Patients with adenoid cystic carcinomas of the salivary glands treated with lenvatinib: Activity and quality of life.

BACKGROUND: The treatment of patients with recurrent and/or metastatic (R/M) salivary gland adenoid cystic carcinoma (ACC) remains an unmet need. METHODS: Patients with R/M disease with a history of clinical or symptomatic disease progression within 6 months and a maximum of 1 previous line of chemotherapy or a multiple kinase inhibitor received oral lenvatinib at a dose of 24 mg/day. The primary endpoint was the objective response rate; secondary endpoints included quality of life (QOL) (according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items [EORTC QLQ-C30] and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Module Head and Neck Module [EORTC QLQ-H&N35]), progression-free survival and overall survival, duration of response, and toxicities. RESULTS: Twenty-eight patients with R/M ACC were enrolled. Among 26 evaluable patients, 3 partial responses (11.5%) were reported. Target lesion reductions between 23% to 28% were observed in 4 of 20 patients with stable disease. Treatment-related adverse events were frequent (all grades, 96%; grade≥3 in 50% of cases according to version 4.03 of the National Cancer Institute Common Terminology Criteria for Adverse Events). The dose of lenvatinib was reduced in 24 patients, whereas in 21 patients the dose was reduced within the first 12 weeks and 4 patients maintained the full dose throughout treatment. The QOL deteriorated between baseline and 6 months with regard to Fatigue and Dry Mouth. There was no evidence of changes in Swallowing and Physical Functioning. At a median follow-up of 29 months, 2 patients remained on treatment, 10 patients were off protocol for disease progression and were alive with disease, and 14 patients had died of disease progression. The median overall survival, progression-free survival, and duration of response were 27 months, 9.1 months, and 3.1 months, respectively. CONCLUSIONS: Lenvatinib appears to have modest activity in ACC. Toxicities are common but manageable and QOL was found to deteriorate in some domains.

The endocytic pathways of carbon dots in human adenoid cystic carcinoma cells.

OBJECTIVES: This study aimed at investigating cellular uptake pathways of carbon dots (CDs) in human adenoid cystic carcinoma cell line ACC-2. MATERIALS AND METHODS: We synthesized CDs using a hydrothermal method with citric acid and polyethylenimine (PEI, Mw = 25 000). The CDs incubated with the ACC-2 cells showed their bioimaging capabilities using a confocal microscopy test. Flow cytometry was used to analyse cellular uptake pathways of CDs in ACC-2 cells. RESULTS: Our findings indicated that CDs possessed good biocompatibility in ACC-2 cells. CDs were endocytosed mainly via micropinocytosis and energy-dependent pathways. CONCLUSIONS: In general, these findings suggested that CDs had excellent biomedical imaging properties for ACC-2 cells and there was a potential opportunity to develop biomedical applications.

Serial patient-derived orthotopic xenografting of adenoid cystic carcinomas recapitulates stable expression of phenotypic alterations and innervation.

BACKGROUND: Patient-derived xenograft (PDX) models have significantly enhanced cancer research, and often serve as a robust model. However, enhanced growth rate and altered pathological phenotype with serial passages have repeatedly been shown in adenoid cystic carcinoma (ACC) PDX tumors, which is a major concern. METHODS: We evaluated the fidelity of ACCs in their natural habitat by performing ACC orthotopic xenotransplantation (PDOX) in salivary glands. FINDINGS: Our PDOX model enabled solid tumors to integrate within the local epithelial, stromal and neuronal environment. Over serial passages, PDOX tumors maintained their stereotypic MYB-NFIB translocation, and FGFR2 and ATM point mutations. Tumor growth rate and histopathology were retained, including ACCs hallmark presentations of cribriform, tubular, solid areas and innervation. We also demonstrate that the PDOX model retains its capacity as a tool for drug testing. INTERPRETATION: Unlike the precedent PDX model, our data shows that the PDOX is a superior model for future cancer biology and therapy research. FUND: This work was supported by the National Institutes of Health (NIH)/National Institute of Dental and Craniofacial Research (NIDCR) grants DE022557, DE027034, and DE027551.

ADENOID CYSTIC CARCINOMA OF DISTAL TRACHEA: A CASE REPORT.

