation, and treatment (surgery, radio-, chemotherapy) receipt., Results: Increasing social vulnerability showed decreases in surveillance/survival; increased odds of advanced-presenting-stage (OR: 1.12, 95% CI: 1.07, 1.17), chemotherapy receipt (OR: 1.13, 95% CI: 1.03, 1.23); decreased odds of primary surgery (0.89, 0.84, 0.94), radiotherapy (0.91, 0.85, 0.97, p = 0.003) for SGCs. Trends were differentially correlated with SES, ML, HH, and HT-vulnerabilities., Conclusions: Through quantifying SDoH-derived SGC-disparities, the SVI can guide targeted initiatives against SDoH that elicit the most detrimental associations for specific sociodemographics., (© 2024 The Authors. Head & Neck published by Wiley Periodicals LLC.)

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., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

Background: Treatment of salivary gland tumors (SGTs) remains challenging. Little is known about the immune landscape of SGTs. We aimed to characterize the tumor microenvironment in benign and malignant SGTs., Methods: Eleven benign and nine malignant tumors were collected from patients undergoing curative intent surgery. Specimens were analyzed using mass cytometry by time-of-flight. Immune cell populations were manually gated, and T cells were clustered using the FlowSOM algorithm. Population frequencies were compared between high-grade and low-grade malignancies, corrected for multiple hypothesis testing., Results: There were trends towards increased CD4+ and CD8+ T cells among malignant tumors. High-grade malignancies exhibited trends towards higher frequencies of CD8+ PD-1+ CD39+ CD103+ exhausted T cells, CD4+ FoxP3+ TCF-1+ CD127- Tregs, and CD69+ CD25- CD4+ T cells compared to low-grade malignancies., Conclusion: SGTs exhibit significant immunologic diversity. High-grade malignancies tended to have greater infiltration of exhausted CD8+ T cells and Tregs, which may guide future studies for immunotherapy strategies., (© 2024 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Background: A minority of patients with recurrent/metastatic (R/M) salivary gland cancers (SGCs) benefit from immune checkpoint inhibitors (ICIs), necessitating reliable biomarkers for ICI response prediction., Methods: Retrospective observational study of R/M SGC patients treated with pembrolizumab between 2016 and 2022, with a primary outcome of 6-month progression-free survival (PFS) and secondary outcome of 2-year overall survival (OS). Univariate and multivariable Cox proportional hazards models were employed., Results: Twenty R/M SGC patients were included. After adjustment, NLR as a continuous variable was independently associated with 6-month PFS (HR 1.30, 95% CI 1.10-1.54, p = 0.002) and 2-year OS (HR 1.33, 95% CI 1.07-1.66, p = 0.010). Similarly, NLR ≥ 5 was associated with higher hazards of progression at 6 months (HR 12.85, 95% CI 2.17-76.16, p = 0.005) and death at 2 years (HR 11.25, 95% CI 1.67-75.77, p = 0.013)., Conclusions: Higher pretreatment NLR was independently associated with inferior 6-month PFS and 2-year OS in pembrolizumab-treated R/M SGC patients., (© 2023 Wiley Periodicals LLC.)

Background: We previously established a patient-derived xenograft (PDX) model, patient-derived organoids (PDOs), and PDX-derived organoids (PDXOs) for salivary duct carcinoma (SDC). Using these models, this study examined the therapeutic effect of human epidermal growth factor receptor 2 (HER2) blockade on HER2-positive SDC., Methods: The therapeutic effect of lapatinib was assessed in SDC PDXOs with regards to cell growth, receptor/downstream signaling molecule expression, phosphorylation levels, and apoptosis. Effect of lapatinib treatment was evaluated in vivo in SDC PDX mice., Results: The siRNA knockdown of HER2 and lapatinib suppressed cell proliferation in SDC PDXOs. Lapatinib inhibited the phosphorylation of HER2 and its downstream targets, and induced apoptosis in SDC PDXOs. Lapatinib also significantly reduced tumor volumes compared with that of the control in SDC PDX mice., Conclusion: For the first time, we demonstrated the efficacy of anti-HER2 therapy in HER2-positive SDC using preclinical models of SDC PDX and PDXO., (© 2023 Wiley Periodicals LLC.)

