Near-Infrared Photoimmunotherapy Using a Protein Mimetic for EGFR-Positive Salivary Gland Cancer.

Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer therapy based on a monoclonal antibody (mAb) conjugated to a photosensitizer (IR700Dye). The conjugate can be activated by near-infrared light irradiation, causing necrotic cell death with high selectivity. In this study, we investigated NIR-PIT using a small protein mimetic (6-7 kDa, Affibody) which has more rapid clearance and better tissue penetration than mAbs for epidermal growth factor receptor (EGFR)-positive salivary gland cancer (SGC). The level of EGFR expression was examined in vitro using immunocytochemistry and Western blotting. Cell viability was analyzed using the alamarBlue assay. In vivo, the volume of EGFR-positive tumors treated with NIR-PIT using the EGFR Affibody-IR700Dye conjugate was followed for 43 days. It was found that NIR-PIT using the EGFR Affibody-IR700Dye conjugate induced the selective destruction of EGFR-positive SGC cells and restricted the progression of EGFR-positive tumors. We expect that NIR-PIT using the EGFR Affibody-IR700Dye conjugate can efficiently treat EGFR-positive SGC and preserve normal salivary function.

[Salivary Gland Tumors: Limitations of International Guidelines and Status of the planned AWMF-S3-Guideline]. / Speicheldrüsentumoren: Limitationen der internationalen Guidelines und Bearbeitungsstand der AWMF-S3-Leitlinie.

Primary salivary gland carcinomas are not among the common head and neck tumors. They are characterized by manifold different histological types. Clinically, malignant tumors often cannot be distinguished from benign tumors, so that in these cases malignancy is only established by histopathological diagnosis. These are all reasons why there are relatively few clinical trials on the diagnosis, therapy and follow-up of these tumors. This in turn has the consequence that often only recommendations with limited evidence can be made in clinical guidelines. The most important international guidelines are the National Comprehensive Cancer Network (NCCN) guideline of 2023, the American Society of Clinical Oncology (ASCO) guideline of 2021, the European Society for Medical Oncology (ESMO) guideline of 2022 and still the British National Multidisciplinary guideline of 2016. These 4 international guidelines with their strengths and limitations are presented and commented here. Against this background, the development of a first German S3 clinical guideline on salivary gland tumors is important and expected to be completed in 2023. For the first time in the German guideline program on oncology, benign and malignant tumors are presented together in order to comprehensively do justice to the special features of salivary gland tumors.

Postoperative Radiation Therapy Refusal in Major Salivary Gland Cancers.

OBJECTIVE: Major salivary gland cancers (MSGCs) are often treated with primary surgery followed by adjuvant therapy for high-risk pathology. Patients with these cancers may opt out of recommended postoperative radiation therapy (PORT) for many reasons and consequently may suffer worse outcomes. STUDY DESIGN: Retrospective cohort study. SETTING: National Cancer Database. METHODS: Patients diagnosed with MSGC from 2004 to 2016 were identified, and overall survival and risk factors for refusal of recommended PORT were analyzed based on demographic, socioeconomic, and clinical factors. Multivariable logistic regression and a Cox model were used to conduct the analysis. RESULTS: 211 out of 4704 qualifying patients (4.5%) refused recommended PORT. Multivariable analysis demonstrated increased PORT refusal for age >74 years (odds ratio OR 4.34, confidence interval [CI] [2.43-7.85]), Asian race (OR 2.25, CI [1.10-4.23]), and certain facility types (comprehensive cancer center, OR 2.39, CI [1.08-6.34]; academic research program, OR 3.29, CI [1.49-8.74]; and integrated network cancer program, OR 2.75, CI [1.14-7.7]). N2 stage was associated with decreased PORT refusal (OR 0.67, CI [0.45-0.98]). The 5-year overall survival for patients who received and refused PORT were significantly different at 65.8% and 53.8%, respectively (p < .001). When controlling for several factors, PORT refusal was independently associated with significantly lower overall survival (HR 1.54, CI [1.21-1.98]). CONCLUSION: Patient refusal of recommended PORT in MSGC is rare, associated with various disease and socioeconomic factors, and may decrease overall survival. Our findings can assist clinicians in counseling patients and identifying those who may be more likely to opt out of recommended PORT.

Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors.

Rationale: Immunosuppression in the tumor microenvironment (TME) is key to the pathogenesis of solid tumors. Tumor cell-intrinsic autophagy is critical for sustaining both tumor cell metabolism and survival. However, the role of autophagy in the host immune system that allows cancer cells to escape immune destruction remains poorly understood. Here, we determined if attenuated host autophagy is sufficient to induce tumor rejection through reinforced adaptive immunity. Furthermore, we determined whether dietary glutamine supplementation, mimicking attenuated host autophagy, is capable of promoting antitumor immunity. Methods: A syngeneic orthotopic tumor model in Atg5+/+ and Atg5flox/flox mice was established to determine the impact of host autophagy on the antitumor effects against mouse malignant salivary gland tumors (MSTs). Multiple cohorts of immunocompetent mice were used for oncoimmunology studies, including inflammatory cytokine levels, macrophage, CD4+, and CD8+ cells tumor infiltration at 14 days and 28 days after MST inoculation. In vitro differentiation and in vivo dietary glutamine supplementation were used to assess the effects of glutamine on Treg differentiation and tumor expansion. Results: We showed that mice deficient in the essential autophagy gene, Atg5, rejected orthotopic allografts of isogenic MST cells. An enhanced antitumor immune response evidenced by reduction of both M1 and M2 macrophages, increased infiltration of CD8+ T cells, elevated IFN-γ production, as well as decreased inhibitory Tregs within TME and spleens of tumor-bearing Atg5flox/flox mice. Mechanistically, ATG5 deficiency increased glutamine level in tumors. We further demonstrated that dietary glutamine supplementation partially increased glutamine levels and restored potent antitumor responses in Atg5+/+ mice. Conclusions: Dietary glutamine supplementation exposes a previously undefined difference in plasticity between cancer cells, cytotoxic CD8+ T cells and Tregs.

[Interpretation and comparison of international guidelines for salivary gland malignancy in 2021].

In order to provide evidence-based recommendations on the management of salivary gland malignancy (SGM), the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) formulated and updated SGM clinical practice guidelines respectively in 2021.The two guidelines are interpreted and compared in this article from six perspectives including preoperative evaluations, surgical diagnostic and therapeutic procedures, appropriate radiotherapy techniques, the role of systemic therapy, follow-up evaluations and recurrent-metastatic diseases' management of SGM, which has guiding significance for diagnosis and treatment of SGM in China.

Interpretation and comparison of international guidelines for salivary gland malignancy in 2021 / 中华口腔医学杂志

In order to provide evidence-based recommendations on the management of salivary gland malignancy (SGM), the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) formulated and updated SGM clinical practice guidelines respectively in 2021.The two guidelines are interpreted and compared in this article from six perspectives including preoperative evaluations, surgical diagnostic and therapeutic procedures, appropriate radiotherapy techniques, the role of systemic therapy, follow-up evaluations and recurrent-metastatic diseases' management of SGM, which has guiding significance for diagnosis and treatment of SGM in China.

Salivary duct carcinoma: Updates in histology, cytology, molecular biology, and treatment.

Salivary duct carcinoma (SDC) is an aggressive subtype of primary salivary gland carcinoma, often with an advanced stage at presentation and high rates of metastasis and recurrence. It most commonly arises in the parotid gland of older men and microscopically resembles high-grade breast ductal carcinoma. While 50 years have lapsed since the first report of this entity, recent intensive studies have shed light on its biologic, genetic, and clinical characteristics. The diagnosis of SDC is aided by the immunohistochemical expression of androgen receptor (AR) coupled with its characteristic histomorphology. Fine-needle aspiration typically reveals cytologic features of high-grade carcinoma, and ancillary studies using cell block material can facilitate the specific diagnosis of SDC. In surgical specimens, certain histologic features are important prognostic factors, including nuclear pleomorphism, mitotic counts, vascular invasion, and the morphology at the invasion front. Several clinical studies have shown promising results using targeted therapy for AR and human epidermal growth factor receptor 2 (HER2), and the latest version of the National Comprehensive Cancer Network guidelines recommends the evaluation of AR and HER2 status before treatment. Recent molecular analyses have revealed multiple heterogeneous alterations in well-known oncogenes and tumor suppressor genes, including TP53, HRAS, PIK3CA, PTEN, and BRAF. Clinical trials of drugs targeting these genes may broaden the treatment options for SDC in the near future.

