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Following facial nerve axotomy, nerve function is not fully restored even after reconstruction. This may be attributed to axon degeneration/neuronal death and sustained neuroinflammation. CD38 is an enzyme that catalyses the hydrolysis of nicotinamide adenine dinucleotide (NAD+) and is a candidate molecule for regulating neurodegeneration and neuroinflammation. In this study, we analyzed the effect of CD38 deletion and NAD+ supplementation on neuronal death and glial activation in the facial nucleus in the brain stem, and on axon degeneration and immune cell infiltration in the distal portion of the facial nerve after axotomy in mice. Compared with wild-type mice, CD38 knockout (KO) mice showed reduced microglial activation in the facial nucleus, whereas the levels of neuronal death were not significantly different. In contrast, the axon degeneration and demyelination were delayed, and macrophage accumulation was reduced in the facial nerve of CD38 KO mice after axotomy. Supplementation of NAD+ with nicotinamide riboside slowed the axon degeneration and demyelination, although it did not alter the level of macrophage infiltration after axotomy. These results suggest that CD38 deletion and supplementation of NAD+ may protect transected axon cell-autonomously after facial nerve axotomy.

We describe a technique for approaching petrous apex cholesteatoma using combined lateral microscopic/endoscopic approaches, and discuss the utility of endoscopy in managing matrix inside the petrous apex. In our two cases, total view inside the petrous apex was achieved under endoscopy without mobilizing the internal carotid artery, and the matrix was successfully removed. Neither patient has presented with postoperative recurrence thanks to the wide-angle endoscopic view inside the petrous apex. Since the number of patients was small, comparisons with microscopic treatments are not yet valid, but endoscopes could offer a helpful tool for operating inside the petrous apex.

Objective To retrospectively evaluate the long-term results of surgery for retrograde bone work, using soft-wall reconstruction of the canal wall, for pediatric cholesteatoma. Methods We retrospectively evaluated a series of 25 consecutive ears of 24 patients who were ≤16 years of age. All children underwent cholesteatoma surgery between October 2002 and August 2008. The type of cholesteatoma, the length of follow-up, the incidence of residual and recurrent cholesteatoma, postoperative hearing results, and the form of the reconstructed external canal wall and tympanic membrane were assessed. Results There were 21 males and 3 females. The procedure was performed on both ears of one patient who had bilateral congenital cholesteatoma (CC). At the initial surgery, 16 cases (64%) had CC and nine (36%) had acquired cholesteatoma (AC). The mean age at surgery was 8.2 years and 10.4 years for CC and AC cases, respectively. The mean postoperative follow-up period after the initial surgery was 90 months for CC cases and 108 months for AC cases. Cholesteatoma recurrence occurred for 6% and 56% of cases with CC and AC, respectively. Successful serviceable hearing was achieved for 93.8% with CC and 100% with AC. Cases with inadequate hearing after surgery were characterized by disease extension to the mastoid and the protympanum. The long-term forms of the reconstructed external canal wall changed depending on their middle ear aeration. Some cases of tympanic membrane perforation and otitis media with effusion were occurred during the follow-up period. Conclusion Overall, the retrograde approach with soft-wall reconstruction of the canal wall achieved a low recurrence rate for cholesteatoma and good hearing outcomes during long-term follow-up for the pediatric case. However, in cases with eustachian tube dysfunction and/or cholesteatoma involving the protympanum, the hearing outcomes were less favorable.

Middle ear salivary choristoma is a rare entity and only 40 cases have been detected since the first report in 1961. Choristoma is a benign tumor, but can cause conductive hearing loss. Therefore, appropriate treatment is important for patients. Here, we have presented one case of salivary gland choristoma in the middle ear with alopecia and have included a review of the literature.