Salivary gland carcinomas (SGC) are a rare and variable group of head and neck cancers with historically poor response to cytotoxic chemotherapy and immunotherapy in the recurrent, advanced, and metastatic settings. In the last decade, a number of targetable molecular alterations have been identified in SGCs including HER2 upregulation, androgen receptor overexpression, Notch receptor activation, NTRK gene fusions, and RET alterations which have dramatically improved treatment outcomes in this disease. Here, we review the landscape of precision therapy in SGC including current options for systemic management, ongoing clinical trials, and promising future directions., (© 2023 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Associations between peripheral blood biomarkers and oncologic outcomes were explored in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HN) and salivary gland cancer (SGC) treated with pembrolizumab and vorinostat on a phase II trial (NCT02538510)., Experimental Design: Twenty-five HN and 25 SGCs were treated with pembrolizumab and vorinostat. Baseline peripheral blood was available in 21 HN and 20 SGCs and evaluated for associations with grade ≥3 adverse events (G ≥ 3AE) by CTCAEv4, objective response rate (ORR), overall survival (OS), and progression-free survival (PFS)., Results: Higher pretreatment neutrophil-to-lymphocyte ratio (NLR) and neutrophils, as well as lower pretreatment lymphocytes and T helper cells correlated with worse OS and PFS. Higher NLR further predicted increased rates of G ≥ 3AEs. No correlations with ORR were observed., Conclusions: In a prospectively evaluated cohort of HN and SGCs treated with pembrolizumab and vorinostat, we observed novel associations between peripheral blood biomarkers and oncologic outcomes and toxicities., (© 2022 Wiley Periodicals LLC.)

Background: This study investigated the effects of adjuvant radiotherapy on outcomes in early-stage major salivary gland cancers., Methods: A total of 655 patients were identified, including 355 (54.2%) received adjuvant radiotherapy and 300 (45.8%) had surgery alone. The effect of adjuvant radiotherapy on 5-year locoregional recurrence and disease-specific survival (DSS) was calculated using the Kaplan-Meier method, Wilcoxon rank sum test, and Cox proportional hazards model., Results: There were no significant differences in locoregional recurrence and DSS between patients receiving adjuvant radiotherapy and those not in both univariate and multivariable analysis. Although patients with positive margin status had a higher locoregional recurrence and those with moderate/poor differentiation had a worse DSS, stratified analysis still indicated there were no protective effects from the use of adjuvant radiotherapy., Conclusions: The use of adjuvant radiation therapy was not associated with improved locoregional recurrence and DSS, even for those with high-risk histopathological factors., (© 2022 Wiley Periodicals LLC.)

Background: The extent of cervical lymphadenectomy required for primary parotid cancer is not well-established., Methods: In this retrospective case-control study, 84 patients who underwent primary parotidectomy and neck dissection for primary parotid cancer between 2010 and 2019 were identified and analyzed., Results: Of the 84 patients, 37 underwent elective level V neck dissection. All six (16.0%) who had occult level V nodes had clinically evident, preoperative anterior cervical metastases, a statistically significant finding. No other clinical factors are correlated with posterior neck involvement. There was no significant difference in disease-free or overall survival for patients with occult level V disease relative to positive lymph nodes in other levels., Conclusions: Patients with clinically evident anterolateral cervical lymphatic metastases from parotid cancer preoperatively have high rates of occult level V nodes. Level V neck dissection can be avoided in cN0 patients and offered no survival advantage., (© 2022 Wiley Periodicals LLC.)