Efficacy and toxicity of sorafenib in patients with adenoid cystic carcinoma of the head and neck: a case series of five patients.

INTRODUCTION: Adenoid cystic carcinoma (ACC) of the head and neck is a rare malignancy of the salivary glands that accounts for approximately 10% of salivary gland carcinoma. Despite aggressive local therapy, local recurrence and distant metastases occur frequently. Response rates (RR) to potential curative and palliative chemotherapy are limited, so new strategies are needed. CASE REPORTS: We describe five case reports of patients with unresectable locally advanced or metastatic ACC of the head and neck who have been treated with sorafenib, a multi-tyrosine kinase inhibitor (mTKI). RESULTS: In this case series, we found that three out of five patients treated with sorafenib survived, respectively, 16, 35 and 35 months. Two patients showed a partial response (PR) and one patient had a prolonged stable disease (SD) for almost three years. Grade 3 adverse events (AE) occur under sorafenib so adequate toxicity management is essential. This retrospective case series hints towards the possibility of clinical benefit for treating ACC patients with sorafenib. Efficacy of sorafenib should be studied in a prospective-randomized clinical trial which is a challenging task due to the rarity of the disease.

The Milan System at Memorial Sloan Kettering: Utility of the categorization system for in-house salivary gland fine-needle aspiration cytology at a comprehensive cancer center.

BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) provides a standardized reporting system for salivary gland fine-needle aspiration (SGFNA). We review the clinical utility of the MSRSGC at a tertiary care cancer center by assessing the rates of malignancy (ROM) among different categories. METHODS: A retrospective search was performed to retrieve all SGFNA cases performed at our institution between 1/1/07 and 12/31/18. The initial primary diagnoses were recorded and cases were then assigned to appropriate MSRSGC categories. ROM was then calculated for all categories. RESULTS: A total of 976 cases were identified, and 373 with follow-up. The ROM was 19.7% (192/976) for all-comers and 51.3% (192/374) among cases with follow-up. Using MSRSGC, SGFNA showed a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 65.6%, 87.4%, 100%, and 72.6%, respectively. ROM for MSRSGC categories I, II, III, IVa, IVb, V, and VI were 20.7%, 30.0%, 45.8%, 3.3%, 50.7%, 100%, and 100%, respectively. Utilizing MSRSGC resulted in a nondiagnostic rate of 14.4%. The nondiagnostic rate was lower when the procedure was performed by pathologists vs nonpathologists (12.9% vs 15.8%) but was comparable when rapid on site evaluation (ROSE) was performed (12.9% vs 11.6%). CONCLUSION: In our patient population, MSRSGC resulted in a perfect PPV and moderate NPV. Utilizing MSRSGC results in a higher nondiagnostic rate due to the inclusion of cases with benign elements or cyst contents only in this category. Performing ROSE is more important in attaining an adequate sample than the specialty of the person performing SGFNA.

Serum Levels of Zinc, Copper and Ferritin in Patients with Salivary Gland Tumors

Background: Variation in serum levels of trace elements including zinc, copper and ferritin has been reported in cancer patients. The aim of this study was to evaluate these trace elements in the patients' sera with benign and malignant salivary gland tumors (SGTs) and compare them with normal individuals. Methods: In this cross-sectional study, 60 patients with SGTs including 16 pleomorphic adenoma and 44 malignant SGTs, as well as 28 healthy controls, were enrolled. Serum levels of zinc, copper and ferritin were determined by atomic absorption and ELISA methods. Data were analyzed using one way ANOVA, Chi-square, Kruskal-Wallis and Mann- Whitney tests. Results: The mean concentration of zinc, copper, ferritin was1.5± 2 ppm, 1.2± 0.5 ppm, and 96.7± 65.7 ng/ml in PA, 1.5± 1.4,1.3± 0.4, and 111.2± 112 in malignant SGTs, and1.1±0.3, 1.2± 0.23 and 124±135.8 in normal control groups. There was no statistically significant difference between the patients and control groups, and between benign and malignant SGTs (P>0.05). Conclusion: The serum levels of trace elements in SGTs were not different from normal individuals. The results might have been affected by some interventional factors. Therefore, designing cohort complementary studies might result in obtaining more accurate data.

