Laryngeal granuloma in experimental rats with gastroesophageal reflux disease and mechanically injured vocal cord mucosa.

OBJECTIVE: This study was undertaken to elucidate the mechanisms underlying laryngeal granuloma formation in a rat model of gastroesophageal reflux disease (GERD) with mechanically injured vocal cord mucosa. METHODS: The rat model of GERD was surgically created by tying the pyloric sphincter and ligating the transitional region between the forestomach and the glandular portion (limiting ridge). The control rats received only a midline incision. In all the animals, a plastic bar was inserted into the trachea, and moved vertically thrice in 3 seconds to cause mechanical injury of the vocal cord mucosa. The rats were sacrificed 2 weeks postsurgically, and their pharynx and larynx were observed histologically. RESULTS: Granulomas were observed in the vocal cord mucosa of the GERD group (3 of 5 animals); they presented a similar pathological structure to that of human laryngeal granulomas. In contrast, only abrasions and blisters were observed on the vocal cord mucosa in the control group (all 5 animals). CONCLUSIONS: The development of laryngeal granuloma may involve both mechanical injury and gastric acid reflux.

Innate immune reactions in locally limited tonsillar cancer.

Tonsillar cancers often present as locally limited tumors but with cervical metastases. When the primary tumors of tonsillar cancers with cervical metastases are as small as clinically occult, the clinical features are diagnosed as primary-unknown cervical metastases. However, little is known as to why small tonsillar cancers establish cervical metastases. The aim of this study was to investigate a possibility that innate immune reactions might suppress the growth of tumors arising in the palatine tonsils, because the palatine tonsils contain various immune effector cells. Infiltration of natural killer (NK) cells and macrophages, which are major innate immune cells, in surgically removed tumors from patients with locally limited tonsillar cancers and tongue cancers was immunohistochemically studied by using anti-CD57 and anti-CD68 antibodies. Phagocytosis of the tumor cells by macrophages was also studied by dual immunofluorescence labeling. The number of infiltrating CD57+ NK cells and CD68+ macrophages was significantly increased in locally limited tonsillar cancers in comparison to normal tonsils and tongue cancers. The phagocytosis of tumor cells by CD68+ macrophages was observed significantly more frequently in tonsillar cancers than in tongue cancers. These results indicated that the innate immune reactions were more strongly induced in locally limited tonsillar cancers than in tongue cancers, and might therefore suppress the growth of primary tumors in palatine tonsils. The innate immune reactions against cancers in palatine tonsils were suggested to be one of the possible etiologies for the developing of primary-unknown cervical metastases.

[A comparative study of concurrent chemoradiotherapy with S-1 or CDDP for pharyngeal or laryngeal cancer].

Adverse events and therapeutic effects were analyzed in patients with pharyngeal or advanced laryngeal squamous cell carcinomas(SCCs)receiving concurrent chemoradiotherapy (CCRT) with S-1 or weekly CDDP between 2004 and 2007. Low-dose CDDP (25 mg/m2) was administered once a week and S-1 (65 mg/m2) was administered for 3 weeks with one-week rest during conventional radiation with 2 Gy/fraction. Both of the two CCRT regimens showed little toxicity with grade 4 toxicities in less than 5%of the patients. However, CCRT with S-1 more frequently induced grade 3 and 4 oral mucositis than CCRT with CDDP. As a result, the completion rate of CCRT with S-1 was lower than that of CCRT with CDDP. The two regimens achieved a similar complete response rate of the primary sites, local control rate(LCR)and larynx preservation rate; the LCR for T1 and 2 disease was more than 70%. However, the LCR for T3 or 4 disease by the two regimens was less than 50%. CCRT with S-1 showed significantly higher LCR in patients with poorly or undifferentiated SCCs than those with well or moderately-differentiated SCCs. It is suggested that the two CCRT regimens are useful treatment modalities for patients with locally(primary site)non-advanced pharyngeal or laryngeal SCCs, and that CCRT with S-1 is highly sensitive to poorly or undifferentiated SCCs. In order to achieve local control and larynx preservation, more intensive CCRT might be necessary for patients with locally(primary site)advanced pharyngeal or laryngeal SCCs.

[Cepharanthin effect on radiation-induced xerostomia and taste disorder in patients with head and neck cancer].