We investigated the usefulness and safety of our cochlear implantation method for two deaf patients with eosinophilic otitis media. The surgical approach was a subtotal petrosectomy to remove the theater of eosinophilic infiltration and to prevent leaching of foreign substances and entry of stimuli that are the cause of eosinophilic inflammations. The operative cavity was obliterated with abdominal fat. There were no complications or recurrent inflammation following surgery in the cases of both patients. It was confirmed by CT scan that the eustachian tube was closed and the operative cavity remained obliterated with abdominal fat. Following the procedure, the hearing threshold results of the two patients were 30 and 34 dB. Cochlear implantation procedures in this report for deaf patients resulting from eosinophilic otitis media may be effective and safe. Using steroids before surgery may be the better option. To further confirm the efficacy and safety of our surgical concept, we need to administer this treatment concept for a large number of cases in a future study.

Objective Microglia are highly specialized tissue macrophages in the central nervous system. Their activation in the auditory system has been reported in adult hearing loss models, but their status in the developing auditory system is less understood. Therefore, we investigated microglial status in the cochlear nucleus (CN) during normal developing periods and after exposing rats to amikacin, a potent ototoxin, around the time of hearing onset. Methods To develop the deafness model, rats were administered with a daily intraperitoneal injection of amikacin (500 mg/kg) from postnatal day 7 (P7) to P15. To evaluate the expression of ionized calcium binding adaptor molecule 1 (Iba1), we performed immunohistochemical analysis using rat brains from P10–60. To compare the expression of microglia-related gene, reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis were performed. Results Immunohistochemical analysis revealed that, under normal conditions, microglia had relatively large cell bodies with several extended processes that surrounded other cells at P10, while the sizes and number of these cells gradually decreased afterward. In contrast, when amikacin was administered from P7 to P15, microglia maintained large cell bodies with relatively shorter processes at both P15 and P21. Furthermore, RT-qPCR analysis revealed upregulation of genes including phagocytotic and anti-inflammatory markers after amikacin administration. Conclusion These results suggest that microglia are activated in the CN, and they may contribute to tissue remodeling after early hearing loss in the developing auditory system.

Recent studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of gastrointestinal cancer, and that cyclooxygenase-2 (COX-2) may be a target enzyme for the prevention or regression of cancer by the use of NSAIDs. Mucin histochemistry has made possible a clear distinction between the differentiated characteristics of gastrointestinal epithelial cells, and the possibility that phenotypic shifts from gastric- to intestinal-type in gastric carcinoma progression has been suggested. To evaluate the role of COX-2 in gastric cancer progression, we immunohistochemically investigated COX-2 expression, and examined its relationship to proliferative activity, mucin phenotype, and clinicopathological parameters in human advanced gastric carcinomas.Forty-five surgical specimens of advanced gastric carcinomas (invaded the muscularis propria or subserosa) were examined. Immunohistochemical staining was performed with monoclonal antibodies against COX-2, Ki-67, CD10 (brush border), MUC-2 (goblet-cell mucin), MUC-5AC (gastric foveolar mucin), and MUC-6 (pyloric mucin). COX-2 expression was scored by the percentage of COX-2-positive neoplastic cells, and proliferative activity was assessed by the Ki-67 labeling index at the deepest area of invasion. The mucin phenotype of the carcinomas was classified into three categories; gastric, intestinal, and unclassified.COX-2 staining was restricted to the cytoplasm, not only in cancer cells but also in intestinal metaplasia and some inflammatory cells and COX-2 expression in cancer cells varied greatly, but the staining in some samples was preferentially found at the invasive front. COX-2 positivity was found to correlate with Ki-67 labeling. The mean COX-2 scores were 2.29%, 2.71%, and 2.75%; and the Ki-67 labeling indices were 23.6%, 40.6%, and 56.5%, in gastric-, intestinal-, and unclassified- type carcinomas, respectively.A close relationship between COX-2 expression and proliferative activity was confirmed in the deepest areas of advanced gastric carcinoma, and the proliferative activity increased from gastric- to intestinal- and to unclassified- type gastric carcinoma, suggesting a role for COX-2 expression and differences in biological behavior according to mucin phenotype expression during gastric cancer progression.