We defined the occult nodal metastasis (ONM) rate of clinical node-negative salivary gland malignancies and examined the role of elective neck dissection (END). Meta-analysis querying four databases, from inception of databases to March 25th, 2020. Fifty-one studies with 11 698 patients were included. ONM rates were 64% for salivary ductal carcinoma (SDC), 51% for undifferentiated carcinoma, 34% for carcinoma ex-pleomorphic adenoma (CXPA), 32% for adenocarcinoma not otherwise specified (ANOS), 31% for lymphoepithelial carcinoma (LE), 20% for mucoepidermoid carcinoma, 17% for acinic cell carcinoma, and 17% for adenoid cystic carcinoma. T3/T4 tumors had a 2.3 times increased risk of ONM than T1/T2 tumors. High-grade tumors had a 3.8 times increased risk of ONM than low/intermediate-grade tumors. ONM rates were exceedingly high for T3/T4, high-grade, and undifferentiated, SDC, ANOS, CXPA, and LE tumors, indicating the potential role of END., (© 2021 Wiley Periodicals LLC.)

Background: Salivary duct carcinoma (SDC) is a rare and aggressive malignancy. Recently, biomarker studies found promising targetable alterations. In this study, we provide a descriptive analysis of tumor and immune biomarkers and survival associations., Methods: We extracted clinical data and performed immunohistochemistry for AR, AR-V7, HER-2, PD-L1, LAG-3, and tumor-infiltrating immune cells., Results: We included 17 patients. Age ranged from 42 to 85 years old; HER-2 was overexpressed or amplified in 65%. AR was positive in 88% of patients, while AR-V7 was positive in 13% by IHC. We found low scores of immune infiltration and a PD-L1 expression in 53%. We found no clinically significant association between biomarkers and survival outcomes., Conclusion: In this small series of SDC, biomarkers do not seem to correlate with disease biology, although they provide additional treatment options. SDC may harbor a different immune profile compared to other subtypes, with an indication of T-cell dysfunction., (© 2021 Wiley Periodicals LLC.)

Background: In patients presenting with recurrent pleomorphic adenoma (rPA), clinical evaluation can fail to recognize carcinoma ex PA (cxPA). We aim to identify the risk factors for cxPA., Methods: This is a single institution retrospective case-control study from 2000 to 2015. CxPA was diagnosed based on surgical pathology. Demographics, clinical, and social histories were collected., Results: A number of 13/106 (12.3%) patients were diagnosed with cxPA, of which only 4/13 (31%) had clinical features suspicious for malignancy. Compared to benign rPA, factors associated with cxPA included age >50 (odds ratio [OR] 6.67, 95% confidence interval [CI]: 1.71-25.98, P < .01), >10 pack-years of smoking history (OR 3.36, 95% CI: 1.01-11.14, P = .04), and the largest tumor being >2 cm on pathology (OR 4.42, 95% CI: 1.14-17.10, P = .03)., Conclusions: In patients presenting with rPA, risk factors for malignant transformation include age >50, significant smoking history, and tumors larger than 2 cm. Clinical signs of malignancy such as rapid growth or pain are not always present., (© 2020 Wiley Periodicals LLC.)

Background: This study compared our proposed N classification including the addition of the number of positive lymph node (LN+) and extranodal extension (ENE) with the current and previous American Joint Committee on Cancer (AJCC) N classifications in salivary gland cancer (SGC)., Methods: This study involved 172 SGC patients who underwent surgery. Cox proportional hazard regression analyses were used to identify factors associated with overall survival (OS) and disease-free survival (DFS)., Results: In multivariate analyses, LN+ number, LN ratio, and ENE were associated with OS and DFS outcomes (all P < .05). Our new N classification proposed three categories: N0 (0 LN+), N1 (1 LN+), and N2 (≥2 LN+ or ENE). The C-index of our N classification showed improvement in OS prediction (0.768) compared with the AJCC seventh (0.743) and eighth (0.756) edition N classifications., Conclusions: Our proposed N classification incorporating LN+ number and ENE may improve prediction of post-treatment survival and recurrence in patients with SGC., (© 2020 Wiley Periodicals, Inc.)