Primary malignant tumors of the trachea are very rare with the incidence of less than two per million people per year, and only ten percent of them are adenoid cystic carcinomas. Eighty percent of all tracheal tumors are malignant. Diagnosis is usually late because the symptoms mimic other conditions such as asthma. Clinical picture may sometimes be dramatic when airway is almost closed and emergency recanalization is necessary. Diagnosis is made by chest computed tomography scan or magnetic resonance imaging. Definitive treatment is surgical resection alone or followed by radiation therapy or radiation therapy alone. Radical resection is only accomplished in about half of all cases because of the submucosal tumor growth and limited length of tracheal resection. The role of adjuvant radiation therapy in negative resection margin cases is not clear but all patients with positive resection margin benefit from radiation therapy. We present a case of a 43-year-old patient with primary adenoid cystic carcinoma of distal trachea treated by emergency bronchoscopic recanalization and resection of the tracheal tumor with end-to-end anastomosis.

Adenoid cystic carcinoma in ventricle of larynx: An interesting case.

RATIONALE: Adenoid cystic carcinomas (ACCs) are malignant tumors and occur in the major and the minor salivary glands. ACCs are rare in the larynx. PATIENT CONCERNS: A 55-year-old female patient who presented with a 12 months history of paraesthesia pharynges and hoarseness for 4 months. Laryngoscopy showed an endophytic lesion in the right supglottic area with no laryngeal stenosis. And magnetic resonance imaging (MRI) confirmed the presence of a submucosal mass in the supglottic area. Supporting laryngoscope was performed under general anesthesia and a lesion biopsy obtained. DIAGNOSES: The lesion was sent for frozen-section biopsy, which shows the lesion was the epithelial-derived tumors of salivary gland, but it was impossible to identify the relationship between the tumor and the surrounding normal tissue, and to judge the nature of the tumor further. So, the lesion was sent for the second frozen-section biopsy, an ACC of the larynx was confirmed and margins were negative. INTERVENTIONS: The patient underwent partial laryngectomy. OUTCOMES: The patient was doing well except hoarseness during the follow-up period with no evidence of disease recurrence or metastasis for 17 months post-operatively. LESSONS: Laryngeal ACC is a rare entity. When the nature of lesion cannot be confirmed, multiple biopsies may be required for confirm the diagnosis of pathology. It not only reduces patient's waiting time for surgery, but also define the diagnosis and surgical removal of lesion through a single anesthesia.

[Adenoid cystic carcinoma of the larynx: a case report]. / Nabliudenie adenokistoznogo raka gortani.

Adenoid cystic carcinoma is one of the rare pathological conditions affecting the larynx. It is known to develop from the glandula elements present in this organ. The authors report a clinical observation of adenoid cystic carcinoma in the form of an exophytic tumour of the pale pink colour having a smooth surface and the well-pronounced vascular patterns at the base. The neoplasm is localized in the arytenoid and retroarytenoid cartilage regions. Being of 3.5-4 cm in size, the tumour causes the narrowing of the larynx in its posterior portions and restricts its mobility. Bearing in mind the considerable extension of the neoplastic process, we undertook laryngectomy including the resection of the orolaryngopharynx and the cervical portion of the oesophagus, the subtotal resection of the thyroid gland and the simultaneous reconstruction of the orolaryngopharynx.

Adenoid cystic carcinoma of the head and neck area: Oncologic treatment and plastic-reconstructive options.

Adenoid cystic carcinoma of the head and neck area is a rare malignant tumor with acceptable short-term but mediocre long-term prognosis. Radical tumor excision with clear resection margins, and sometimes resection of the facial nerve due to perineural growth, remains the fundamental therapy. We present 3 distinct clinical cases and discuss the current therapeutic options with special focus on plastic-reconstructive techniques. For reconstruction, the full armament of local and free flaps, as well as prosthetics, may be necessary. Adjuvant radiotherapy increases local control in advanced stages or close resection margins. However, systemic treatment options are limited. Further multicenter clinical trials are necessary due to the rare occurrence of the tumor.

Cytokeratin-14 contributes to collective invasion of salivary adenoid cystic carcinoma.

