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A 68-year-old man presented with generalfatigue due to anemia. Gastrointestinalendoscopy showed a tumor approximately 60mm in diameter in the lesser curvature of the angle of the stomach. Large cell neuroendocrine carcinoma was diagnosed by biopsy of a tumor specimen. Computed tomography revealed bulky regional lymph node metastases, solitary liver metastasis, and left adrenal metastasis. After three courses of combined chemotherapy with S-1 and CDDP, the gastric lesion and lymph node metastases shrunk, but the liver metastasis and left adrenal metastasis enlarged. After three courses of combined chemotherapy with ramucirumab and paclitaxel, the liver metastasis and left adrenal metastasis also shrunk, and no other new metastatic lesions appeared. Accordingly, total gastrectomy with lymph nodes dissection, partial resection of the liver and left adrenalectomy were performed for a curative resection. The histological findings revealed neuroendocrine carcinoma and adenocarcinoma of the stomach. The lesions of the liver and lymph nodes were all burned out, and a tiny metastatic lesion of neuroendocrine carcinoma was left in the left adrenal gland. S-1 was administrated for 3 months after surgery. The patient has been alive for 16months without recurrence after surgery.

Aim: The aim of the study was to evaluate the efficacy and safety of nivolumab combined with ipilimumab in treatment-naïve Japanese patients with advanced melanoma., Methods: In this multicentre, single-arm study, treatment-naïve Japanese patients with unresectable stage III/IV or recurrent melanoma received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for four doses, followed by biweekly doses of nivolumab (3 mg/kg). The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included overall survival (OS), progression-free survival (PFS), disease control rate and safety., Results: The subtypes of the thirty patients enrolled were: 12, mucosal; eight, non-acral cutaneous; seven, acral; two, uveal and one, unknown primary melanoma. The ORR was 43.3% (95% confidence interval [CI]: 25.5, 62.6) with central and local assessment. The centrally and locally assessed disease control rate (95% CI) were 73.3% (54.1, 87.7) and 86.7% (69.3, 96.2), respectively. At the median follow-up period of 14.1 months (range 5.2-27.7), median OS and centrally assessed PFS were not reached. OS (95% CI) at 6, 12, 18 and 24 months was 93.3% (75.9, 98.3), 83.3% (64.5, 92.7), 72.9% (50.0, 86.5) and 65.6% (40.4, 82.2), respectively. Treatment-related adverse events (AEs) occurred in all patients. Grade III-IV and serious AEs occurred, mostly during the combination phase, in 23 (76.7%) and 20 (66.7%) patients, respectively. No treatment-related deaths occurred., Conclusions: This study confirmed the efficacy and safety of nivolumab plus ipilimumab in treatment-naïve Japanese patients with advanced melanoma including rare subtypes. Incidence rates for grade III-IV AEs were high but manageable with appropriate medical attention and treatment., Trial Registration: JapicCTI-152869., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Leukocyte mono-immunoglobulin-like receptor (LMIR)/CD300 proteins comprise a family of immunoglobulin-like receptors that are widely expressed on the immune cell surface in humans and mice. In general, LMIR3/CD300f suppresses the inflammatory response, but it can occasionally promote it. However, the precise roles of LMIR3 in the function of neutrophils remain to be elucidated. In the present study, we investigated LMIR3 expression in mature and immature neutrophils, and evaluated the effects of LMIR3 deficiency in mouse neutrophils. Our results indicated that bone marrow (BM) neutrophils expressed LMIR3 on their cell surface during cell maturation and that surface LMIR3 expression increased in response to Pseudomonas aeruginosa infection in a TLR4/MyD88-dependent manner. LMIR3-knockout (KO) neutrophils displayed significantly increased hypochlorous acid production, and elastase release, as well as significantly augmented cytotoxic activity against P. aeruginosa and Candida albicans; meanwhile, inhibitors of elastase and myeloperoxidase offset this enhanced antimicrobial activity. Furthermore, LMIR3-KO mice were significantly more resistant to Pseudomonas peritonitis and systemic candidiasis, although this may not be entirely due to the enhanced activity of neutrophils. These results demonstrate that LMIR3/CD300f deficiency augments the antimicrobial activity of mouse neutrophils.

