Publications by authors named "Kazuhira Endo"

65 Publications

In Response to Low Skeletal Muscle Mass Is a Risk Factor for Aspiration Pneumonia.

Laryngoscope 2021 Aug 5. Epub 2021 Aug 5.

Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.

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http://dx.doi.org/10.1002/lary.29792DOI Listing
August 2021

Epstein-Barr Virus LMP1 Induces Soluble PD-L1 in Nasopharyngeal Carcinoma.

Microorganisms 2021 Mar 15;9(3). Epub 2021 Mar 15.

Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan.

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy. The principal oncogene of EBV, latent membrane protein 1 (LMP1), induces the expression of programmed death-ligand 1 (PD-L1), which is an immunosuppressive transmembrane protein and a promising therapeutic target for various malignancies. Recent studies have revealed an association between the level of soluble PD-L1 (sPD-L1) and disease progression. However, the role of sPD-L1 in NPC or its relevance to LMP1 has not been elucidated. This study aimed to examine whether LMP1 induces sPD-L1 in vitro and analyze the clinical relevance of LMP1, PD-L1, and sPD-L1 in NPC patients. Analysis of nasopharyngeal cell lines revealed that LMP1 induces both cellular PD-L1 and sPD-L1. Analysis of biopsy specimens from 32 NPC patients revealed that LMP1 expression was significantly correlated with PD-L1 expression. Finally, the serum sPD-L1 level in NPC patients was higher than that in the controls. Moreover, the sPD-L1 level in the advanced stage was higher than that in the early stage. However, LMP1 expression, PD-L1 expression, and sPD-L1 levels were not associated with prognosis. These results suggest that LMP1 induces both sPD-L1 and PD-L1, which are associated with NPC progression.
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http://dx.doi.org/10.3390/microorganisms9030603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998736PMC
March 2021

Xenografts derived from patients with head and neck cancer recapitulate patient tumour properties.

Oncol Lett 2021 May 16;21(5):385. Epub 2021 Mar 16.

Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.

Rodent models mimic the heterogeneity of head and neck cancer (HNC) malignancies and are used to investigate HNC-associated biomarkers and evaluate drug responses. To assess the utility of patient-derived xenografts (PDXs) as an HNC model, 18 tumour samples were obtained from surgical specimens of patients with HNC and implanted into non-obese diabetic severe combined immunodeficient mice. The histological features of PDXs and corresponding patient samples were compared. Furthermore, the present study investigated how PDX responses to anticancer drugs mimic patient clinical responses, as well as the expression of adenosine triphosphate-binding cassette transporters through chemotherapy in an HNC-PDX model. A total of five PDXs from patients with HNC exhibiting high correspondence with histopathological features of the original patient samples were established (establishment rate, 28%). The responses of three PDXs to cisplatin were associated with clinical responses of the patients. ABC transporter expression was augmented in one PDX model after anticancer drug treatment, but not in PBS-treated passaged PDXs. PDX models exhibited similar biological and chemosensitive characteristics to those of the primary tumours. PDXs could be a useful preclinical tool to test novel therapeutic agents and identify novel targets and biomarkers in HNC.
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http://dx.doi.org/10.3892/ol.2021.12646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988720PMC
May 2021

Management of tracheostomy in COVID-19 patients: The Japanese experience.

Auris Nasus Larynx 2021 Jun 9;48(3):525-529. Epub 2021 Jan 9.

Department of Otolaryngology - Head and Neck Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, North 15 West 7, Sapporo 060-8638, Japan. Electronic address:

Objective: Involvement in the tracheostomy procedure for COVID-19 patients can lead to a feeling of fear in medical staff. To address concerns over infection, we gathered and analyzed experiences with tracheostomy in the COVID-19 patient population from all over Japan.

Methods: The data for health-care workers involved in tracheostomies for COVID-19-infected patients were gathered from academic medical centers or their affiliated hospitals from all over Japan.

Results: Tracheostomies have been performed in 35 COVID-19 patients with a total of 91 surgeons, 49 anesthesiologists, and 49 surgical staff members involved. Twenty-eight (80%) patients underwent surgery more than 22 days after the development of COVID-19-related symptoms (11: 22-28 days and 17: ≥29 days). Thirty (85.7%) patients underwent surgery ≥ 15 days after intubation (14: 15-21 days, 6: 22-28 days, and 10: ≥29 days). Among the total of 189 health-care workers involved in the tracheostomy procedures, 25 used a powered air-purifying respirator (PAPR) and 164 used a N95 mask and eye protection. As a result, no transmission to staff occurred during the 2 weeks of follow-up after surgery.

Conclusion: No one involved in tracheostomy procedures were found to have been infected with COVID-19 in this Japanese study. The reason is thought to be that the timing of the surgery was quite late after the infections, and the surgery was performed using appropriate PPE and surgical procedure. The indications for and timing of tracheostomy for severe COVID-19 patients should be decided through multidisciplinary discussion.
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http://dx.doi.org/10.1016/j.anl.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794599PMC
June 2021

Low Skeletal Muscle Mass Is a Risk Factor for Aspiration Pneumonia During Chemoradiotherapy.

Laryngoscope 2021 05 8;131(5):E1524-E1529. Epub 2020 Oct 8.

Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.

Objectives: This study aimed to investigate whether pretreatment skeletal muscle mass index (SMI) is a predictor for the risk of aspiration pneumonia and to explore the relationship between low SMI and overall survival (OS) in patients with head and neck squamous cell carcinoma (HNSCC) receiving chemoradiotherapy (CRT).

Methods: We retrospectively reviewed the data of patients with HNSCC who received CRT during 2010-2019. Patients received a combination of radiotherapy and cisplatin-based chemotherapy (3 cycles of 80 mg/m cisplatin on days 1, 22, and 43). Aspiration pneumonia were defined as the presence of both subjective and objective symptoms. Kaplan-Meier curves were generated to analyze survival.