Coronavirus disease 2019 (COVID-19) pandemic forced significant changes in current approach to outpatient evaluation of common otolaryngology complaints as hospitals around the world are trying to limit the spread of the virus and to preserve health care resources. These changes raise a lot of questions regarding patient triage and treatment decisions in clinical situations when it is unclear if the workup and management can be postponed. In this communication, we present our approach to evaluation and triage of new patients with complaints concerning for salivary gland disease., (© 2020 Wiley Periodicals, Inc.)

Background: Patients with prognosis recurrent/metastatic (R/M) salivary gland carcinomas (SGCs) are poor. Activity of axitinib was demonstrated in adenoid cystic carcinoma (ACC). We tested axitinib in a larger cohort of R/M SGCs including non-ACC., Methods: Axitinib was administered at 10 mg daily (dose escalation allowed) until progression or unacceptable toxicity. Null hypothesis would be rejected if more than 3 of 26 responses were observed., Results: Twenty-six patients (50% were male; 6 ACC, 20 non-ACC) were treated. Response rate was 8% (2 partial responses), 13 stable disease (>6 months in 7 patients) and 11 disease progression. Median progression-free survival and overall survival were 5.5 and 26.2 months, respectively. All patients had at least one adverse event: stomatitis (69%), fatigue (58%) and hypertension (54%) were the most frequent., Conclusions: This trial did not meet its primary endpoint hence axitinib should not be considered for further investigations in SGCs. Safety profile was in line with the scientific literature., (© 2019 Wiley Periodicals, Inc.)

Background: The role of molecular markers in salivary gland carcinoma (SGC) is not well understood. We evaluated molecular marker expression and their prognostic value., Methods: Immunohistochemical analysis of 124 tumor specimens was performed to determine expression of androgen (AR), estrogen (ER), and progesterone (PR) receptors and epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), programmed death ligand 1 receptor (PD-L1), and PD-L1 in tumor-infiltrating mononuclear cell (TIMC). Survival outcomes (disease-free survival [DFS] and overall survival [OS]), pT and N classification, margin status, and treatment failure were assessed., Results: Most patients (78; 62.9%) had early-stage SGC. AR positivity and EGFR positivity were detected in 21.0% and 78.6%, respectively, of tumors. AR positivity and PD-L1 negativity were associated with locally advanced disease. PD-L1-negativity was associated with higher recurrence (38.5% vs 0%; P < .001) and worse DFS. OS and DFS were worse in patients with AR+ or HER2+ disease., Conclusions: Several molecular markers-AR and HER2 positivity and PD-L1 negativity-were associated with worse clinical outcomes. Prospective, multi-institutional trials are needed to determine the prognostic value of these markers., (© 2019 Wiley Periodicals, Inc.)

Salivary gland cancers represent a rare group of tumors composed by over 20 histological subtypes. Initially treated as one single disease, its diagnosis, prognosis, and treatment are currently being stratified based on morphology. More recently, insight has been provided on the molecular characterization of each subtype, further improving diagnostic accuracy and paving the way for personalized therapy. In this article, we provide a comprehensive review of recent breakthroughs, preliminary results of novel therapy, and future directions on the treatment of these complex malignancies., (© 2018 Wiley Periodicals, Inc.)