Objectives: Candida species are a major cause of hospital infections, including ocular candidiasis, but few studies have examined the propensities of specific species to invade the eye or the unique immunological responses induced. This study examined the frequency and characteristics of species-specific Candida eye infections by epidemiology and experiments using a mouse ocular candidiasis model. Methods: We reviewed medical records of candidemia patients from January 2012 to March 2017. We also evaluated ocular fungal burden, inflammatory cytokine and chemokine profiles, and inflammatory cell profiles in mice infected with Candida albicans , Candida glabrata , or Candida parapsilosis. Results: During the study period, 20 ocular candidiasis cases were diagnosed among 99 candidemia patients examined by ophthalmologists. Although C . parapsilosis was the most frequent candidemia pathogen, only C . albicans infection was significantly associated with ocular candidiasis by multivariate analysis. In mice, ocular fungal burden and inflammatory mediators were significantly higher during C . albicans infection, and histopathological analysis revealed invading C . albicans surrounded by inflammatory cells. Ocular neutrophil and inflammatory monocyte numbers were significantly greater during C . albicans infection. Conclusion: Candida albicans is strongly associated with ocular candidiasis due to greater capacity for invasion, induction of inflammatory mediators, and recruitment of neutrophils and inflammatory monocytes.

Memory B cells (B mem cells) are the basis of long-lasting humoral immunity. They respond to re-encountered antigens by rapidly producing specific antibodies and forming germinal centers (GCs), a recall response that has been known for decades but remains poorly understood. We found that the receptor for the cytokine IL-9 (IL-9R) was induced selectively on B mem cells after primary immunization and that IL-9R-deficient mice exhibited a normal primary antibody response but impaired recall antibody responses, with attenuated population expansion and plasma-cell differentiation of B mem cells. In contrast, there was augmented GC formation, possibly due to defective downregulation of the ligand for the co-stimulatory receptor ICOS on B mem cells. A fraction of B mem cells produced IL-9. These findings indicate that IL-9R signaling in B mem cells regulates humoral recall responses.

A pan-azole-resistant Aspergillus fumigatus strain with the cyp51A mutations Gly138Ser and Asn248Lys was isolated from a patient receiving long-term voriconazole treatment. PCR fragments containing cyp51A with the mutations were introduced along with the Cas9 protein and single guide RNA into the azole-resistant/susceptible strains. Recombinant strains showed increased susceptibility via the replacement of Ser138 by glycine. Genetic recombination, which has been hampered thus far in clinical isolates, can now be achieved using CRISPR/Cas9 genome editing., (Copyright © 2018 American Society for Microbiology.)

CD1d-restricted invariant natural killer T ( i NKT) cells are innate-type lymphocytes that express a T-cell receptor (TCR) containing an invariant α chain encoded by the Vα14 gene in mice and Vα24 gene in humans. These i NKT cells recognize endogenous, microbial, and synthetic glycolipid antigens presented by the major histocompatibility complex (MHC) class I-like molecule CD1d. Upon TCR stimulation by glycolipid antigens, i NKT cells rapidly produce large amounts of cytokines, including interferon-γ (IFNγ) and interleukin-4 (IL-4). Activated i NKT cells contribute to host protection against a broad spectrum of microbial pathogens, and glycolipid-mediated stimulation of i NKT cells ameliorates many microbial infections by augmenting innate and acquired immunity. In some cases, however, antigen-activated i NKT cells exacerbate microbial infections by promoting pathogenic inflammation. Therefore, it is important to identify appropriate microbial targets for the application of i NKT cell activation as a treatment or vaccine adjuvant. Many studies have found that i NKT cell activation induces potent adjuvant activities promoting protective vaccine effects. In this review, we summarize the functions of CD1d-restricted i NKT cells in immune responses against microbial pathogens and describe the potential applications of glycolipid-mediated i NKT cell activation for preventing and controlling microbial infections.

Nivolumab is an antibody against programmed cell death 1 and functions as an immune checkpoint inhibitor for various malignancies, including unresectable melanomas. Nivolumab causes several immune-related adverse events, which typically include skin rash, pneumonitis, thyroid dysfunction, hepatitis, and colitis; in rare cases, anemia may be present. There are several reports of autoimmune hemolytic anemia that has developed in response to nivolumab; however, there are few reports of pure red cell aplasia (PRCA). We describe a patient who developed PRCA during nivolumab administration. A 70-year-old Japanese woman received nivolumab for cardiac metastasis from malignant melanoma from an unknown site. Twenty-one months after nivolumab administration (31 courses), treatment was discontinued because she developed severe anemia. Blood test results indicated normocytic, normochromic anemia, and reticulocytopenia, but all other components were normal. Bone marrow aspiration showed increased megakaryocytes and decreased erythroblasts; these findings were consistent with PRCA. Anemia improved without recurrence after treatment with corticosteroids and blood transfusions. The steroid dosage was reduced gradually, and to date, the patient has not experienced recurrence of anemia. The tumor decreased in size and the patient has shown a continued response to treatment with decrease in disease for 3 years. Although it is unclear how nivolumab causes PRCA, hematological toxicities have been reported in patients treated with immunotherapy drugs. PRCA might be an unrecognized immune-mediated adverse event that did not manifest during the clinical trial phase.