Results: Among the 159 patients, 36 (22.6%) developed aspiration pneumonia during treatment. Median SMI in patients with and without pneumonia was 12.4 cm /m (9.0-20.7) and 13.6 cm /m (8.1-19.7), respectively (P < .01). Multivariate logistic regression revealed that SMI was the only independent predictor of aspiration pneumonia (P = .0026). Mean OS was significantly shorter for patients with low SMI than for patients with normal SMI (66.9 months vs. 92.7 months, P = .001).

Conclusion: Pretreatment low SMI predicts development of aspiration pneumonia and is a strong negative prognostic predictor for OS in patients with HNSCC undergoing CRT. Supportive treatment can be provided to patients at high risk of a low SMI. This study is the first to report SMI as a prognostic predictor in HNSCC. Laryngoscope, 131:E1524-E1529, 2021.
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http://dx.doi.org/10.1002/lary.29165DOI Listing
May 2021

Influences of Semaphorin 3A Expression on Clinicopathological Features, Human Papillomavirus Status, and Prognosis in Oropharyngeal Carcinoma.

Microorganisms 2020 Aug 22;8(9). Epub 2020 Aug 22.

Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.

Human papillomavirus (HPV) infection is now identified as a major etiologic factor for oropharyngeal cancer (OPC), and HPV positivity is well established better prognostic marker in OPC. Now, predictable markers for the prognosis of the patients who are stratified by HPV has been investigated in. Semaphorin 3A (SEMA3A) is a well-known axon guidance molecule in the nervous system. It is also known as a tumor suppressor in various cancers. In the present study, we examined the relationships between SEMA3A and clinicopathologic features, especially HPV status, and neoangiogenesis, and its prognostic significance for OPC patients. Thirty-two OPC patients and 17 normal patients were analyzed for SEMA3A expression by immunohistochemical analysis. We also analyzed 22 OPC specimens for CD34 expression as a marker of neoangiogenesis. SEMA3A was significantly downregulated in OPC compared with chronic tonsillitis tissues ( = 0.005). SEMA3A expression was negatively correlated with CD34 expression ( = -0.466, = 0.033). Moreover, the higher SEMA3A expression cohort showed better survival than the lower SEMA3A expression cohort regardless of HPV status ( = 0.035). These results suggest that SEMA3A expression is a prognostic marker for survival regardless of HPV status and is associated with anti-angiogenesis in OPC.
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http://dx.doi.org/10.3390/microorganisms8091286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565979PMC
August 2020

EBV-LMP1 induces APOBEC3s and mitochondrial DNA hypermutation in nasopharyngeal cancer.

Cancer Med 2020 10 20;9(20):7663-7671. Epub 2020 Aug 20.

Division of Otorhinolaryngology and Head and Neck Surgery, Kanazawa University, Kanazawa, Japan.

An Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is a principal oncogene that plays a pivotal role in EBV-associated malignant tumors including nasopharyngeal cancer (NPC). Recent genomic landscape studies revealed that NPC also contained many genomic mutations, suggesting the role of LMP1 as a driver gene for the induction of these genomic mutations. Nonetheless, its exact mechanism has not been investigated. In this study, we report that LMP1 alters the expression profile of APOBEC3s(A3s), host deaminases that introduce consecutive C-to-U mutations (hypermutation). In vitro, LMP1 induces APOBEC3B (A3B) and 3F(A3F), in a nasopharyngeal cell line, AdAH. Overexpression of LMP1, A3B, or A3F induces mtDNA hypermutation, which is also detectable from NPC specimens. Expression of LMP1 and A3B in NPC was correlated with neck metastasis. These results provide evidence as to which LMP1 induces A3s and mtDNA hypermutation, and how LMP1 facilitates metastasis is also discussed.
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http://dx.doi.org/10.1002/cam4.3357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571841PMC
October 2020

Overexpression of Semaphorin 3A is a Marker Associated with Poor Prognosis in Patients with Nasopharyngeal Carcinoma.

Microorganisms 2020 Mar 17;8(3). Epub 2020 Mar 17.

Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara, Kanazawa, Ishikawa 920-8641, Japan.

Semaphorins were discovered as guidance signals that mediate neural development. Recent studies suggest that semaphorin 3A (Sema3A), a member of the semaphorin family, is involved in the development of several cancers. This study aimed to analyze the association of Sema3A with the clinical features of nasopharyngeal carcinoma (NPC), an Epstein-Barr virus-associated carcinoma, and the Epstein-Barr virus primary oncogene latent membrane protein 1 (LMP1). The expression of Sema3A and LMP1 was immunohistochemically examined in the 35 NPC specimens. The mean expression scores for Sema3A and LMP1 were 20.8% ± 14.5% and 13.9% ± 14.8%, respectively. The expression of Sema3A significantly correlated with that of LMP1 (r = 0.41, = 0.014). In addition, the Sema3A high cohort showed significantly poorer prognosis than the Sema3A low cohort. Sema3A expression was higher in the LMP1-positive KH-1 and KR-4 cell lines compared to the LMP1-negative HeLa cells. Overexpression of LMP1 in the LMP1-negative AdAH cell line upregulated Sema3A expression, both at the transcriptional and translational level. Finally, Sema3A expression was associated with poor prognosis in patients with NPC. Our data suggest that LMP1 induces the expression of Sema3A, which may promote tumor progression in NPC.
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http://dx.doi.org/10.3390/microorganisms8030423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7143379PMC
March 2020

Bone invasion-targeted chemotherapy with a novel anionic platinum complex (3Pt) for oral squamous cell carcinoma.

Cancer Sci 2019 Oct 22;110(10):3288-3295. Epub 2019 Aug 22.