Background: Evidence surrounding the effect of adjuvant treatment in salivary gland cancers is limited. The benefit of adding chemotherapy to adjuvant treatment is also of interest. We investigated the association of these treatments with survival and whether this differed by stage or the presence of adverse features., Methods: A retrospective study of adult salivary gland cancer cases diagnosed from 2004 to 2013 in the National Cancer Data Base (NCDB) was conducted., Results: Treatment with adjuvant radiotherapy was associated with improved survival for both patients with early-stage (hazard ratio [HR] 0.744; P = .004) and late-stage (HR 0.688; P < .001) disease with adverse features. Further addition of chemotherapy to the adjuvant treatment of patients with late-stage disease with adverse features was not associated with a survival benefit (HR 1.028; P = .705)., Conclusion: Adjuvant radiotherapy is associated with improved survival for patients with adverse features, regardless of stage. The addition of chemotherapy to the adjuvant treatment of patients with late-stage disease with adverse features is not associated with improved outcomes., (© 2018 Wiley Periodicals, Inc.)

Background: This study examined the microtubule inhibitor eribulin in recurrent/metastatic salivary gland cancers (RMSGCs), a disease where no therapeutic standard exists., Methods: This phase II clinical trial treated patients with progressive recurrent/metastatic salivary gland cancers with eribulin 1.4 mg/m 2 i.v. on days 1 and 8 of a 21-day cycle until disease progression/unacceptable toxicities. The primary endpoint was the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 objective response rate., Results: Between May 2012 and August 2015, 29 patients were enrolled in this study. The median age was 63 years (range 34-75 years) and 20 of the subjects were men (69%). The most common histologies were adenoid cystic carcinoma (ACC; n = 11) and adenocarcinoma (n = 4). Neutropenia was the most common toxicity (grade 3; n = 5; 17% and grade 4 n = 3; 10%). The objective responses were observed in 3 of 29 patients (10%), 20 of 29 patients (69%) demonstrated a decrement in tumor size, and disease control was observed in 26 of 29 patients (90%)., Conclusion: Although the objective responses to eribulin were uncommon, disease control was observed in the majority of patients., (© 2017 Wiley Periodicals, Inc.)

Background: The purpose of this study was to investigate the efficacy and safety of vinorelbine plus cisplatin chemotherapy in patients with recurrent and/or metastatic salivary gland cancer of the head and neck., Methods: In this single-arm phase II study, patients with recurrent and/or metastatic salivary gland cancer were treated with i.v. vinorelbine (25 mg/m 2 ) on days 1 and 8 plus cisplatin (80 mg/m 2 ) on day 1 every 3 weeks for 4 or 6 cycles. The primary endpoint was the objective response rate. Progression-free survival (PFS), overall survival (OS), and adverse events were also assessed., Results: Between September 2008 and November 2014, 40 patients with recurrent and/or metastatic salivary gland cancer received vinorelbine plus cisplatin chemotherapy. The objective response rate was 35.0%, including 1 complete response. Median PFS and OS rates were 6.3 months and 16.9 months, respectively. No treatment-related deaths occurred., Conclusion: Administering vinorelbine plus cisplatin chemotherapy to patients with recurrent and/or metastatic salivary gland cancers is safe and effective., (© 2017 Wiley Periodicals, Inc.)

Background: Previous genomic studies revealed phosphotidylinositol-3-kinase (PI3K)/Akt pathway mutation in human salivary gland adenoid cystic carcinoma (ACC). No validation of its prognostic value has been reported., Methods: P-Akt, pan-Akt, phosphorylated-mammalian target of rapamycin (p-mTOR), PI3K, and insulin-like growth factor-1 receptor beta (IGF-1Rβ) were detected on 120 salivary gland ACC/adjacent salivary gland pairs immunohistochemically and were correlated with clinicopathological data., Results: Expression of cytoplasmic and nuclear p-Akt, cytoplasmic p-mTOR, nuclear pan-Akt, and nuclear IGF-1Rβ were higher in ACC than in adjacent salivary glands. P-Akt, p-mTOR, PI3K, and IGF-1Rβ expression were correlated with one another in both cytoplasm and nucleus. Low p-mTOR expression in both subcellular compartments was associated with locoregional recurrence, poor disease-free survival (DFS), and overall survival (OS). Low nuclear p-Akt (Ser473) and p-mTOR expression were independent predictors for poor OS and DFS, respectively., Conclusion: High level of Akt/mTOR activation in ACC is correlated with a significantly improved survival. P-mTOR and nuclear p-Akt are prognostic biomarkers of salivary gland ACC. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1145-1154, 2017., (© 2017 Wiley Periodicals, Inc.)