Collective invasion of cells plays a fundamental role in tissue growth, wound healing, immune response and cancer metastasis. This paper aimed to investigate cytokeratin-14 (CK14) expression and analyze its association with collective invasion in the invasive front of salivary adenoid cystic carcinoma (SACC) to uncover the role of collective invasion in SACC. Here, in the clinical data of 121 patients with SACC, the positive expression of CK14 was observed in 35/121(28.93%) of the invasive front of SACC. CK14 expression in the invasive front, local regional recurrence and distant metastasis were independent and significant prognostic factors in SACC patients. Then, we found that in an ex vivo 3D culture assay, CK14 siRNA receded the collective invasion, and in 2D monolayer culture, CK14 overexpression induced a collective SACC cell migration. These data indicated that the presence of characterized CK14+ cells in the invasive front of SACC promoted collective cell invasion of SACC and may be a biomarker of SACC with a worse prognosis.

Downregulation of nucleophosmin expression inhibited proliferation and induced apoptosis in salivary gland adenoid cystic carcinoma.

BACKGROUND: This study aimed to explore the relationship between nucleophosmin (NPM1) and patient clinical characteristics. Moreover, we investigated the effect of NPM1 in tumor proliferation and apoptosis of salivary gland adenoid cystic carcinoma (SACC). MATERIALS AND METHODS: NPM1 expression was examined in 74 specimens of SACC and 31 non-cancerous epithelium adjacent to carcinoma (NCEAC) by immunohistochemistry (IHC). RNA interference technology was used to silence NPM1 expression in SACC cells. We used transwell culture assay, cell counting kit-8 tests, and colony formation assay to test the proliferation, cisplatin resistance, migration, and invasiveness of SACC cells. RESULTS: The nuclear and cytoplasmic expression of NPM1 in SACC tissue was overexpressed and was tightly linked to perineural invasion and lymph node metastasis. The downregulation of NPM1 inhibited proliferation and induced apoptosis in SACC cells. Knockdown of NPM1 expression had no effect on chemoresistance migration, or invasiveness. CONCLUSIONS: NPM1 may play an important role in tumor progress in SACC and is a potential biomarker for SACC.

Antitumor effect of human TRAIL on adenoid cystic carcinoma using magnetic nanoparticle-mediated gene expression.

To overcome treatment limitations of adenoid cystic carcinoma, we developed a novel treatment combining gene therapy and nanotechnology. In this study, we created a plasmid, pACTERT-TRAIL, which used the human telomerase reverse transcriptase promoter, a tumor-specific promoter, to drive tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). A Fe(3)O(4)-PEI-plasmid complex (FPP) was generated, in which the iron oxide nanoparticles were modified by positively charged polyethylenimine (PEI) to enable them to carry the negatively charged plasmid. In vitro transfection assays showed that efficiency of magnetofection (i.e., FPP transfection) was sixfold higher compared to PEI alone or Lipofectamine 2000 (hereafter referred to as lipofectin) (P < 0.05). Importantly, apoptotic assays demonstrated that FPP-mediated TRAIL gene transfer could efficiently induce apoptosis of SACC-83 cells in vitro and in vivo. These results demonstrate that magnetofection of the plasmids driven by the tumor-specific promoter hTERT provides an effective way to deliver therapeutic genes for the treatment of adenoid cystic carcinoma in the future. FROM THE CLINICAL EDITOR: In this novel study addressing adenoid cystic carcinoma, the authors created a plasmid to drive tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Following that, a Fe(3)O(4)-PEI-plasmid complex (FPP) was generated, in which the iron oxide nanoparticles were modified by positively charged polyethylenimine (PEI) enabling them to carry the negatively charged plasmid, giving rise to sixfold higher transfection rates compared to standard technology.

Carcinoma adenoideo quístico / Adenoid cystic carcinoma

El carcinoma adenoide quístico representa aproximadamente un 25 por ciento de los tumores de cabeza y cuello, ubicado principalmente a nivel de paladar, labio y mucosa bucal. Mantiene un curso lento pero con probabilidad de metástasis a largo plazo con diseminación de predominio vascular y raramente a nódulos linfáticos. Clínicamente se manifiesta como indolente manifestado principalmente como una masa. El método diagnóstico más importante es el examen físico con exámenes complementarios por medio de ultrasonido y dependiendo de características propias de la masa se solicitar resonancia magnética para delimitar patología como guía durante procedimiento quirúrgico. Como tratamiento de primera línea se utiliza la resección quirúrgica y se ha demostrado mejores resultados con la agregación de radioterapia.