Division of Otolaryngology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.

Cisplatin (CDDP) is an important drug for chemotherapy in patients with head and neck squamous cell carcinoma. Nephrotoxicity and lack of an effect on bone invasion are limitations of CDDP. To increase its antitumor effect on bone invasion and reduce toxicity problems, anionic Pt complex (3Pt) has been developed. The present study aimed to characterize the basis of the cytotoxicity of the novel platinum complex 3Pt in comparison with that of CDDP for oral squamous cell carcinoma. The ionic platinum complex was prepared to increase solubility and avoid platinum nephrotoxicity. Furthermore, 3Pt was designed to target bone hydroxyapatite and has germinal bisphosphonate moieties for drug delivery. In vitro antitumor activity was assayed in two oral squamous cell carcinoma cell lines. To investigate the antitumor and nephrotoxic effects of 3Pt, nude mice with OSC-19 were given 3Pt and CDDP. The in vitro growth-inhibitory effect of 3Pt was significantly less than that of CDDP. However, both 3Pt and CDDP showed equivalent antitumor effects in vivo. Mice injected with CDDP developed renal cell apoptosis; however, those injected with 3Pt were almost free of renal cell injury. In addition to similar in vivo antitumor effects, 3Pt decreased the volume of bone resorption compared to that with CDDP in a bone invasion model using OSC-19. In conclusion, considering the potential advantages in terms of noticeable antitumor activity on bone invasion and reduced nephrotoxicity, 3Pt represents a significant improvement in the development of bone-targeting platinum drugs.
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http://dx.doi.org/10.1111/cas.14145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778662PMC
October 2019

Expression of estrogen receptor alpha is associated with pathogenesis and prognosis of human papillomavirus-positive oropharyngeal cancer.

Int J Cancer 2019 09 22;145(6):1547-1557. Epub 2019 Jun 22.

Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.

Human papillomavirus (HPV) has been identified as a causative agent of cervical cancer and oropharyngeal cancer (OPC). Intriguingly, estrogen and HPV were shown to play synergistic roles in cervical carcinogenesis. We recently demonstrated that the apolipoprotein B mRNA-editing catalytic polypeptide 3 (APOBEC3, A3) family, which is inducible by estrogen, could lead to HPV DNA hypermutation and cause viral DNA integration. In the present study, we examined the relationships between estrogen-estrogen receptor α (ERα) and A3s in HPV-positive OPC. ERα expression was associated with HPV positivity in OPC biopsy samples using immunohistochemical analysis and reverse-transcription quantitative polymerase chain reaction. In addition, ERα was significantly associated with improved overall survival in HPV-positive OPC (hazard ratio, 0.26; p = 0.029). APOBEC3A (A3A) mRNA was induced by estrogen in HPV and ERα-positive OPC cells. Furthermore, A3A mRNA and protein expression were significantly higher in ERα-positive cases than in ERα-negative ones, among HPV-positive biopsy samples (p = 0.037 and 0.047). These findings suggest that A3A is associated with a good prognosis in ERα-positive OPC, and indicate the prognostic significance of ERα in HPV-positive OPC. This is the first study to demonstrate the prognostic role of ERα in HPV-positive OPC.
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http://dx.doi.org/10.1002/ijc.32500DOI Listing
September 2019

Detection of sentinel lymph node using contrast-enhanced agent, Sonazoid, and evaluation of its metastasis with superb microvascular imaging in oral and oropharyngeal cancers: a preliminary clinical study.

Acta Otolaryngol 2019 Jan 24;139(1):94-99. Epub 2019 Jan 24.

a Department of Otolaryngology, and Head & Neck Surgery , Kanazawa University , Kanazawa , Japan.

Background: In sentinel lymph node (SLN) biopsy for head and neck cancers, the radioisotope method has been the gold standard. However, this method has several problems, such as unavoidable radiation exposure and requirements of expensive equipment.

Aims/objectives: To overcome these problems, we evaluated the contrast-enhanced ultrasonography (CEUS)-guided SLN-detection method, and predicted the SLN metastatic status using novel ultrasound technology, superb microvascular imaging (SMI).

Methods: Ten patients (6 with oral and 4 with oropharyngeal cancers) without neck lymph node metastasis were enrolled in this study. Ultrasound contrast agent, Sonazoid, was infiltrated into the mucosa at the primary site to observe the lymphatic ducts and SLNs in the neck field. The detected SLNs were examined for blood flow using SMI to categorize the SLNs metastases-positive or negative.

Results: SLNs were successfully detected in 8 out of 10 cases. In 7 out of the 8 cases, in whom SLNs were successfully detected, the metastatic status of SLNs was correctly diagnosed with SMI.

Conclusions And Significance: Although more clinical data are needed based on a larger cohort, establishing the CEUS-guided SLN-detection and criteria for the accurate diagnosis of SLN-metastases using SMI would be valuable as an alternative to radioisotope method, in oral and oropharyngeal cancers.
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http://dx.doi.org/10.1080/00016489.2018.1535193DOI Listing
January 2019

Inhibition of autophagy by chloroquine makes chemotherapy in nasopharyngeal carcinoma more efficient.

Auris Nasus Larynx 2019 Jun 2;46(3):443-450. Epub 2018 Dec 2.

Division of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan. Electronic address:

Objectives: A combination of platinum-based chemotherapy and radiotherapy is the standard treatment for nasopharyngeal carcinoma (NPC). However, the efficacy of chemotherapy has reached a plateau. Many autophagy studies suggest that autophagy can either promote or suppress to cancer progression. Thus, a role of autophagy in the acquisition of chemoradioresistance has recently been a notable event. Therefore, we examined the relationship between autophagy and chemotherapy in NPC.