Background: Salivary ductal carcinoma and carcinoma ex pleomorphic adenoma (CEPA) are aggressive salivary gland cancers with poor prognosis. The standard of care is resection with or without radiotherapy, and there are no established systemic therapy options., Methods: We describe 1 patient with metastatic CEPA and 1 patient with metastatic recurrent salivary duct carcinoma whose tumors were evaluated by comprehensive genomic profiling. Testing identified human epidermal growth factor receptor 2 (HER2) amplification in both patients, and an additional activating HER2 mutation in the CEPA case., Results: Both patients were treated with the HER2-targeting monoclonal antibody trastuzumab (herceptin) plus chemotherapy and experienced rapid responses. Subsequently, both patients were given single-agent maintenance trastuzumab and continue to experience durable disease control., Conclusion: Given the poor prognosis for salivary gland cancers and the limited treatment options upon recurrence or metastasis, patients should be tested for all classes of HER2 alterations. In cases with HER2 overexpression or activation, targeted therapies, such as trastuzumab are promising. © 2016 Wiley Periodicals, Inc. Head Neck 39: E40-E44, 2017., (© 2016 Wiley Periodicals, Inc.)

Background: The purpose of this study was to evaluate salivary gland cancer incidence among patients with a previous cancer diagnosis and explore the potential relationship of salivary gland cancer among women with a previous diagnosis of breast cancer., Methods: We obtained information from the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed between 1973 and 2011. Incidence, annual percent change (APC), and survival were examined., Results: Women were more likely than men to experience subsequent salivary gland cancer, female observed to expected (O/E) = 1.63 (95% confidence interval [CI], 1.49-1.78) versus male O/E = 1.34 (95% CI, 1.25-1.44). Index breast cancer does not confer greater risk of salivary gland cancer. Women demonstrate improved overall survival (OS) and cause-specific survival (CSS) compared with men for subsequent salivary gland cancer., Conclusion: Among patients with a previous cancer diagnosis, the risk of subsequent salivary gland cancer is greater among women than men. More research is needed to determine the relationship between index breast cancer and subsequent salivary gland cancer risk. © 2015 Wiley Periodicals, Inc. Head Neck 38: E446-E451, 2016., (© 2015 Wiley Periodicals, Inc.)

Background: The purpose of this study was to evaluate risk factors that influence overall survival (OS)/disease-free survival (DFS)/locoregional recurrence-free survival (LRFS), and distant metastases-free survival (DMFS) in patients with high-risk primary salivary gland carcinoma who underwent surgery and postoperative (chemo)radiotherapy with curative intention., Methods: We reviewed data of 63 patients with high-risk primary salivary gland carcinoma in a retrospective single-center audit., Results: At a median follow-up of 31 months (range, 5-145 months), cumulative OS and DFS were 91.7%, 77.6%, and 62.9%, and 82.1%, 65.6%, and 57.7%, respectively, after 1, 2, and 5 years. LRFS and DMFS were 92%, 86%, and 86%, and 83.4%, 70.4%, and 62.3% after 1, 2, and 5 years, respectively. Of all patient-related, tumor-related, and treatment-related factors, high-grade histology (G3) was the only factor in univariate and multivariate analysis that was predictive for a shorter DMFS (low/intermediate vs high-grade: 100%, 100%, and 89.4% vs 72.9%, 54.3%, and 42.8% after 1, 2, and 5 years, respectively) and a shorter DFS (low/intermediate vs high-grade: 100%, 90%, and 84.4% vs 71.2%, 50.1%, and 39.4% after 1, 2, and 5 years, respectively) and OS (low/intermediate vs high-grade: 100%, 100%, and 86.5% vs 86.5%, 63.2%, and 46.5% after 1, 2, and 5 years, respectively)., Conclusion: High-grade tumor histology is a highly significant predictor of a shorter DMFS, OS, and DFS in salivary gland carcinoma, irrespective of histological subtype. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2041-E2048, 2016., (© 2016 Wiley Periodicals, Inc.)