Postoperative radiotherapy for T1/2N0M0 mucoepidermoid carcinoma positive for CRTC1/3-MAML2 fusions.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) guidelines recommend considering postoperative radiotherapy (PORT) for completely resected T1/2N0M0 salivary mucoepidermoid carcinomas when they show tumor spillage, perineural invasion, or intermediate/high-grade histology. CRTC1/3-MAML2 fusions have been associated with a favorable clinical outcome. METHODS: Forty-seven T1/2N0M0 mucoepidermoid carcinoma cases positive for CRTC1/3-MAML2 fusions were completely resected and were not treated with PORT. RESULTS: Pathologically, none of the cases showed tumor spillage or perineural invasion. Cases with intermediate/high-grade histology numbered 9 (19%) to 26 (55%) with the currently used 3 different grading systems. During the follow-up (median 60 months), locoregional tumor recurrence occurred in 4 cases, which were treated with surgery alone. At the last follow-up (median 60 months; 7-160), all patients were alive with no evidence of disease. CONCLUSION: An excellent prognosis may be achieved without PORT in T1/2N0M0 mucoepidermoid carcinoma patients positive for CRTC1/3-MAML2 fusions when the tumors are completely resected without tumor spillage.

A multiplex preclinical model for adenoid cystic carcinoma of the salivary gland identifies regorafenib as a potential therapeutic drug.

Adenoid cystic carcinomas (ACC) are rare salivary gland cancers with a high incidence of metastases. In order to study this tumor type, a reliable model system exhibiting the molecular features of this tumor is critical, but none exists, thereby inhibiting in-vitro studies and the analysis of metastatic behavior. To address this deficiency, we have coupled an efficient method to establish tumor cell cultures, conditional reprogramming (CR), with a rapid, reproducible and robust in-vivo zebrafish model. We have established cell cultures from two individual ACC PDX tumors that maintain the characteristic MYB translocation. Additional mutations found in one ACC culture also seen in the PDX tumor. Finally, the CR/zebrafish model mirrors the PDX mouse model and identifies regorafenib as a potential therapeutic drug to treat this cancer type that mimic the drug sensitivity profile in PDX model, further confirming the unique advantages of multiplex system.

Silymarin and its active component silibinin act as novel therapeutic alternatives for salivary gland cancer by targeting the ERK1/2-Bim signaling cascade.

PURPOSE: Approximately 20% of all salivary gland cancer patients who are treated with current treatment modalities will ultimately develop metastases. Its most common form, mucoepidermoid carcinoma (MEC) is a highly aggressive tumor with an overall 5-year survival rate of ~30%. Until now, several chemotherapeutic drugs have been tested for the treatment of salivary gland tumors, but the results have been disappointing and the drugs often cause unwanted side effects. Therefore, several recent studies have focused on the potential of alternative and/or complementary therapeutic options, including the use of silymarin. METHODS: The effects of silymarin and its active component silibinin on salivary gland cancer-derived MC3 and HN22 cells and their underlying molecular mechanisms were examined using trypan blue exclusion, 4'-6-diamidino-2-phenylindole (DAPI) staining, Live/Dead, Annexin V/PI staining, mitochondrial membrane potential (ΔΨm) measurement, quantitative RT-PCR, soft agar colony formation and Western blotting analyses. RESULTS: We found that silymarin and silibinin dramatically increased the expression of the pro-apoptotic protein Bim in a concentration- and time-dependent manner and, concomitantly, induced apoptosis in MC3 and HN22 cells. We also found that ERK1/2 signaling inhibition successfully sensitized these cells to the apoptotic effects of silymarin and silibinin, which indicates that the ERK1/2 signaling pathway may act as an upstream regulator that modulates the silymarin/silibinin-induced Bim signaling pathway. CONCLUSIONS: Taken together, we conclude that ERK1/2 signaling pathway inhibition by silymarin and silibinin increases the expression of the pro-apoptotic Bcl-2 family member Bim which, subsequently, induces mitochondria-mediated apoptosis in salivary gland cancer-derived cells.