Methods: The expression of Beclin 1 and microtubule-associated protein light chain 3 (LC3), a marker of autophagy, was determined by immunohistochemistry in the biopsy samples of patients with NPC before and after the first course of chemotherapy. Additionally, to investigate in the effect of autophagy suppression in chemotherapy, NPC cell line C666-1 cells were treated with cisplatin and/or chloroquine, an inhibitor of autophagy.

Results: The expression of Beclin 1 increased after chemotherapy in all patients. In NPC cell line C666-1, compared to cisplatin alone, combination therapy (cisplatin and chloroquine) reduced cell viability, and promoted cell apoptosis.

Conclusions: These results suggest that autophagy, represented by Beclin 1, is upregulated after chemotherapy in both in vitro and in vivo NPC studies. Inhibition of autophagy could therefore be new strategy for NPC treatment.
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http://dx.doi.org/10.1016/j.anl.2018.10.013DOI Listing
June 2019

Effects of l-carnitine administration on health-related quality of life during cisplatin-based chemoradiotherapy in patients with head and neck squamous cell carcinoma.

Auris Nasus Larynx 2019 Jun 12;46(3):431-436. Epub 2018 Nov 12.

Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa 920-8640, Japan.

Objectives: Cancer-related fatigue impairs daily functioning and negatively impacts health-related quality of life (HRQoL). Our previous study revealed that cisplatin-based chemoradiotherapy (CRT) impairs the carnitine system and carnitine deficiency leads to poor physical functioning. This open label, randomized, controlled prospective study investigated the effects of l-carnitine administration on plasma carnitine concentration, CRT-induced fatigue, and decline in HRQoL in patients with head and neck squamous cell carcinoma (HNSCC).

Methods: Patients were divided into experimental group (received 1000mg of oral liquid l-carnitine once daily for 8 weeks) and control group. The primary and secondary endpoints were the change in HRQoL scores and the change in carnitine levels, respectively, from baseline (pre-CRT) to after CRT.

Results: The mean total plasma carnitine concentration in the control group decreased significantly, 2 weeks after the end of chemotherapy, while no significant differences were seen in the l-carnitine group. l-carnitine administration, therefore, kept the physical functioning score unchanged.

Conclusion: Our study shows that patients who receive CRT experience chemotherapy-induced damage of carnitine homeostasis leading to deficiency of carnitine and impairment of HRQoL. l-carnitine administration is beneficial in improving the HRQoL in patients with HNSCC.
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http://dx.doi.org/10.1016/j.anl.2018.10.007DOI Listing
June 2019

[V. Supportive Management in Head and Neck Cancer - Current Status and Future Perspectives].

Gan To Kagaku Ryoho 2018 Jul;45(7):1061-1064

Dept. of Otolaryngology, Head and Neck Surgery, Graduate School of Medical Science Kanazawa University.

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July 2018

Expression and subcellular localisation of AID and APOBEC3 in adenoid and palatine tonsils.

Sci Rep 2018 01 17;8(1):918. Epub 2018 Jan 17.

Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.

Activation-induced cytidine deaminase (AID) and apolipoprotein B mRNA-editing catalytic polypeptide 3 (A3) family are cytidine deaminases that play critical roles in B-cell maturation, antiviral immunity and carcinogenesis. Adenoids and palatine tonsils are secondary lymphoid immune organs, in which AID and A3s are thought to have several physiological or pathological roles. However, the expression of AID or A3s in these organs has not been investigated. Therefore, we investigated the expression profiles of AID and A3s, using 67 samples of adenoids and palatine tonsils from patients, with reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical analyses. AID and A3s expression levels in the adenoids and the palatine tonsils of the same individual significantly correlated with each other. Of note, AID expression level in the adenoids negatively correlated with the age (r = -0.373, P = 0.003). The younger group with adenoid vegetation and tonsillar hypertrophy showed more abundant AID expression than the older group with recurrent tonsillitis and peritonsillar abscesses (P = 0.026). Moreover, immunohistochemical analysis revealed the distribution of AID and A3s in the epithelial cells as well as germinal centres. The localisation of AID expression and its relation to age may contribute to adenoid vegetation and inflammation.
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http://dx.doi.org/10.1038/s41598-017-18732-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772672PMC
January 2018

Modulation of the tumor microenvironment by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma.

Cancer Sci 2018 Feb 21;109(2):272-278. Epub 2018 Jan 21.

Department of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.

Latent membrane protein 1 (LMP1) is a primary oncogene encoded by the Epstein-Barr virus, and various portions of LMP1 are detected in nasopharyngeal carcinoma (NPC) tumor cells. LMP1 has been extensively studied since the discovery of its transforming property in 1985. LMP1 promotes cancer cell growth during NPC development and facilitates the interaction of cancer cells with surrounding stromal cells for invasion, angiogenesis, and immune modulation. LMP1 is detected in 100% of pre-invasive NPC tumors and in approximately 50% of advanced NPC tumors. Moreover, a small population of LMP1-expressing cells in advanced NPC tumor tissue is proposed to orchestrate NPC tumor tissue maintenance and development through cancer stem cells and progenitor cells. Recent studies suggest that LMP1 activity shifts according to tumor development stage, but it still has a pivotal role during all stages of NPC development.
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http://dx.doi.org/10.1111/cas.13473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797826PMC
February 2018

Multifocal human papillomavirus detection in palatine and pharyngeal tonsils.

Acta Otolaryngol 2018 May 29;138(5):483-486. Epub 2017 Nov 29.

b Department of Otolaryngology-Head and Neck Surgery , Kanazawa University , Kanazawa , Japan.

Background: Multifocal human papillomavirus (HPV) infection into the palatine and pharyngeal tonsils, which might be linked to a second primary tumor of HPV-positive oropharyngeal cancer (OPC), was investigated.