Background: Various chemotherapeutic agents have been used largely for the treatment of salivary gland cancer. However, results are disappointing, and these agents can cause some serious side effects. Therefore, recent studies have focused on the possible roles of natural products to overcome these limitations., Methods: Salivary gland cancer cells treated with or without Convallaria keiskei (MECK) for 24 hours. Apoptotic changes were evaluated by live/dead assay, immunoblotting, and expression levels of caspase-3 and B-cell lymphoma-2 family member., Results: MECK significantly inhibited salivary gland cancer growth. At the molecular level, MECK dramatically reduced myeloid cell leukemia-1 (Mcl-1) in a translation-dependent manner and thereby induced apoptosis through Bax/Bid. Furthermore, we found that Mcl-1 could be a potential therapeutic target of MECK-induced apoptosis and its stability is regulated by extracellular signal-regulated kinases 1/2 (ERK1/2) signaling, Conclusion: MECK can be used as a safe and efficient therapeutic alternative for the treatment of salivary gland cancer. © 2015 Wiley Periodicals, Inc. Head Neck 38: E761-E770, 2016., (© 2015 Wiley Periodicals, Inc.)

Background: Hyalinizing clear cell carcinoma (HCCC) is a rare neoplasm of salivary gland origin which is low-grade in nature. In this series, we report on 9 cases of HCCC and update the literature., Methods: A comprehensive literature search was performed. Our institutional database was queried for cases of HCCC. Pathology reports and slides were reviewed. Data was extracted, including demographics, staging, primary treatment, histopathologic findings, recurrence, and disease status. Statistical analysis was performed using a Pearson's chi-square test., Results: One hundred thirty-six total cases were included for analysis. The overall recurrence rate was 19.8%. Necrosis was associated with risk of recurrence (p = .003). Positive margins and lymph node status were associated with risk of recurrence. Prognosis was good with only 3 of 82 patients reported dying with disease., Conclusion: HCCC has an overall good prognosis with potential for aggressive behavior. The presence of necrosis, locoregional disease, or positive margins is associated with risk for recurrence., (© 2015 Wiley Periodicals, Inc.)

Background: Adenoid cystic carcinomas (ACCs) are malignant salivary gland tumors noteworthy for high rates of late failure with limited salvage therapy options. We have previously shown increased Akt signaling is common in ACC and the human immunodeficiency virus (HIV) protease inhibitor nelfinavir (NFV) inhibits in vitro tumor growth by suppressing Akt signaling. This phase II trial was conducted to determine progression-free survival in response to NFV in patients with recurrent/endstage ACC who have failed standard therapies., Methods: Eligible patients had recurrent or end-stage ACC and measureable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria. NFV was provided at 1250 mg twice daily., Results: Among 15 trial participants, median progression-free survival was 5.5 months (lower 95% bound 4.4 months). No patient achieved a RECIST partial or complete response to therapy., Conclusion: NFV monotherapy does not result in a meaningful improvement in clinical outcomes among patients with recurrent ACC., (© 2014 Wiley Periodicals, Inc.)