Postoperative iodine-125 interstitial brachytherapy for the early stages of minor salivary gland carcinomas of the lip and buccal mucosa with positive or close margins.

BACKGROUND: The purpose of this study was to present our preliminary exploration of safety and efficacy of postoperative low-dose-rate brachytherapy for the early clinical stages of minor salivary gland carcinomas of the lip and buccal mucosa. METHODS: Twenty-seven patients with the early stages of minor salivary gland carcinomas of the lip and buccal mucosa received postoperative 125 I seed interstitial brachytherapy from March 2005 to May 2015. Actuarial likelihood estimates for local control, overall survival, and disease-free survival were calculated by Kaplan-Meier method. RESULTS: The actuarial 3-year, 5-year, and 10-year local control rates were 94.7%, 82.9%, and 82.9%, respectively. The actuarial 3-year, 5-year, and 10-year overall survival rates were 93.3%, 93.3%, and 77.8%, respectively. No patient experienced toxicity above grade 2. CONCLUSION: Postoperative 125 I seed interstitial brachytherapy is an alternative to radical surgery for early stages of minor salivary gland carcinomas of the lip and buccal mucosa, which offers satisfactory cosmetic and functional outcomes. © 2017 Wiley Periodicals, Inc. Head Neck 39: 572-577, 2017.

A phase II study of sorafenib in recurrent and/or metastatic salivary gland carcinomas: Translational analyses and clinical impact.

BACKGROUND: Pre-clinical and clinical evidence suggests a rationale for the use of anti-angiogenic agents, including sorafenib, in recurrent and/or metastatic salivary gland carcinomas (RMSGCs). This study evaluates the activity of sorafenib in patients with RMSGCs and also investigates whether the activity of sorafenib could be related to its main tailored targets (i.e. BRAF, vascular endothelial growth factor receptor 2 [VEGFR2], platelet-derived growth factor receptor α [PDGFRα] and ß, RET, KIT). PATIENTS AND METHODS: Patients received sorafenib at 400 mg BID. The primary end-point was response rate (RR) including complete response or partial response (PR); secondary end-points included RR according to Choi criteria, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). RESULTS: Thirty-seven patients (19 adenoid cystic cancers, ACC) were enrolled. Six PRs were recorded. RR was 16% (95% confidence interval [CI]: 6-32; 11% in ACC and 22% in non-ACC). Choi criteria could be applied in 30 out of 37 cases with a RR of 50% (95% CI: 31-69%); DCR was 76% (95% CI: 59-88%). Incidence of ≥G3 adverse events was 29.7%. Median PFS and OS for the entire population were 5.9 months and 23.4 months, respectively. Median PFS and OS were 8.9 and 26.4 months for ACC versus 4.2 and 12.3 months for non-ACC patients. All the cases showed expression of PDGFRß in the stroma and VEGFR2 in endothelial cells; PDGFRα positivity was found in the stroma of four (27%) cases. All except for two cases showed no PDGFRß, VEGFR2 and PDGFRα expression in the tumour cells. KIT expression was restricted to ACC and a weak RET expression was limited to one adenocarcinoma, not otherwise specified (NOS). No BRAF mutation was found. No correlation was observed between the sorafenib activity and the expression of its markers although all six responders (two ACC, one adenocarcinoma, NOS, one salivary duct cancer [SDC], one high-grade mucoepidermoid [HG-MEC] and one poorly-differentiated cancer) are enriched in the stromal component showing a PDGFRß immunodecoration. In ACCs, immunohistochemistry revealed MYB protein expression in 15/16 cases (94%) and the MYB-NFIB fusion oncogene was observed in 9/14 (64%). CONCLUSIONS: Sorafenib is the first anti-angiogenic agent to demonstrate activity in RMSGC patients, particularly in some histotypes such as HG-MEC, SDC and adenocarcinoma, NOS. The PDGFRß-positive rich stromal component characterising these histotypes and the lack of correlation between the activity of sorafenib and its targets suggests anti-angiogenic effect as the prevalent mechanism of action of sorafenib in SGCs.

Convallaria keiskei as a novel therapeutic alternative for salivary gland cancer treatment by targeting myeloid cell leukemia-1.

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.