Patients And Methods: One hundred and five patients with various head and neck diseases including 14 patients with OPC were enrolled in this study. Swabs from the palatine and pharyngeal tonsils were collected in each individual, and auto-nested GP5+/GP6+ PCR for HPV DNA was performed.

Results: HPV DNA was detected in the palatine tonsil or the pharyngeal tonsil in a small subset of upper respiratory tract cancer other than OPC (URTC) and non-cancer diseases. Furthermore, HPV DNA was detected in both the palatine and pharyngeal tonsils in the same individual in 2 of 48 (4%) URTC cases, and 1 of 43 (2%) non-cancer cases. On the other hand, p16-positive OPC cases demonstrated a higher HPV DNA detection rate (4 of 9, 44.4%) compared with other disease groups.

Conclusion: HPV DNA detection in both the palatine and pharyngeal tonsils in the same individual, especially in HPV-OPC, suggested the ability of HPV to infect tonsillar tissues of Waldeyer's ring multifocally.
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http://dx.doi.org/10.1080/00016489.2017.1408143DOI Listing
May 2018

Progression of understanding for the role of Epstein-Barr virus and management of nasopharyngeal carcinoma.

Cancer Metastasis Rev 2017 09;36(3):435-447

Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8640, Japan.

Nasopharyngeal carcinoma (NPC) is very common in southern China and Southeast Asia. In regions where NPC is endemic, undifferentiated subtypes constitute most cases and are invariably associated with Epstein-Barr virus (EBV) infection, whereas the differentiated subtype is more common in other parts of the world. Undifferentiated NPC is a unique malignancy with regard to its epidemiology, etiology, and clinical presentation. Clinically, NPC is highly invasive and metastatic, but sensitive to both chemotherapy and radiotherapy (RT). Overall prognosis has dramatically improved over the past three decades because of advances in management, including the improvement of RT technology, the broader application of chemotherapy, and more accurate disease staging. Despite the excellent local control with modern RT, distant failure remains a challenging problem. Advances in molecular technology have helped to elucidate the molecular pathogenesis of NPC. This article reviews the contribution of EBV gene products to NPC pathogenesis and the current management of NPC.
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http://dx.doi.org/10.1007/s10555-017-9693-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613035PMC
September 2017

Expression of interferon regulatory factor 7 correlates with the expression of Epstein-Barr Virus latent membrane protein 1 and cervical lymph node metastasis in nasopharyngeal cancer.

Pathol Int 2017 Sep 16;67(9):461-466. Epub 2017 Jul 16.

Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.

Interferon regulatory factor 7 (IRF7) has oncogenic properties in several malignancies such as Epstein-Barr virus (EBV)-associated lymphoma. However, there is no evidence whether IRF7 is associated with the oncogenesis of nasopharyngeal cancer (NPC), the pathogenesis of which is closely associated with EBV. Herein, we report that expression of IRF7 was increased in normal nasopharyngeal cells that expressed the EBV principal oncoprotein, latent membrane protein 1 (LMP1). In addition, IRF7 was mainly expressed in the nucleus in both normal nasopharyngeal cells and nasopharyngeal cancer cells that expresses LMP1. On immunohistochemical analysis, IRF7 was predominantly localized in the nucleus in biopsy samples of NPC tissues. In total, IRF7 expression was detected with 36 of 49 specimens of these tissues. Furthermore, the expression score of IRF7 correlated with the expression score of LMP1. Moreover, the expression score of IRF7 is associated with cervical lymph-node metastasis, which reflects the highly metastatic nature of this cancer. Taken together, our results suggest that expression of IRF7 is one of the metastatic effectors of LMP1 signalling in EBV-associated NPC.
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http://dx.doi.org/10.1111/pin.12561DOI Listing
September 2017

Usefulness of human papillomavirus detection in oral rinse as a biomarker of oropharyngeal cancer.

Acta Otolaryngol 2017 Jul 17;137(7):773-777. Epub 2017 Jan 17.

a Department of Otolaryngology-Head and Neck Surgery , Kanazawa University , Kanazawa , Japan.

Conclusion: The detection of human papillomavirus (HPV)-DNA in oral rinse with auto-nested GP5+/GP6 + PCR is useful as a biomarker of oropharyngeal cancer.

Background: This study aimed to determine the usefulness of oral rinse to detect HPV-DNA as a biomarker of HPV-positive oropharyngeal cancer (OPC).

Patients And Methods: One hundred and ten patients with various head and neck diseases, including 19 patients with OPC, were enrolled. Oral rinse and tonsillar swab were collected, and auto-nested GP5+/GP6 + PCR for HPV-DNA was performed. For oropharyngeal cancer, p16 immunostaining was also conducted.

Results: The rate of HPV-DNA detection in both oral rinse and tonsillar swab was significantly higher in OPC compared with non-OPC upper respiratory tract cancer and non-cancer diseases. HPV-DNA was detected in oral rinse in nine out of 12 p16-positive OPC cases, while none of the p16-negative OPC cases demonstrated detectable HPV-DNA. All p16-positive cases were also positive for HPV-DNA in tumor tissue. Based on p16 immunostaining, the sensitivity and specificity of HPV-DNA detection in oral rinse were 75% and 100%, respectively. Among eight of nine evaluable OPC cases positive for HPV-DNA in oral rinse at diagnosis, HPV-DNA was undetectable in oral rinse in seven cases after treatment.
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http://dx.doi.org/10.1080/00016489.2016.1274426DOI Listing
July 2017

EBV infection is prevalent in the adenoid and palatine tonsils in adults.

J Med Virol 2017 06 5;89(6):1088-1095. Epub 2016 Dec 5.

Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.