Carcinoma adenoide quístico / Adenoid cystic carcinoma

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Mammalian target of rapamycin regulates isoliquiritigenin-induced autophagic and apoptotic cell death in adenoid cystic carcinoma cells.

Previous studies, including those from our laboratory, have demonstrated that isoliquiritigenin (ISL), a flavonoid isolated from licorice, is a promising cancer chemotherapeutic agent. However the mechanisms underlying its anticancer effects are still far from clear. We now show, for the first time, that ISL triggers the mammalian target of rapamycin (mTOR)-dependent autophagic and apoptotic cell death in adenoid cystic carcinoma (ACC). Exposure of both ACC-2 and ACC-M cells to ISL resulted in several specific features for autophagy, including the appearance of membranous vacuoles, formation of acidic vesicular organelles, punctate pattern of LC3 immunostaining, and an increase in autophagic flux. Moreover, ISL treatment also resulted in significantly increased apoptosis in ACC cells. The ISL-mediated autophagic and apoptotic cell death were obviously attenuated by transfection with dominant negative Atg5 (DN-Atg5(K130R)) plasmids or treatment with 3-methyladenine(3-MA). In additon, the data also revealed that the autophagic and apoptotic cell death induced by ISL occurred through a mTOR-dependent pathway. More importantly, the xenograft model using ACC-M cells provided further evidence of the occurrence of ISL-induced autophagy and apoptosis in vivo, correlating with the suppresson of mTOR activation as well as up-regulation of Atg5 expression. Taken together, these findings in our study suggest that induction of mTOR-dependent autophagic and apoptotic cell death may be an important mechanism in cancer chemotherapy by ISL.

Therapeutic management of advanced adrenocortical carcinoma: what do we know in 2011?

The prognosis of advanced adrenocortical carcinoma (ACC) is dismal but heterogeneous. In 2011, mitotane is the only drug approved in Europe and US for the treatment of advanced ACC. Mitotane exerts both antisecretory and antiproliferative effects, which are delayed over time, and requires careful biological and morphological evaluations coupled with mitotane plasma measurement monitoring. In the absence of demonstration of any superior activity of combined polychemotherapy, the least toxic regimen should be considered in routine care. Locoregional therapies, including surgery of the primary tumor and metastases, should be considered part of the therapeutic arsenal. A prolonged survival can be observed in the case of tumor objective response and/or high plasma mitotane levels. New protocols are urgently needed, coupled with ancillary studies dedicated to progress in the findings of predictors or surrogates. International networks and comprehensive databases gathering clinical and biological data constitute the prerequisites for progress.

Shikonin inhibits tumor invasion via down-regulation of NF-κB-mediated MMP-9 expression in human ACC-M cells.

OBJECTIVE: The aim of this study was to examine the anti-invasion effect of Shikonin on human high-metastatic adenoid cystic carcinoma (ACC-M) cells and to explain the possible molecular mechanism involved. METHODS: The ACC-M cells were treated with Shikonin (0, 2.5, 5, 10 µM) for 24 h. The protein levels and gelatinolytic activities of MMP-2 and MMP-9 were analyzed using Western blot and Gelatin zymography test, respectively. Matrigel invasion assays were used to investigate tumor invasive potential and electromobility shift assays were used to determine the activity of NF-κB. RESULTS: The invasiveness of ACC-M cells was reduced in a dose dependent manner following 24-h treatment of up to 10 µM of the Shikonin at which concentration no cytotoxicity occurred. The protein levels and gelatinolytic activities of MMP-9 were significantly suppressed by increasing Shikonin concentrations. The down-regulation of MMP-9 appeared to be via the inactivation of NF-κB as the treatment with Shikonin suppressed the protein level of phosphate-IkBa, which was accompanied by a decrease in DNA-binding level of the factor. CONCLUSIONS: Shikonin inhibits tumor invasion via downregulation of MMP-9 expression in ACC-M cells. Pharmacologic inhibition of the NF-κB-mediated MMP-9 expression by Shikonin might be a powerful treatment option for ACC patients in future.

Treatment outcomes of patients with adenoid cystic carcinoma of the airway.