Mucoepidermoid carcinoma of the salivary glands: a retrospective study of 51 cases and review of the literature / Carcinoma mucoepidermoide de glándulas salivales. estudio retrospectivo de 51 casos y revisión de la literatura

The aim of this study is to present the casuistic of mucoepidermoid carcinoma of salivary glands in patients diagnosed at “Dr. Eduardo Cáceres Graziani” National Institute for Neoplastic Diseases, Lima, Perú. From January 2002 to December 2012, 51 cases were diagnosed as mucoepidermoid carcinoma. The number of female patients was higher, with 28 cases (54.9%), and regarding age distribution, 33.3% of the patients were under 30 years old. Pain was one of the main symptoms, and 74.5% of the mucoepidermoid carcinomas were located in the parotid gland. It is concluded that epidemiology regarding age and gender of the 51 cases analyzed was in the same range as other studies, and that most cases were located in major salivary glands, in agreement with reports on other populations. Other characte ristics showed a homogeneous distribution.

El propósito de este estudio es presentar la casuística del carcinoma mucoepidermoide de glándulas salivales de pacientes diagnosticados en el Instituto Nacional de Enfermedades Neoplásicas “Dr. Eduardo Cáceres Graziani” Lima, Perú, desde el 2002 hasta el 2012. Realizamos un estudio retrospectivo en el cual fueron incluidos sujetos con diagnóstico primario de carcinoma mucoepidermoide en glándulas salivales. Entre enero de 2002 y diciembre de 2012, se registraron 51 casos. El número de pacientes de sexo femenino fue mayor, con 28 casos (54,9%) y con respecto a la distribución por edades, el 33,3% de los pacientes eran menores de 30 años de edad. El dolor fue uno de los síntomas principales. El 74,5% de los carcinomas mucoepidermoides se localizaron en la glándula parótida. De los hallazgos obtenidos se concluye principalmente que en lo que respecta a la distribución epidemiológica de edad y género de los 51 casos analizados estas variaron en el mismo rango de otros estudios. También se distingue que el mayor número de casos estuvieron localizados en glándulas salivales mayores, dato en concordancia con otras poblaciones reporta das. Las demás características presentaron una distribución homogénea.

WIP1 stimulates migration and invasion of salivary adenoid cystic carcinoma by inducing MMP-9 and VEGF-C.

The wild-type p53 induced phosphatase 1 (WIP1) is an oncogene overexpressed in a variety of human cancers. Here, we demonstrated that WIP1 silencing reduced MMP-9 and VEGF-C expression as well as migration and invasion of salivary adenoid cystic carcinoma (ACC) cells. Overexpression of MMP-9 or VEGF-C restored migration and invasion in WIP1 knockdown cells, indicating that MMP-9 and VEGF-C are downstream targets of WIP1 signaling. Levels of cyclin D1 and c-Myc, targets of Wnt/ß-catenin pathway, were significantly decreased by WIP1 silencing. In addition, WIP1 expression was positively associated with metastasis and prognosis of ACC patients as well as with MMP-9 or VEGF-C in ACC tissues.

Phase II trial of sorafenib in advanced salivary adenoid cystic carcinoma of the head and neck.

BACKGROUND: There is a need to improve the systemic treatment of advanced adenoid cystic carcinoma (ACC). Response rates to chemotherapy are poor and preliminary investigations of molecularly targeted agents have been disappointing. In this study, we evaluate sorafenib, an oral multikinase inhibitor, which has an attractive targeting profile for this disease. METHODS: In a single-arm phase II trial, patients with unresectable locally recurrent and/or metastatic ACC were treated with sorafenib 400 mg bid. RESULTS: Twenty-three patients, median age 51 years, were recruited from 2009 to 2011. Median progression-free survival (PFS) and overall survival (OS) were 11.3 and 19.6 months, respectively. PFS at 6 and 12 months were 69.3% and 46.2%, respectively. Sorafenib was only reasonably well tolerated, and 13 patients (57%) experienced grade 3 toxicity. CONCLUSION: Sorafenib showed modest activity in ACC with a 12-month PFS of 46.2%. Sorafenib 400 mg bid was associated with significant toxicity and, taken together with limited effectiveness, cannot be enthusiastically recommended for further evaluation.