Epstein-Barr virus (EBV) is associated with the pathogenesis of several diseases in both adults and children. However, there have been no reports on the prevalence and amount of EBV in the adenoids of adults; thus, it is important to investigate these in the adenoids and tonsils of adults and children. In this study, 67 patients who underwent tonsillectomy or adenotonsillectomy were included and divided into two groups: adults aged ≥ 16 years (n = 35) and children aged <16 years (n = 32). Patients' adenoid and tonsil tissues were analyzed using quantitative polymerase chain reaction for EBV DNA. EBV was detected in 26 (74%) adenoids and 25 (71%) tonsils among the adult group and was detected 21 (66%) adenoids and 20 (63%) tonsils in the child group. There was no significant difference in EBV DNA prevalence between the adenoids and tonsils for each group. However, there was a significant correlation between EBV DNA load in the adenoids and tonsils of the same individual in both groups (r = 0.579, P < 0.01, adult group; r = 0.919, P < 0.01, child group). In conclusion, EBV infection is prevalent in the adenoids and tonsils in adults and children. These results indicate that EBV continuously reside in the nasopharyngeal region after primal infection and may develop several diseases.
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http://dx.doi.org/10.1002/jmv.24737DOI Listing
June 2017

Potential Interest in Circulating miR-BART17-5p As a Post-Treatment Biomarker for Prediction of Recurrence in Epstein-Barr Virus-Related Nasopharyngeal Carcinoma.

PLoS One 2016;11(9):e0163609. Epub 2016 Sep 29.

Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, Kanazawa, 920-8640, Japan.

Objectives: Epstein-Barr virus (EBV)-related micoRNAs (miRNAs), BamHI-A rightward transcripts (BART)-miRNAs, are released in a stable form from viable cells, which are abundant in patients with EBV-positive nasopharyngeal carcinoma (NPC). We estimated copy numbers of circulating miR-BART2-5p, miR-BART17-5p, and miR-BART18-5p as well as BamHI-W DNA as biomarkers.

Materials And Methods: Serums from 31 EBV-positive (confirmed by in situ hybridization for EBV-encoded small RNAs) NPC patients and 40 non-NPC controls were analyzed. Among the 31 NPC patients, serums at the initial diagnosis and three months after treatment were obtained from 20 patients, and serums only at three months after treatment were obtained from 11 patients.

Results: The sensitivity/specificity of circulating BamHI-W DNA, miR-BART2-5p, miR-BART17-5p, and miR-BART18-5p for the diagnosis of NPC before treatment were 100 / 100, 85 / 85, 60 / 95, and 25 / 100%, respectively. For BamHI-W DNA, NPC patients with stage IV disease had significantly higher copy numbers than those with I-III. Copy numbers decreased significantly post-treatment. In contrast, copy numbers of the three BART-miRNAs showed no significant correlation with the clinical stage at diagnosis or any significant post-treatment change. After treatment, BamHI-W DNA and miR-BART17-5p were detected in 5 and 6 cases out of 11 patients with recurrent or residual tumors, respectively. However, BamHI-W DNA and miR-BART17-5p were absent in all 20 patients without relapse or residual tumors.

Conclusion: The copy number of circulating BamHI-W DNA is a more useful biomarker for the initial diagnosis of NPC than the three BART-miRNAs examined. Post-treatment detection of miR-BART17-5p is a potential biomarker of a poor prognosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163609PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042478PMC
September 2016

Siah-1 is associated with expression of hypoxia-inducible factor-1α in oral squamous cell carcinoma.

Auris Nasus Larynx 2017 Apr 8;44(2):213-219. Epub 2016 Sep 8.

Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan. Electronic address:

Objective: Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of the HIF-1α and HIF-1β subunits. HIF-1 is a central regulator of responses to hypoxia; it enhances metastasis-related factors such as matrix metalloproteinases and vascular endothelial growth factor (VEGF). We have reported critical roles for HIF-1α in tumor microenvironments, and oncogenic properties of HIF-1α have been suggested in malignancies. Seven in absentia homologue (Siah) appeared to upregulate HIF-1 production, which prompted us to investigate the Siah association with HIF-1α expression in oral squamous cell carcinoma (OSCC).

Methods: Samples from fifty-five patients with OSCC were evaluated by immunohistochemistry for the protein expressions of Siah-1 and -2, HIF-1α, and VEGF. The expression levels of each protein and clinicopathological data were statistically analyzed.

Results: Siah-1 and, Siah-2, HIF-1α, and VEGF were immunolocalized on the cell membranes and cytoplasm of the tumor cells. The expression of Siah-1 showed a linear dependence on the expression of HIF-1α (r=0.627, p<0.001). In 17 cases of the large tumor size category (T3 and 4), the mean Siah-1 expression score was significantly higher than in 41 cases of the small tumor size category (T1 and 2; p=0.001). In addition, in 16 cases of the lymph node metastasis-positive category (N1-3), the mean Siah-1 expression score was significantly higher than that in 42 cases of the lymph node metastasis-negative category (N0, p=0.001).

Conclusion: These results suggested that the expressions of Siah-1 and HIF-1α were clearly correlated in OSCC. Moreover, Siah-1 appears to be correlated with clinicopathological data, particularly tumor size.
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http://dx.doi.org/10.1016/j.anl.2016.06.007DOI Listing
April 2017

The influence of human papillomavirus on nasopharyngeal carcinoma in Japan.

Auris Nasus Larynx 2017 Jun 4;44(3):327-332. Epub 2016 Aug 4.

Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan.

Objective: Although Japan is a non-endemic area with nasopharyngeal carcinoma (NPC), the proportion of WHO type I NPC in Japan are different from that in non-endemic areas such as North America and Europe. Recently, it is said that not only Epstein-Barr virus (EBV) but also human papillomavirus (HPV) has an influence on NPC in non-endemic areas. The aim of this study is to clarify the influence of HPV on NPC in Japan.