In epithelial tissue, cell-matrix and cell-cell adhesive interactions have important roles in the normal organization and stabilization of the cell layer. The malignant conversion of epithelial cells involves alterations in the expression and function of these adhesion systems that enable a switch to a migratory phenotype in tumor invasion and metastasis. Fascin is an actin-crosslinking protein that is found in the core actin bundles of cell-surface spikes and projections that are implicated in cell motility. We demonstrate that fascin is not detectable in normal colonic epithelium, but is dramatically up-regulated in colorectal adenocarcinoma. To test the hypothesis that fascin could participate in tumor invasive behavior, we developed a cell culture model to examine the effect of fascin expression on the adhesive interactions, invasiveness, and differentiation of colonic epithelial cells. We report marked effects on the organization of cell-surface protrusions, actin cytoskeleton, and focal adhesions in the absence of alterations in the protein levels of the major components of these structures. These effects correlate with alterations in cell movements on two-dimensional matrix, and increased invasiveness in three-dimensional matrix. The cells also show increased proliferation and decreased capacity for normal glandular differentiation in collagen gels. We propose that up-regulation of fascin, by promoting the formation of protrusive, actin-based, cell-motility structures, could be a significant component in the acquisition of invasive phenotype in colonic carcinoma.

Recent studies have shown that cyclooxygenase-2 (COX-2) inhibitors may participate in the proliferation of cancer cells. Because the cadherin-catenin complex is not only a key component of the adherens junction but also has been suggested to regulate cell proliferation, modulation of these molecules may be a mechanism by which COX-2 activity affects cell proliferation. In this study, we evaluated the effect of a COX-2 inhibitor on the proliferation and expression of E-cadherin-complexes in gastrointestinal cancer cell lines. Methods: The gastrointestinal cancer cell lines Caco2, HT29, and MKN45 were grown for 24 h in the presence and absence of a selective COX-2 inhibitor, etodolac (10−5, 10−4, and 10−3 M). Cell proliferation was assessed by 3H-thymidine incorporation, and the expression of E-cadherin and catenins was assessed by Western blotting, Northern blotting, and immunofluorescence. Results: Etodolac induced a significant reduction in cell proliferation in Caco2 and MKN45 cells. E-cadherin expression was upregulated after stimulation with etodolac in Caco2 cells, whereas the expression of α-, β-, γ- and p120-catenins was not modified. The expression of E-cadherin mRNA was also upregulated in Caco2 cells, and was upregulated also in MKN45 cells, which did not express normal E-cadherin protein by the use of a mouse monoclonal antibody against human E-cadherin, HECD-1 antibody. Immunofluorescence revealed that the increased E-cadherin was localized at the cytoplasmic membrane. Conclusions: The inhibition of cell growth by etodolac in Caco-2 cells was associated with a dose-dependent upregulation and intense cytoplasmic localization of E-cadherin. No quantitative change in catenin expression was found in this phenomenon. These findings suggest that the COX-2 inhibitor affects the transcription of E-cadherin, or that there may be some homeostatic link between the cell cycle and E-cadherin transcription.

E-cadherin and its associated cytoplasmic proteins, alpha-, beta-, and gamma-catenins, play an essential role in the control of epithelial differentiation. We have previously shown that loss or down-regulation of E-cadherin/catenin correlates with poor survival in advanced gastric adenocarcinoma. The aim of this study was to assess the expression of E-cadherin and catenins in early gastric cancers (EGCs). Immunohistochemical staining for E-cadherin and alpha-, beta-, and gamma-catenins was performed on 41 paraffin-embedded gastrectomy specimens of EGC using an indirect immunoperoxidase technique. The pattern of expression and cellular localization of the E-cadherin/catenin complex in tumour cells were correlated with the macroscopic appearance of the tumour according to the Japanese Endoscopic Society classification. The tumours were classified as follows: three type I (protruding) and 38 type II (superficial), of which ten were type IIa (elevated), one was type IIb (flat), and 27 were type IIc (depressed). E-cadherin and alpha-, beta-, and gamma-catenins were expressed at the cell-cell junctions in normal mucosa. Forty out of 41 tumours showed abnormal expression (loss of membranous immunoreactivity and/or nuclear staining) of at least one component of the E-cadherin catenin complex. Loss of E-cadherin immunoreactivity was more frequently seen in type IIb (1/1, 100%) and type IIc (27/27, 100%) than in type I (1/3, 33%) and type IIa (1/10, 10%) (p

