•Salivary duct carcinoma (SDC) is a rare and aggressive salivary malignancy.•Several recent studies have identified common mutations in SDC.•Anti-ErbB2 therapy, androgen deprivation, and ...immunotherapy deserve further study.
Salivary duct carcinoma (SDC) is a rare, aggressive salivary malignancy that is often diagnosed at an advanced stage. Previously, little was known about outcomes of this disease due to its rarity. In the past several years, much has been learned about salivary duct carcinoma after publication of outcomes from several large single-institution series and national database searches. Recent studies of genomic alterations have helped elucidate the biology and pathogenesis of this aggressive disease. Here we review outcomes of the disease, effects of treatment, prognostic factors, and genomic alterations in SDC. Studies of targeted therapy and promising future directions are also discussed.
Natural killer (NK)-cell-based immunotherapy may overcome obstacles to effective T-cell-based immunotherapy such as the presence of genomic alterations in IFN response genes and antigen presentation ...machinery. All immunotherapy approaches may be abrogated by the presence of an immunosuppressive tumor microenvironment present in many solid tumor types, including head and neck squamous cell carcinoma (HNSCC). Here, we studied the role of myeloid-derived suppressor cells (MDSC) in suppressing NK-cell function in HNSCC.
The ability of peripheral and tumor-infiltrating MDSC from mice bearing murine oral cancer 2 (MOC2) non-T-cell-inflamed tumors and from patients with HNSCC to suppress NK-cell function was studied with real-time impedance and ELISpot assays. The therapeutic efficacy of SX-682, a small-molecule inhibitor of CXCR1 and CXCR2, was assessed in combination with adoptively transferred NK cells.
Mice bearing MOC2 tumors pathologically accumulate peripheral CXCR2
neutrophilic-MDSC (PMN-MDSC) that traffic into tumors and suppress NK-cell function through TGFβ and production of H
O
. Inhibition of MDSC trafficking with orally bioavailable SX-682 significantly abrogated tumor MDSC accumulation and enhanced the tumor infiltration, activation, and therapeutic efficacy of adoptively transferred murine NK cells. Patients with HNSCC harbor significant levels of circulating and tumor-infiltrating CXCR1/2
CD15
PMN-MDSC and CD14
monocytic-MDSC. Tumor MDSC exhibited greater immunosuppression than those in circulation. HNSCC tumor MDSC immunosuppression was mediated by multiple, independent, cell-specific mechanisms including TGFβ and nitric oxide.
The clinical study of CXCR1/2 inhibitors in combination with adoptively transferred NK cells is warranted.
•Cisplatin/oxaliplatin induce changes associated with immunity in HNSCC cells.•Cisplatin/oxaliplatin are weak inducers of immunogenic cell death in a mouse model.•Efficacy of both cisplatin and ...oxaliplatin is enhanced by anti-PD-1.
Prior studies suggest that oxaliplatin is unique among platinum chemotherapy drugs in its ability to enhance anti-tumor immunity, but the immune mechanisms of different platinum chemotherapy drugs have not been previously compared in preclinical models of head and neck squamous cell carcinoma (HNSCC).
Human HNSCC cell lines were treated with cisplatin or oxaliplatin, then assessed for markers associated with immunogenic cell death (ICD) and antigen processing. A syngeneic mouse model of oral cancer was then used to compare the effects of cisplatin vs. oxaliplatin, alone or in combination with anti-PD-1 immunotherapy, on tumor growth and survival. A subset of spleens and tumors were analyzed for ICD markers and immune cell infiltrates by flow cytometry.
Cisplatin and oxaliplatin both increased cell surface levels of calreticulin, HSP70, MHC class I and PD-L1 in multiple cell lines. Inoculation of immunocompetent mice with cells killed in vitro by either drug resulted in failure of subsequently-injected live tumor cells to establish and grow in a small proportion of animals. Systemic cisplatin and oxaliplatin induced similar tumor growth delay when combined with anti-PD-1 therapy.
Treatment of HNSCC cells with platinum chemotherapy appears to induce some features of anti-tumor immunity, which may be enhanced by anti-PD-1 therapy. Cisplatin, the standard drug for HNSCC, appears to affect anti-tumor immunity in a similar fashion to oxaliplatin in these preclinical models.
Salivary duct carcinoma is a rare, aggressive malignancy of the salivary glands. Owing to its rare nature, clinical data are limited, and only a few clinical studies comprise more than 50 patients.
...To review the University of Pittsburgh Medical Center's experience with salivary duct carcinoma over a 20-year period, focusing on demographics, presentation, treatment, and outcome.
This investigation was a retrospective cohort study in a multihospital institution with tertiary referral. A pathology database was reviewed for all cases of histopathologically diagnosed salivary duct carcinoma from January 1, 1995, to October 20, 2014. Patients who were referrals for pathology review only and were never seen at the institution were excluded. In total, 75 study patients were identified. The electronic medical record was reviewed for details regarding demographics, presentation, treatment, and outcome, including overall survival (OS) and disease-free survival (DFS). This study was supplemented with a review of the institution's Head and Neck Oncology Database for further clinical details.
Primary outcome measures consisted of OS and DFS.