Methods: Paraffin-embedded tumor specimens were available for 59 patients with NPC diagnosed between 1996 and 2015. We detected the virus status by p16 immunohistochemistry, HPV PCR, and in situ hybridization for Epstein-Barr virus (EBV)-encoded RNA. Kaplan-Meier curves were used to compare the overall survival by viral status.

Results: Among the 59 patients, 49 (83%) were EBV-positive/HPV-negative, 2 (3%) were EBV-positive/HPV-positive, and 8 (16%) were EBV-negative/HPV-negative. All HPV-positive NPCs were co-infected with EBV. There were no significant differences between the overall survival in the three groups (p=0.111).

Conclusion: In Japan, HPV was detected in a few patients with NPC, and we suggest that HPV has no influence on NPC carcinogenesis in this population.
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http://dx.doi.org/10.1016/j.anl.2016.07.015DOI Listing
June 2017

[Pharyngoesophageal Reconstruction Using a Laryngotracheal Flap Following Resection for Hypopharyngeal Cancer].

Nihon Jibiinkoka Gakkai Kaiho 2016 Jun;119(6):880-5

We used hemilaryngotracheal tissue without tumor involvement as a laryngotracheal flap (LTF) for immediate repair of a pharyngoesophageal defect following resection for hypopharyngeal cancer. Five cases of lateralized advanced hypopharyngeal cancer were treated in our department. The median age was 82 years, ranging from 64 to 90 years. Four tumors were T3 stage, and the other was T2. A pharyngocutaneous fistula developed in one patient. The postoperative swallowing function was satisfactory, but one patient developed difficulty in eating a normal diet, because of pharyngoesophageal stenosis at 7 months after chemoradiotherapy. During the follow-up period, there was no locoregional recurrence. One patient had lung metastasis, and died of the disease. One patient died of another cause. Three patients are alive without evidence of the disease. Reconstruction of the hypopharynx with an LTF is a minimally invasive method compared with the radial forearm free flap and free jejunal flap. For selected cases of advanced hypopharyngeal cancer, this method would be one of the choices to reconstruct the pharyngoesophageal defect.
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June 2016

T-status and an oral fluoropyrimidine, S-1, adjuvant chemotherapy are prognostic factors in reduced-RADPLAT for resectable hypopharyngeal cancer.

Acta Otolaryngol 2016 Aug 23;136(8):834-40. Epub 2016 Mar 23.

a Division of Otolaryngology-Head and Neck Surgery , Graduate School of Medical Science, Kanazawa University , Kanazawa , Japan.

Conclusion: Reduced-RADPLAT for HPC achieved comparative survival and locoregional control rates with lower toxicities compared with concurrent chemoradiotherapies including original RADPLAT. S-1 adjuvant chemotherapy showed a survival benefit.

Objectives: To evaluate the efficacy and toxicities of targeted intra-arterial (IA) infusion of cisplatin with concurrent radiotherapy with a reduced dose (reduced-RADPLAT) for resectable hypopharyngeal cancer (HPC).

Methods: Between 1999-2012, 50 patients with stage II-IVA HPC primarily treated by reduced-RADPLAT were analyzed. They were treated by 2-5 courses of IA cisplatin infusion (100 mg per body) with simultaneous systemic infusion of sodium thiosulfate concurrent with conventional radiotherapy (66-70 Gy). After 2003, S-1, an oral fluoropyrimidine, adjuvant chemotherapy was administered to all eligible patients.

Results: During a median follow-up of 48.6 months, the estimated 3- and 5-year overall survival (OS), progression-free survival (PFS), locoregional control, and laryngoesophageal dysfunction-free survival (LEDFS) rates were 76.0% and 62.0%, 58.0% and 50.0%, 66.0% and 62.0%, and 56.0% and 54.0%, respectively. Grade 3 toxicities were observed in 30.0%. No patient had grade 4 or higher toxicities. No patient required tube feeding or tracheotomy at 3 months after treatment. T4-lesions and S-1 administration were significant factors predicting poor and good OS, PFS, and LEDFS, respectively.
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http://dx.doi.org/10.3109/00016489.2016.1157728DOI Listing
August 2016

Intralesional cidofovir injection for recurrent respiratory papillomatosis in Japan.

Auris Nasus Larynx 2016 Oct 6;43(5):541-5. Epub 2016 Feb 6.

Department of Otolaryngology, Head and Neck Surgery, School of Medicine, Kanazawa University, Japan.

Objective: The treatment of recurrent respiratory papillomatosis (RRP) continues to be difficult. Adjuvant pharmacological treatment is increasingly being used, and intralesional cidofovir injection remains the leading option. Almost all papers regarding the treatment come from the United States and Europe. The present study demonstrated it for the first time from Asia.

Methods: Ten patients with RRP were treated with intralesional cidofovir injection. The severity of papillomatosis and adverse events including blood leukocytes, blood neutrophils, and serum creatinine were evaluated before and after the completion of treatment.

Results: Human papillomavirus (HPV) type 6 was detected in nine patients, and no types of HPV were detected in a remaining patient. Severity scores significantly improved after treatment (p=0.005). However, complete resolution was achieved in only one patient. No significant differences were observed between before and after treatment with respect to adverse events (p=0.866 for blood leukocytes, p=0.866 for blood neutrophils, and p=0.933 for serum creatinine). Squamous cell carcinoma occurred three and half years after the completion of treatment in a patient without HPV detection. However, the link between cidofovir and the occurrence of carcinoma in the case remains questionable.

Conclusion: This initial report of intralesional cidofovir injection for RRP from Asia demonstrated acceptable efficacy without obvious adverse events. However, the uncontrolled spread of this treatment should be avoided, and eighteen statements approved by the task force of the United States should be referred to while planning this treatment.
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http://dx.doi.org/10.1016/j.anl.2016.01.005DOI Listing
October 2016

Primary Tumor-Secreted Lymphangiogenic Factors Induce Pre-Metastatic Lymphvascular Niche Formation at Sentinel Lymph Nodes in Oral Squamous Cell Carcinoma.