In evaluating the effect of cepharanthin on xerostomia and taste disorder in 40 patients undergoing radiotherapy for head and neck cancer, we administered cepharanthin intravenously during chemoradiotherapy to 22 patients, with 18 others as a control group. Cepharanthin did not significantly affect salivary secretion during and after chemoradiotherapy, although taste disorder and oral discomfort were alleviated. Cepharanthin may thus be effective in maintaining the quality of life of patients with head and neck cancer.

Dental and oropharyngeal lesions in rats with chronic acid reflux esophagitis.

OBJECTIVE: In this study, we evaluated pathological changes in the tooth and pharynx of GERD rats to elucidate the association between gastric acid reflux and oral and pharyngeal diseases. METHODS: An experimental rat model of chronic acid reflux esophagitis was surgically created. The oral cavities were observed histologically every 2 weeks until 20 weeks after surgery. RESULTS: At 10 weeks after surgery, molar crown heights in GERD rats were shorter than that in control rats, and inflammatory cell infiltration by gastric acid reflux was found in the periodontal mucosa of GERD rats. Furthermore, dental erosion progressed in GERD rats at 20 weeks after surgery, and enamel erosion and dentin exposure were observed. During the same period, inflammatory cell infiltration was observed in the mucosa of the posterior part of the tongue. These findings suggest that gastric acid reflux may be one of the exacerbating factors of dental erosion, periodontitis and glossitis. CONCLUSION: We investigated oral changes in an experimental rat model of GERD and observed development of dental erosion, periodontitis and glossitis. Our findings suggested chronic gastric acid reflux may be involved in the pathogenesis of oral disease.

Didactic surgical experience of thyroid metastasis from renal cell carcinoma: A case report.

BACKGROUND: The optimal therapeutic strategy in treating thyroid metastasis from renal cell carcinoma (RCC) has not been clearly established. Here we describe a case of didactic surgical experience of the disease which caused massive intraoperative bleeding. CASE SUMMARY: A 59-year-old male patient presented with a thyroid left lobe soft mass detected by chest computed tomography scans prior to the surgical treatment of RCC of the left kidney. The thyroid mass was initially considered to be benign, then he underwent left radical nephrectomy. One year after the nephrectomy, stereotactic radiosurgery was performed for brain metastasis. During follow-up, the thyroid nodule gradually grew, and the patient manifested swallowing discomfort. Under a clinical diagnosis of thyroid follicular neoplasm, left hemithyroidectomy was performed. Although hemithyroidectomy is usually a safe and straightforward procedure, massive bleeding from markedly developed tumor vessels made the operation very difficult. The thyroid tumor was finally diagnosed as metastasis from clear cell RCC. CONCLUSION: For proper timing of the surgery, a clinician should take into consideration the possibility of thyroid metastasis of RCC when a thyroid lesion is found in patients with RCC or in patients with a previous history of RCC. We recommend that thyroid metastasis of RCC should be resected as early as possible even if a patient has other metastatic sites.

A case of an upper cervical bronchogenic cyst in an adult.

We herein report a case of a rare cervical cystic lesion, namely a congenital bronchogenic cyst, which presented as an asymptomatic upper cervical mass in a 22-year-old female. Although cervical bronchogenic cysts are rare lesions in adults which are very difficult to accurately diagnose preoperatively, they deserve inclusion in the differential diagnosis of cervical cystic lesions.

[Blood concentration of laminin gamma2 chain in patients with head and neck cancer].

Laminin gamma2 chain (LN gamma2), expressed in human cancer cells and correlated with cancer malignancy, is cleaved by proteases and secreted into circulation. We measured the blood concentration of LN gamma2 in patients with head and neck cancer by an immuno-fluorescence assay using monoclonal antibodies against human LN gamma2. The normal blood concen- showed normal LN gamma2 concentration less than 50 ng/ml and 20 (33%) increased concentration exceeding 50 ng/ml. The relative ratio of the number of patients who showed increased LN gamma2 concentration correlated with the clinical stages of cancer. The blood concentration of LN gamma2 in 24 who initially showed normal concentrations did not change after radical treatments. Five who initially showed increased LN gamma2 concentration showed decreased concentration of less than 50 ng/ml after radical treatment. Four showed increased LN gamma2 concentration after treatment, and presented residual cancer, which killed them. Three of the 4 patients showed marked increase in LN gamma2 concentration exceeding 100 ng/ml and developed multiple distant metastases to the lung, liver, bone, and skin. The blood concentration of LN gamma2 in patients with head and neck cancer may thus indicate the amount of highly malignant cancer cells expressing LN gamma2. The blood concentration of LN gamma2 could therefore serve as a new tumor marker that might indicate the malignancy of and efficacy of treatments for head and neck cancer.