The study sample comprised 75 participants with a mean age at diagnosis of 66.0 years (age range, 33-93 years), and 29% (n = 22) were female. Most primary tumors were from the parotid gland (83%), with the next most frequent site being the submandibular gland (12%). Overall, 41% of the cases were carcinoma ex pleomorphic adenoma. Rates of other histologic features included the following: perineural invasion (69%), extracapsular spread (58%), ERBB2 (formerly HER2) positivity (31%) (62% of those who were tested), and vascular invasion (61%). The median OS was 3.1 years, and the median DFS was 2.7 years. Univariate Kaplan-Meier survival analyses demonstrated that facial nerve sacrifice and extracapsular spread were associated with lower OS (2.38 vs 5.11 years and 2.29 vs 6.56 years, respectively) and DFS (2.4 vs 3.88 years and 1.44 vs 4.5 years, respectively). Although underpowered, multivariable analysis demonstrated significantly worse OS in patients with N2 and N3 disease (hazard ratio HR 8.42, 95% CI, 1.84-38.5) but did not show significantly worse DFS or OS for facial nerve sacrifice or extracapsular spread. There was no association between ERBB2 positivity and survival and no difference in survival between patients receiving radiation therapy vs radiation therapy plus chemotherapy. No patients had recurrence or distant metastasis after 5 disease-free years.
Salivary duct carcinoma is an aggressive disease. A large number of cases in this review were carcinoma ex pleomorphic adenoma and had classic negative prognostic indicators, such as perineural invasion, vascular invasion, and extracapsular spread. ERBB2 positivity was not associated with any difference in survival. Facial nerve involvement appears to indicate worse prognosis, as does nodal stage higher than N1. Recurrence and metastasis after 5 years are rare.
Abstract
Access to computationally based visualization tools to navigate chemical space has become more important due to the increasing size and diversity of publicly accessible databases, associated ...compendiums of high-throughput screening (HTS) results, and other descriptor and effects data. However, application of these techniques requires advanced programming skills that are beyond the capabilities of many stakeholders. Here we report the development of the second version of the ChemMaps.com webserver (https://sandbox.ntp.niehs.nih.gov/chemmaps/) focused on environmental chemical space. The chemical space of ChemMaps.com v2.0, released in 2022, now includes approximately one million environmental chemicals from the EPA Distributed Structure-Searchable Toxicity (DSSTox) inventory. ChemMaps.com v2.0 incorporates mapping of HTS assay data from the U.S. federal Tox21 research collaboration program, which includes results from around 2000 assays tested on up to 10 000 chemicals. As a case example, we showcased chemical space navigation for Perfluorooctanoic Acid (PFOA), part of the Per- and polyfluoroalkyl substances (PFAS) chemical family, which are of significant concern for their potential effects on human health and the environment.
Graphical Abstract
Graphical Abstract
Representation of the perfluorooctanic acid (PFOA) and its neighborhood chemicals on the space computed using over 1 million chemicals from the Distributed Structure-Searchable Toxicity (DSSToxMap).
Background
Preclinical models are invaluable for studies of head and neck cancer. There is growing interest in the use of orthotopic syngeneic models, wherein cell lines are injected into the oral ...cavity of immunocompetent mice. In this brief report, we describe injection of mouse oral cancer 1 (MOC1) cells into the buccal mucosa and illustrate the tumor growth pattern, lymph node response, and changes in the tumor immune microenvironment over time.
Methods
MOC1 cells were injected into the buccal mucosa of C57BL6 mice. Animals were sacrificed at 7, 14, 21, or 27 days. Tumors and lymph nodes were analyzed by flow cytometry.
Results
All mice developed tumors by day 7 and required euthanasia for tumor burden and/or weight loss by day 27. Lymph node mapping showed that these tumors reliably drain to a submandibular lymph node. The proportion of intratumoral CD8+ T cells decreased over time, while neutrophilic myeloid cells increased dramatically. Growth of orthotopic MOC2 and MOC22 also showed similar growth patterns versus published data in flank tumors.
Conclusions
When used orthotopically in the buccal mucosa, the MOC1 model induces a robust lymph node response and distinct pattern of immune cell infiltration, with peak immune infiltration by day 14.
Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A ...higher frequency of PD-1
TIL has been reported in human papillomavirus (HPV)
HNC patients, despite the role of PD-1 in T-cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T-cell function and prognostic impact, because PD-1
T cells may be more exhausted than PD-1
T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy. In this study, PD-1 expression was indeed upregulated on HNC patient TIL, and the frequency of these PD-1
TIL was higher in HPV
patients (
= 0.006), who nonetheless experienced significantly better clinical outcome. However, PD-1
CD8
TILs were more frequent in HPV
patients and represented a more dysfunctional subset with compromised IFN-γ secretion. Moreover, HNC patients with higher frequencies of PD-1
CD8
TIL showed significantly worse disease-free survival and higher hazard ratio for recurrence (
< 0.001), while higher fractions of PD-1
T cells associated with HPV positivity and better outcome. In a murine HPV
HNC model, anti-PD-1 mAb therapy differentially modulated PD-1
populations, and tumor rejection associated with loss of dysfunctional PD-1
CD8
T cells and a significant increase in PD-1
TIL. Thus, the extent of PD-1 expression on CD8
TIL provides a potential biomarker for anti-PD-1-based immunotherapy.
.
Laryngeal cancer is declining in incidence in many parts of the world, as smoking becomes a less common habit. However, challenging cases of laryngeal cancer still exist and require expertise from ...otolaryngologists. This article reviews the relevant anatomy and lymphatic drainage pathways of the larynx because they pertain to cancer spread. The molecular and immune landscapes of laryngeal cancer, which are tightly linked to smoking, are also discussed.
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