PLoS One 2015 2;10(12):e0144056. Epub 2015 Dec 2.

Division of Otolaryngology, and Head & Neck Surgery, Kanazawa University, Kanazawa, Ishikawa, Japan.

Objectives: The objectives of this study were to evaluate the formation of lymphvascular niches in lymph nodes of patients with oral squamous cell carcinoma (OSCC), and investigate the roles of lymphangiogenic and angiogenic factors, such as vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D, expressed in the primary tumors.

Materials And Methods: Forty-four patients with previously untreated clinically late T2 or T3 OSCC of cN0 were evaluated for primary tumors and 166 sentinel lymph nodes (SLNs). Primary tumors were immunohistochemically analyzed for expressions of VEGFs. Densities of lymphatic vessels (LVDpodoplanin) and high endothelial venules (HEVD) in the SLNs were also calculated using antibodies for each marker, podoplanin and MECA-79, respectively.

Results: In 25 patients, all lymph nodes were metastasis-negative, whereas, in 19 patients, metastasis was positive for at least one lymph node (either at SLN, non-SLN, or nodal recurrence). From the analyses of 140 SLNs without metastasis, LVDpodoplanin in 50 SLNs of metastasis-positive cases was significantly higher than that in 90 SLNs of metastasis-negative cases (p = 0.0025). HEVD was not associated with lymph node metastasis. The patients with VEGF-A-High or VEGF-D-High tumors had significantly higher LVDpodoplanin than patients with their Low counterparts (p = 0.0233 and p = 0.0209, respectively). In cases with lymph node metastasis, the VEGF-D-expression score was significantly higher than in those without lymph node metastasis (p = 0.0006).

Conclusions: These results suggest that lymph node lymphangiogenesis occurs before metastasis in OSCC. VEGF-A and VEGF-D play critical roles in this process. VEGF-D is a potential predictive marker of positive lymph node metastasis in cN0 patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144056PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668078PMC
June 2016

Expression of secreted protein acidic and rich in cysteine is an independent prognostic indicator of a poor clinical outcome in oropharyngeal carcinoma patients.

Acta Otolaryngol 2016 2;136(2):189-94. Epub 2015 Nov 2.

a Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science , Kanazawa University , Kanazawa , Japan.

Conclusion: SPARC-expression is an indicator of the prognosis in terms of OS, independent of HPV-infection. HPV-negative patients with SPARC-Low show survival as favorable as HPV-positive patients, probably because of their higher salvage rate after relapse than SPARC-High patients.

Objective: The objectives of the study were to clarify the correlation between the expression of secreted protein acidic and rich in cysteine (SPARC) and HPV-status, and to determine the prognostic value of SPARC-expression in oropharyngeal squamous cell carcinoma (OPSCC) patients.

Methods: Fifty-three formalin-fixed and paraffin-embedded tissues were obtained from patients with OPSCC who underwent curative treatment. The SPARC protein was detected by immunohistochemistry. SPARC-expression level was divided into two categories, SPARC-High and SPARC-Low, according to the staining index.

Results: Twenty-two out of the 53 OPSCC patients were HPV-positive. There was no significant correlation between the HPV-status and SPARC-expression level. Multivariate Cox proportional hazards regression analysis revealed that the HPV-status and SPARC-expression are independent prognostic indicators of favorable and unfavorable overall survival (OS) (p = 0.021 and p = 0.012), respectively. For disease-free survival, the HPV-status was the only predictive factor (p = 0.022). After stratification by the HPV-status, high SPARC-expression was a significant predictor of poor OS in HPV-negative OPSCC patients using Kaplan-Meier analysis and the log-rank test (p = 0.014). Ten out of 28 SPARC-Low patients relapsed, among which six patients (60%) were salvaged. However, 14 out of 25 SPARC-High patients relapsed, and only three patients (21.4%) were salvaged.
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http://dx.doi.org/10.3109/00016489.2015.1103381DOI Listing
October 2016

IL-18 is highly expressed in inflammatory infiltrates of submandibular glands in patients with immunoglobulin G4-related disease.

Hum Pathol 2015 Dec 24;46(12):1850-8. Epub 2015 Aug 24.

Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan. Electronic address:

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a new disease entity characterized by high serum IgG4 concentrations, infiltration of IgG4-positive plasmacytes, and fibrosis of various organs. Several groups have reported that IgG4-RD is a unique inflammatory disorder characterized by an immune reaction predominantly mediated by T helper (Th) 2 and regulatory T cells. Meanwhile, recent studies have demonstrated that interleukin (IL) 18 has a potential to trigger the production of Th2 cytokines by Th1 cells. We analyzed IL-18 expression in submandibular glands of patients with IgG4-RD (20 cases) and controls (19 cases) by immunohistochemical analysis and quantitative real-time reverse-transcription polymerase chain reaction. We found that IL-18 was highly expressed in submandibular glands of patients with IgG4-RD than in controls with both protein (P < .05, χ(2) test) and messenger RNA levels (P < .05, Mann-Whitney U test). In addition, the expression of IL-18 and IL-13 was correlated in submandibular glands of patients with IgG4-RD. Moreover, by analyzing dual immunofluorescence staining, a few numbers of cells were double positive for IL-13 and interferon γ at the inflammatory infiltrates of submandibular glands of patients with IgG4-RD. These data suggest a possibility that IL-13 is produced by Th1 cells. We speculated that IL-18 stimulates Th1 cells producing Th2 cytokines and enhances the immune reaction of Th2 cytokines in pathogenesis of IgG4-RD.
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http://dx.doi.org/10.1016/j.humpath.2015.08.002DOI Listing
December 2015
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