p120(ctn) is a substrate of the tyrosine kinase pp60 src. Tyrosine kinases such as src localize to the adherens junctions and phosphorylate junctional proteins in both normal and transformed cells.(1) p120(ctn) forms a complex with E-cadherin at the adherens junction and is phosphorylated by ligands such as epidermal growth factor receptor as well as pp60 src. Phosphorylation of p120(ctn) has been shown to correlate with cell transformation. The aim of this study was to investigate in vivo expression of p120(ctn) in gastric carcinoma and to examine any relationship to pathological characteristics and patient survival. Immunohistochemical staining for p120(ctn) was performed in 68 gastric carcinoma specimens (19 diffuse, 49 intestinal type), in 22 lymph node metastases, and in gastric mucosal biopsies from 16 patients with gastric dysplasia and ten healthy controls. Up-regulation of p120(ctn) cytoplasmic staining was seen in six (37 per cent) of the gastric dysplasia cases and in 45 (66 per cent) tumours (89 per cent of diffuse and 57 per cent of intestinal tumours). Loss of membranous distribution of staining for p120(ctn) was seen in 22 (32 per cent) tumours (52 per cent of diffuse and 24 per cent of intestinal tumours). The staining pattern in the primary tumour showed no correlation with tumour type, grade, or stage, or patient survival. Of 22 lymph node metastases examined, 13 (60 per cent) showed loss of membranous staining. In conclusion, staining for p120(ctn) in gastric carcinoma and dysplasia revealed marked up-regulation of cytoplasmic staining, sometimes associated with reduced membranous expression. Up-regulation of expression of p120(ctn) has not previously been described in human epithelial malignancy. The significance of these findings is uncertain, but they may reflect a change in tyrosine kinase signal transduction pathways, and a role for p120(ctn) in ligand-induced mitogenic signalling and cell transformation.

Catenins are cytoplasmic proteins associated with E-cadherin, the prime mediator of cell-cell adhesion. Perturbation in any of these molecules results in altered intercellular adhesion, cell differentiation, and increased migration. In this study, the expression and cellular localization of catenins and E-cadherin in inflammatory bowel disease were examined. The expression of E-cadherin; alpha-, beta-, and gamma-catenin; and p120 was evaluated immunohistochemically in 31 paraffin-embedded colonic specimens from 21 patients with ulcerative colitis and Crohn's disease. Loss of normal membranous E-cadherin and alpha-catenin staining was detected at the mucosal edges around epithelial ulcerations in all cases of active ulcerative colitis and in 50 per cent of cases with active Crohn's disease. Reduced expression of p120 protein was also found at the margins of ulcerated mucosa in all cases of active ulcerative colitis and in 75 per cent of those with active Crohn's disease. There was a statistically significant correlation between the expression of E-cadherin, alpha-catenin and p120 and disease activity. There were no changes in beta- and gamma-catenin expression in either ulcerative colitis on Crohn's disease. These findings indicate that altered expression of E-cadherin, alpha-catenin, and p120 occurs during mucosal ulceration in inflammatory bowel disease. These changes may be involved in promoting cell migration during epithelial restitution of the gastrointestinal mucosa.

Recent reports have suggested an association between Helicobacter pylori infection and both gastric mucosa associated lymphoid tissue (MALT) lymphoma and thrombocytopenic purpura. Although treatments eradicating H pylori lead to regression of these diseases in some cases, the exact mechanisms are still controversial. This case report describes a patient with thrombocytopenic purpura accompanied by an early stage gastric MALT lymphoma. Endoscopic mucosal resection of the lesion in this patient led to dramatic regression of thrombocytopenic purpura, and t(11;18)(q21;q21), which means resistance more likely to H pylori eradication therapy, was confirmed by fluorescence in situ hybridisation. There is no evidence of recurrence and his platelet count is within normal limits after 24 months of follow up. This is the first case report describing regression of thrombocytopenic purpura after mucosal resection of a gastric MALT lymphoma. We suggest that while some cases of thrombocytopenic purpura may be induced by H pylori, others may be due to an autoreactive antibody produced by MALT lymphoma B cells.