Background: The purpose of this study was to determine the antitumor activity of the epidermal growth factor receptor (EGFR) inhibitor gefitinib in patients with recurrent/metastatic salivary gland cancer., Methods: We conducted a phase II study in adenoid cystic carcinoma (ACC) and non-ACC. Gefitinib was administered 250 mg orally daily. The primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and disease control rates. EGFR and human epidermal growth factor receptor 2 (HER2) expression were evaluated and correlated with outcomes., Results: Thirty-seven patients were enrolled in this study, and 36 were evaluable (18 with ACC and 18 with non-ACC). No responses were observed. Median PFS was 4.3 months and 2.1 months, and median OS was 25.9 months and 16 months for patients with ACC and non-ACC, respectively. The disease control rate at 8 weeks was higher in patients with ACC. No unexpected toxicities occurred. EGFR and HER2 overexpression did not correlate with outcomes., Conclusion: We did not observe significant clinical activity of gefitinib in advanced salivary gland cancer. NCT00509002., (© 2015 Wiley Periodicals, Inc.)

Background: Malignant tumors of the salivary glands comprise about 3% to 5% of all head and neck carcinomas. The purpose of our study was to find possible predictive and/or prognostic markers for parotid cancer., Methods: A total of 46 tissue samples of carcinomas of the parotid gland were immunohistochemically stained for ß-catenin, cyclin D1, and PIN1. The factors were analyzed regarding their prognostic value for disease-free and overall survival., Results: An overexpression of the cytoplasmatic ß-catenin was linked to a statistically significant worse outcome regarding disease-free (p = .0296) and overall survival (p = .0416). The 5-year overall survival was 83.9% in patients without and 0% in patients presenting with overexpression of cytoplasmatic ß-catenin. Additionally, Union Internationale Contre le Cancer (UICC) stage correlated with overall survival (p = .0306) and disease-free survival (DFS; p = .0473)., Conclusion: Multivariate analysis showed that overexpression of cytoplasmatic ß-catenin and the UICC stage are 2 independent prognostic markers for survival in patients with parotid cancer., (© 2014 Wiley Periodicals, Inc.)

Background: This study compares clinicopathological parameters with novel molecular markers for predicting cervical lymph node metastasis in salivary gland cancer., Methods: Three hundred sixteen salivary gland carcinomas were included in this study. Genomic epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), phosphatase and tensin homolog (PTEN), and hepatocyte growth factor receptor (MET) was determined by fluorescence in situ hybridization (FISH). Chi-square tests, multivariate regression, and Kaplan-Meier survival analysis were used for statistics., Results: Nodal staging determines long-term survival. Clinicopathological parameters associated with positive neck nodes are advanced age (p = .006), T3/T4 classification, histological high-grade malignancy, and diagnosis of salivary duct carcinoma (p < .001 each). Neck node metastases also correlate with copy number gain of EGFR (p = .004) and HER2, aberration of MET, and deletion of PTEN (p < .001 each). Multivariate analysis showed SDC (p = .002) to be the strongest predictor of lymph node metastasis, followed by MET aberration (p = .009), T3/T4 classification (p = .017), PTEN deletion (p = .042), and adenocarcinoma not otherwise specified (NOS; p = .047)., Conclusion: The histological subtype is crucial for decisions regarding neck dissection. New molecular parameters may also indicate elective treatment of the neck., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: The purpose of this study was to reveal prognostic factors for surgical complications and survival in young and elderly patients with malignant salivary gland tumors., Methods: Retrospective analysis of surgically treated patients with malignant major salivary gland tumors was performed. Of the 111 patients, 33 patients were 70 years or older and 78 patients were under 70. Comorbidity was recorded using the Adult Comorbidity Evaluation-27 index and complications using the Clavien-Dindo classification., Results: Comorbidity and complications were significantly more frequent in elderly patients (p < .05). Age, comorbidity, and length of surgery were not significant independent predictors of complications. Stage was the only independent predictive factor for postoperative complications and disease-specific survival., Conclusion: Based on this retrospective analysis reviewing surgically treated patients, age alone should not be a reason to treat elderly patients differently, as it was not a predictor of either complications or disease-specific survival., (Copyright © 2013 Wiley Periodicals, Inc., A Wiley Company.)