Recent studies indicated that isolated pulmonary metastases could define a favorable subgroup in metastatic pancreatic cancer. We report a case of isolated pulmonary metastases after curative resection of pancreas head cancer treated with chemotherapy and pulmonary metastasectomy survived for 79 months after recurrence. A 72-year-old male underwent pancreatoduodenectomy for pancreas head cancer. Adjuvant chemotherapy was done with gemcitabine hydrochloride (GEM)for 6 months and then S-1 for 2 months. Twenty-seven months after surgery, 2 small metastatic nodules in the left lung was detected. Chemotherapy with GEM was performed but the lesions grew larger very slowly. A new metastatic nodule was detected in the right lung 40 months after surgery and pleural effusion was detected 52 months after surgery. Then combination chemotherapy with GEM and S-1 was performed for 3 months followed chemotherapy with S-1 alone. Seventytwo months after surgery, chemotherapy with GEM was performed again because of patient's intolerance to S-1. Ninety months after initial surgery, pulmonary metastasectomy of the right lung was performed because of its resistance to chemotherapy. Chemotherapy with GEM was started again 4 months after pulmonary metastasectomy but serum levels of tumor markers remained increase. Combination chemotherapy with GEM and nab-paclitaxel was started 8 months after pulmonary metastasectomy but the patient died 16 months after pulmonary metastasectomy.

Tie-over bolster dressing after skin grafting can prolong operative time, and cause hematoma and seroma formation because of uneven pressure application. To describe the possibility of discontinuing the use of tie-over dressing, we carried out a retrospective comparative study of patients who underwent skin grafting at an institution between January 2009 and December 2014. We investigated and compared the take rate, healing period, wound infection rate and hematoma formation rate for the tie-over dressing group and the non-tie-over dressing group. Among 266 patients, 148 and 118 patients were included in the tie-over dressing group and non-tie-over dressing group, respectively. There were no significant differences between the take rate, healing period, wound infection rate and hematoma formation rate for the two groups. Multivariate analysis showed that the complete graft take rate was not significantly influenced by tie-over dressing, age, sex, graft site, graft procedure and skin graft diameter. Although the use of tie-over dressing might remain necessary on sites with a free margin, including the eyelids, lips or nostrils, because of the difficulty in using tape fixation, the present study showed that alternative dressing with polyurethane foam is also useful in most cases of skin grafting., (© 2017 Japanese Dermatological Association.)

Temporomandibular joint dysfunction (TMD) is a collection of clinical symptoms that involve masticatory muscles and the temporomandibular joint (TMJ). Common symptoms include limited jaw motion and joint sound/pain, along with TMJ disc displacement. TMD is frequently associated with synovitis, a chronic inflammation of the synovium. Fibroblast‑like synovial cells have been identified to produce several inflammatory mediators and may have an important role in the progression of TMJ inflammation. Degradation of the extracellular matrix molecule elastin may lead to the release of bioactive peptides. The present study aimed to explore the role of elastin‑derived peptides (EDPs) in human temporomandibular disorders. Therefore, interleukin‑6 (IL‑6) expression in the synovial fluid obtained from patients with TMD correlated significantly with two clinical parameters, specifically TMJ locking and pain/jaw function on a visual analog scale (VAS). To the best of our knowledge, this is the first study to determine that the concentration of EDPs in synovial fluid from patients with TMD may also be significantly correlated with the duration of TMJ locking, the VAS score and IL‑6 expression. In vitro, EDPs act on human TMJ synovial cells to promote upregulation of IL‑6 and the elastin‑degrading enzyme matrix metalloproteinase‑12 (MMP‑12). The upregulation of IL‑6 and MMP‑12 expression by EDPs may be mediated through elastin‑binding proteins (EBP) and a protein kinase A signalling cascade. These findings suggest a model for inflammation in the TMJ where EDPs are generated by harmful mechanical stimuli, induce both a pro‑inflammatory cascade and increase expression of MMP‑12 through activation of the EBP signalling cascade. This may lead to further increases in EDP levels, establishing a positive feedback loop leading to chronic inflammation in the TMJ. Therefore, significantly elevated levels of EDPs and IL‑6 in the synovial fluid of the TMJ may be indicators of the pathological conditions of the joint.