A 65-year-old man who presented with adrenal insufficiency was admitted on Feburuary 9, 1988. CT scan showed bilateral swelling of adrenals; open biopsy of the tumor revealed non-Hodgkin's lymphoma. The serum level of catecholamines and calcitonin was elevated. A combination chemotherapy was started. After 3 courses of the treatment remission was achieved, following recovery from adrenal insufficiency. In November, 1988, he had pulmonary infiltration and high fever, resolved by the administration of antibiotics and antifungal drugs. On January 27, 1989, he underwent emergency operation because of perforation of gastric ulcer. In Feburuary, tumor increased in size, and the disease became progressive. On April 2, 1989, he died of respiratory failure. Autopsy revealed a definite diagnosis of malignant lymphoma, diffuse large cell type. Immunohistological studies revealed B cell origin of the cells based on positive LCA and pan B markers.

Background: Numerous methods have been developed to resect early-stage gastric and esophageal cancers, but it is difficult to resect lesions viewed tangentially with the endoscope. Methods: We have designed and developed an original method of endoscopic mucosal resection using a partial transparent hood to treat difficult cases in which the lesions are located tangentially to the endoscope. The hood was attached on the right side of the endoscope and, after insertion into the stomach or the esophagus, was lightly pressed on the orad side of the lesion. Then the lesion was resected using grasping forceps and electrosurgical current snare. Results: The average diameter of specimens was 26 ± 8 mm in gastric lesions and 20 ± 3 mm in esophageal lesions, both 6 mm larger than those obtained by previous methods. Conclusion: This device and technique were extremely useful for mucosal resection of lesions located tangentially to the endoscope.

Basic fibroblast growth factor-2 (FGF-2) has an important role in angiogenesis, and has been demonstrated to promote ulcer healing. However, the actual part played by FGF-2 in the process of ulcer healing is not well understood. In this study, we investigated expression of FGF-2 transcripts at each stage of gastric ulcer healing, using an acetic acid model in rats. We made ulcers in the rat stomach by direct application of acetic acid, and 3 days and 1, 2, 3, 4, 8 weeks after treatment, we examined expression of FGF-2 transcripts by in situ hybridization. On day 3, FGF-2 transcripts were detected in mononuclear cells infiltrating the submucosal layer around the ulcer. After 1 and 2 weeks, expression of FGF-2 transcripts was prominent in spindle-shaped mesenchymal cells and endothelial cells, which proliferated in the ulcerative region. Some of the spindle-shaped cells which expressed FGF-2 transcripts also showed immunoreactivity for alpha-smooth muscle actin. After 3 and 4 weeks, FGF-2 expression was seen mainly in endothelial cells of vessels. These results suggest that different cells produce FGF-2 during the process of gastric ulcer healing, and some of the spindle-shaped cells expressing FGF-2 transcripts in the early phase are myofibroblasts.

Dysfunction of the cadherin–catenin complex, a key component of adherens junctions, is thought to confer invasive potential to cells. The aim of this study is to examine the expression and function of the E-cadherin/catenin complex in gastric carcinoma cell lines. Expression of E-cadherin, α, β and γ-catenin and p120ctn, and of the adenomatous polyposis coli protein (APC), together with function of the cadherin–catenin complex was examined in a panel of gastric carcinoma cell lines, using immunocytochemistry, Western blotting and a cell–cell aggregation assay. Protein interactions were examined by sequential immunoprecipitation and immunoblotting with antibodies to E-cadherin, α, β and γ-catenin, p120ctn and APC. Abnormalities of E-cadherin, α- and β-catenin expression, were associated with disturbance of E-cadherin–catenin complex composition, loss of membranous localization and loss of calcium-dependent aggregation in six gastric carcinoma cell lines. APC protein expression and interaction with β-catenin was preserved in five cell lines. We demonstrate frequent abnormalities of expression and function of E-cadherin and catenins, and associated disturbance of E-cadherin-mediated intercellular adhesion in gastric carcinoma cell lines. These findings support the tumour suppressor role of the E-cadherin and its contribution to the development and progression of the neoplastic phenotype in gastric carcinoma. © 1999 Cancer Research Campaign