Experimental pulmonary fibrosis in rats with chronic gastric acid reflux esophagitis.

OBJECTIVE: To elucidate the association between gastric acid reflux and respiratory diseases by studying the histological changes of the lower airway in rats with chronic acid reflux esophagitis. METHODS: An experimental rat model of chronic acid reflux esophagitis was surgically created. The lower airways of these rats were histologically observed for more than 50 weeks. RESULTS: Although there were no histological changes which induced gastric acid reflux at 10 weeks after surgery, thickening of the basal laminae and the proliferation of the collagenous fibers were observed in the alveolar epithelium at 20 weeks after surgery. At 50 weeks after surgery, the collagenous fibers obliterated the pulmonary alveoli and bronchial lumen. These findings observed in the GERD rats are similar to the pathological findings of human pulmonary fibrosis. CONCLUSION: In this study, we reported pathological changes in the lower airways of GERD rat models observed for more than 50 weeks. These results suggest that gastric acid reflux may be one of the pathogenic or exacerbating factors of pulmonary fibrosis.

Coccoid Helicobacter pylori exists in the palatine tonsils of patients with IgA nephropathy.

PURPOSE: Helicobacter pylori infection is acquired by oral ingestion. H. pylori has been reported to be present in the palatine tonsils. To clarify the route and mode of infection, the prevalence of tonsillar H. pylori was evaluated, and an attempt was made to culture tonsillar H. pylori. METHODS: In a prospective study, 55 patients with recurrent pharyngotonsillitis or IgA nephropathy underwent a tonsillectomy. The carbon 13-urea breath test and enzyme-linked immunosorbent assay for the detection of H. pylori IgG antibodies in the serum were performed. Tonsillar H. pylori was cultured under conventional culture conditions for gastric H. pylori with or without the following shock methods; heat shock, hydrogen-peroxide-degrading compounds, or parasitizing amoebae. Immunofluorescence and immunoelectron microscopy using antibodies against H. pylori and cytotoxin-associated antigen A were used to identify tonsillar H. pylori. RESULTS: H. pylori in the coccoid form was present in tonsillar crypts. Of 55 patients, 43 (78.2%) had tonsillar H. pylori, and 15 (27.3%) were infected with gastric H. pylori. All patients with gastric H. pylori also had tonsillar H. pylori (p < 0.01). Cytotoxin-associated antigen A was observed in 38 (88.4%) of 43 tonsillar H. pylori. Tonsillar H. pylori could not be cultured in any culture conditions. All patients with IgA nephropathy had tonsillar H. pylori (p < 0.01). CONCLUSIONS: The present research might provide some insight into clarifying the route and mode of H. pylori infection. Our findings may indicate that tonsillar H. pylori is one of the antigens causative of IgAN.

Histological changes of the pharynx and larynx in rats with chronic acid reflux esophagitis.

CONCLUSIONS: The histological changes of the pharynx and the larynx associated with surgically induced chronic acid reflux esophagitis were observed in rats. Chronic inflammatory change due to gastric acid reflux was found microscopically in the pharynx and larynx. This indicated that inflammatory changes due to gastric acid reflux are associated with the pathogenesis of laryngopharyngeal reflux disease (LPRD). OBJECTIVE: To clarify the pathological mechanism of LPRD by studying the histological changes of the pharynx and the larynx in rats with chronic acid reflux esophagitis. MATERIALS AND METHODS: An experimental rat model of chronic acid reflux esophagitis was created surgically. The pharynx, larynx, trachea, lung, and esophagus of these rats were observed histologically every 2 weeks until 20 weeks after the operation. RESULTS: At 8 weeks after the operation, mucosal thickening and inflammatory cell infiltration were observed in the hypopharynx of the rat model. Moreover, chronic inflammation with proliferation of fibroblasts, deposition of collagen fibers, and proliferation and dilatation of the capillaries were found as time progressed. However, little macroscopic change was observed in the hypopharyngeal mucosa. In addition, at 16 weeks post-operation, inflammatory cell infiltration was identified in the nerve cells around the thoracic esophagus, the arytenoid region, and the lung.