BACKGROUND: Adenoid cystic carcinoma (ACC) of the airway is a slowly growing tumor and airway narrowing is one of the main causes of death. The purposes of this study were to investigate treatment outcomes, prognostic factors, and the indications and outcomes of bronchoscopic interventions in patients with ACC of the airway. METHODS: We retrospectively analyzed the clinical characteristics, treatment modalities, and clinical outcomes of patients with histologically-proven ACC of the airway treated between January 1995 and June 2009 at Samsung Medical Center. RESULTS: A total of 30 patients were included in the study. Sixteen patients were male and the median age was 45 years. Multiple treatment modalities were required for the patients; 17 for surgery, 13 for definitive radiation therapy, 10 for adjuvant radiation therapy, and 1 for adjuvant chemotherapy. Bronchoscopic interventions were required to improve airway narrowing in 20 patients. After bronchoscopic intervention, 19 patients (95%) showed immediate improvement of airway narrowing and suffered no serious complications. The 5- and 10-year overall survival (OS) rates in these patients were 84% and 70%, respectively. The prognostic factors associated with OS were tumor size, tumor location, clinical T stage, surgery as an initial treatment, and bronchoscopic intervention. CONCLUSIONS: ACC of the airway had a good long-term prognosis but bronchoscopic interventions were frequently required during the course of the disease due to the development of airway narrowing. Bronchoscopic interventions may be considered as a bridge therapy before surgery or radiation therapy and as a palliative therapy for airway narrowing.

Silencing Id-1 with RNA interference inhibits adenoid cystic carcinoma in mice.

BACKGROUND: The helix-loop-helix (HLH) protein Id-1 (inhibitor of DNA binding/differentiation) has been demonstrated to play an important role in tumor development. Our previous in vitro research has shown that Id-1 is a potential target in the treatment of human adenoid cystic carcinoma (ACCM). The purpose of this study was to analyze the influence of Id inhibition on ACCM in mice. MATERIALS AND METHODS: To suppress the expression of Id-1 gene, we used lentivirus-mediated RNA interference to silence the Id-1 gene post-transcriptionally in ACCM models that stably express GFP in mice. Tumor development was evaluated by size measurement. Effects of Id-1 siRNA on mRNA and protein expression of Id-1 were analyzed using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting respectively. Ki-67 expression was measured by immunohistochemistry. In vitro studies of Hoechst staining for cell apoptosis, Boyden-chamber assay for cell invasion, and MTT-tests for cell growth were performed as well. RESULTS: Id-1 knockdown resulted in inhibition of tumor growth in mice. Id-1 siRNA significantly decreased not only Id-1 in mRNA and protein level, but also Ki-67 expression. In addition, apoptosis was induced and cell proliferation activity and invasion were significantly reduced. CONCLUSIONS: Lentivirus-mediated gene knockdown by silencing Id-1 constitute a valid methodological approach, which may represent an attractive, potent and specific therapeutic tool for the treatment of ACCM.

Emerging roles of deubiquitinases in cancer-associated pathways.

Deubiquitinases (DUBs) are emerging as important regulators of many pathways germane to cancer. They may regulate the stability of key oncogenes, exemplified by USP28 stabilisation of c-Myc. Alternatively they can negatively regulate ubiquitin-dependent signalling cascades such as the NF-kappaB activation pathway. We review the current literature that associates DUBs with cancer and discuss their suitability as drug targets of the future.

Surgical treatment of patients with stenosis of the central airway due to tracheal tumours.

This study retrospectively evaluated bronchoscopic and surgical treatments for patients with central airway stenosis due to tracheal tumours. Seven patients treated by resection and reconstruction of the trachea for tracheal tumours between 1994 and 2008 were retrospectively reviewed. The most common histological finding was thyroid carcinoma (n = 3), followed by adenoid cystic carcinoma (n = 2), a metastatic thyroid tumour (n = 1), and a benign granular cell tumour (n = 1). Three of the patients required preoperative laser treatment (Nd:YAG) for recanalization. Five patients underwent end-to-end anastomosis for reconstruction. There was no postoperative mortality or morbidity such as anastomotic insufficiency of the reconstructed trachea. Three patients with a microscopic residual tumour required postoperative external radiotherapy. Surgical resection of malignant tracheal tumours is recommended not only for curative purposes, but also for reduction of the risk of smothering.