Background and Study Aims: To date, the accepted criteria for endoscopic resection of early gastric cancer have been: a) elevated-type mucosal cancer less than 2 cm in size, and b) depressed-type mucosal cancer without ulceration less than 1 cm in size. In this study, we attempted to expand these indications. Patients and Methods: Sixty patients with early gastric cancer who did not meet the above criteria underwent endoscopic treatment, and were divided into four groups: those with elevated tumours larger than 2 cm with submucosal invasion (group 1 a); those without submucosal invasion (group 1b); those with depressed tumours larger than 1 cm (group 2); and those with ulcerated tumours (group 3). The patients were treated with endoscopic resection using a two-channel scope, followed by additional laser irradiation or heater-probe coagulation (combination therapy) if residual cells were found. Follow-up was by endoscopy and biopsy for more than two years. Results: Endoscopic treatment was effective in 87% of the patients (52 of 60), half of whom required combination therapy. In submucosal cancers, endoscopic treatment was effective in 76% of patients (13 of 17). How: ever, tumours with deep invasion into the submucosa could not be cured. Mucosal cancers larger than 20 mm could be completely resected in 44% of patients (eight of 18) using endoscopic resection, but all five patients with tumours larger than 30 mm had incomplete resections. Conclusions: These results indicate that complete resecttion using endoscopic resection alone is possible in early gastric cancers measuring up to 30 mm in diameter. Tumours larger than 30 mm, and those with deep submucosal invasion, cannot be curatively treated by the current endoscopic modalities.

We examined the expression of FGF-2 mRNA in 16 early and 14 advanced gastric cancer by in situ hybridisation to elucidate its role in cancer progression. Anti-sense RNA probes were synthesized by transcribing the subcloned vector with T7 RNA polymerase in the presence of digoxigenin-labeled UTP. FGF-2 mRNA was located mainly in the cytoplasm around the nuclei of endothelial cells, fibroblasts and carcinoma cells. The expression was more frequently in the diffuse type carcinomas (4/7, 57%) than in the intestinal type tumours (5/23, 22%). The survival rates of advanced gastric cancers with FGF-2 mRNA expression were significantly lower than those without FGF-2 mRNA expression (p < 0.01). No significant correlation was seen with other clinicopathological factors. These results suggest that FGF-2 may play an important role for the growth of diffuse type gastric cancers, particularly at their advanced stage.

We report an 80-year-old man who presented with sponta- neous regression of hepatocellular carcinoma (HCC). He complained of sudden right flank pain and low-grade fever. The level of protein induced by vitamin K antagonist (PIVKA)-II was 1137 mAU/mL. A computed tomography scan in November 2000 demonstrated a low-density mass located in liver S4 with marginal enhancement and a cystic mass of 68 mm × 55 mm in liver S6, with slightly high density content and without marginal enhancement. Angiography revealed that the tumor in S4 with a size of 25 mm × 20 mm was a typical hypervascular HCC, and transarterial chemoembolization was performed. However, the tumor in S6 was hypovascular and atypical of HCC, and thus no therapy was given. In December 2000, the cystic mass regressed spontaneously to 57 mm × 44 mm, and aspiration cytology revealed bloody fluid, and the mass was diagnosed cytologically as class I. The tumor in S4 was treated successfully with a 5 mm margin of safety around it. The PIVKA-II level normalized in February 2001. In July 2001, the tumor regressed further but presented with an enhanced area at the posterior margin. In November 2001, the enhanced area extended, and a biopsy revealed well-differentiated HCC, although the previous tumor in S4 disappeared. Angiography demonstrated two tumor stains, one was in S6, which was previously hypovascular, and the other was in S8. Subsequently, the PIVKA-II level started to rise with the doubling time of 2-3 wk, and the tumor grew rapidly despite repeated transarterial embolization with gel foam. In February 2003, the patient died of bleeding into the peritoneal cavity from the tumor that occupied almost the entire right lobe. Considering the acute onset of the symptoms, we speculate that local ischemia possibly due to rapid tumor growth, resulted in intratumoral bleeding and/or hemorrhagic necrosis, and finally spontaneous regression of the initial tumor in S6.