Serum concentrations of laminin gamma2 fragments in patients with head and neck squamous cell carcinoma.

BACKGROUND: The laminin (LN) gamma2 chain expression has been linked to tumor invasion and prognosis. To provide a convenient clinical use, procedures that analyze LNgamma2 expression by using the serum and/or urine of patients should be developed. METHODS: The serum concentrations of the N-terminal fragments of the LNgamma2 chain in 73 patients with head and neck squamous cell carcinomas were measured by immunoassay. RESULTS: The concentrations of the LNgamma2 fragments ranged between 14.5 and 324.2 ng/mL, and the normal upper limit was estimated to be 50 ng/mL. The LNgamma2 fragment concentrations increased according to the T classification. The amount of elevated LNgamma2 fragment concentrations decreased after the use of curative treatments. Three patients displayed a continuous increase of the concentrations and subsequently died of the diseases. CONCLUSIONS: The serum concentrations of the LNgamma2 fragments may prove useful in assessing the treatment results and clinical courses of patients with head and neck squamous cell carcinomas.

Induction of long-term lipopolysaccharide tolerance by an agonistic monoclonal antibody to the toll-like receptor 4/MD-2 complex.

We have established an agonistic monoclonal antibody, UT12, that induces stimulatory signals comparable to those induced by lipopolysaccharide (LPS) through Toll-like receptor 4 and MD-2. UT12 activated nuclear factor kappaB and induced the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in peritoneal exudative cells. In addition, mice injected with UT12 rapidly fell into endotoxin shock concomitant with the augmentation of serum TNF-alpha and IL-6 levels, followed by death within 12 h. On the other hand, when the mice were pretreated with a sublethal dose of UT12, the mice survived the subsequent lethal LPS challenges, with significant suppression of serum TNF-alpha and IL-6, indicating that UT12 induced tolerance against LPS. This effect of UT12 was maintained for at least 9 days. In contrast, the tolerance induced by LPS continued for less than 3 days. These results illuminate a novel potential therapeutic strategy for endotoxin shock by the use of monoclonal antibodies against the Toll-like receptor 4/MD-2 complex.

Requirement for MD-1 in cell surface expression of RP105/CD180 and B-cell responsiveness to lipopolysaccharide.

RP105 is a B-cell surface molecule that has been recently assigned as CD180. RP105 ligation with an antibody induces B-cell activation in humans and mice, leading to proliferation and up-regulation of a costimulatory molecule, B7.2/CD86. RP105 is associated with an extracellular molecule, MD-1. RP105/MD-1 has structural similarity to Toll-like receptor 4 (TLR4)/MD-2. TLR4 signals a membrane constituent of Gram-negative bacteria, lipopolysaccharide (LPS). MD-2 is indispensable for TLR4-dependent LPS responses because cells expressing TLR4/MD-2, but not TLR4 alone, respond to LPS. RP105 also has a role in LPS responses because B cells lacking RP105 show hyporesponsiveness to LPS. Little is known, however, regarding whether MD-1 is important for RP105-dependent LPS responses, as MD-2 is for TLR4. To address the issue, we developed mice lacking MD-1 and generated monoclonal antibodies (mAbs) to the protein. MD-1-null mice showed impairment in LPS-induced B-cell proliferation, antibody production, and B7.2/CD86 up-regulation. These phenotypes are similar to those of RP105-null mice. The similarity was attributed to the absence of cell surface RP105 on MD-1-null B cells. MD-1 is indispensable for cell surface expression of RP105. A role for MD-1 in LPS responses was further studied with anti-mouse MD-1 mAbs. In contrast to highly mitogenic anti-RP105 mAbs, the mAbs to MD-1 were not mitogenic but antagonistic on LPS-induced B-cell proliferation and on B7.2 up-regulation. Collectively, MD-1 is important for RP105 with respect to B-cell surface expression and LPS recognition and signaling.