Cryptococcosis caused by highly virulent Cryptococcus gattii (Hv-Cg) is an emerging infectious disease that affects immunocompetent individuals. The Hv-Cg outbreak began in 1999, but the mechanisms responsible for its hyper-virulence as well as protective immunity against Hv-Cg infection remain to be elucidated. To better understand the protective immunity against Hv-Cg infection, we developed a novel immunization method using antigen-pulsed dendritic cells (DCs). We constructed a capsule-deficient Cg strain (∆cap60) and used it as a vaccine antigen. Mouse bone marrow-derived DCs were pulsed with ∆cap60 and transferred into mice twice before pulmonary infection with Hv-Cg strain R265. This DC-based immunization strongly induced cell-mediated immunity, including Th1 cells, Th17 cells, and multinucleated giant cells enclosing fungal cells in lungs. This vaccination significantly ameliorated the fungal burden and the survival rate after pulmonary infection with R265. The efficacy of DC-based immunization was significantly but partially reduced in IFNγ-deficient mice, thereby suggesting that the Th1 and Th17 responses play roles in vaccine-induced protection against Hv-Cg infection. This approach might provide new insights into overcoming Hv-Cg infections in immunocompetent subjects. In this chapter, we describe the procedures for DC-vaccine preparation and the analysis of cytokine-producing CD4 + T cells.

A 69-year-old man with perianal pain was diagnosed with an anal fistula and a rectal tumor by magnetic resonance imaging and pulmonary tuberculosis by computed tomography. A colonoscopy confirmed the presence of a circular mass in the rectum 6 cm from the anal verge. Histological examination revealed a moderately differentiated adenocarcinoma. Initially, seton drainage was used to improve the perianal pain. After 2 months of anti-tuberculosis therapy, the patient underwent low anterior resection for the rectal cancer. Six months after surgery, a perianal tumor was detected at the postoperative site of the anal fistula. Biopsy of the tumor revealed adenocarcinoma. Because the histological appearance of the second tumor was identical to the rectal cancer, it was diagnosed as a metastatic anal fistula cancer. The tumor shrunk after 3 courses of neoadjuvant chemotherapy with S-1 plus oxaliplatin (SOX) plus bevacizumab and there was no evidence of distant metastasis. Local resection of the anal fistula cancer was performed. Six months postoperatively, the patient is doing well and shows no sign of recurrence.

We describe a nematode larva in a subcutaneous nodule excised from a 44-year-old Chinese male who had been living in Japan for 15 years. Morphological features suggested that the worm was a dioctophimatid nematode. PCR amplification and sequencing of small subunit ribosomal DNA and mitochondrial cytochrome subunit c oxidase genes allowed us to identify the larva as the giant kidney worm, Dioctophyme renale (Goeze, 1972). This is the first molecularly confirmed human case of a dermal D. renale infection., (© 2013.)

Background: We examined the course of a primary hepatic neuroendocrine carcinoma (PHNEC) patient and analyzed the postoperative outcome of all reported PHNEC cases., Methods: A literature search for PHNEC cases was performed using PubMed. All reported cases and our present patient were analyzed in this study. Survival analysis was performed using the Kaplan-Meier method. Risk factors for the recurrence of PHNEC following hepatic resection were investigated., Results: A total of 43 patients were analyzed in this study. The 3-, 5-, and 7-year overall survival rates were 55%, 48%, and 48%, respectively. The 3-, 5-, and 7-year overall survival rates in surgery patients were 78% each, and 25%, 17%, and 17%, respectively in nonsurgery patients. Lymph node metastasis posed a significant risk factor for postoperative recurrence., Conclusions: Hepatic surgery is an appropriate therapeutic treatment for PHNEC without distant metastasis nor lymph node metastasis. Adjuvant chemotherapy might be necessary for PHNEC patients with lymph node metastases.

Conventional surgical excision (SE) is commonly used to treat patients with basal cell carcinoma (BCC). There have been few studies, however, evaluating the long-term prognosis of Japanese patients receiving SE for treatment of BCC. The purpose of this retrospective study is to determine the effectiveness of SE in accomplishing the long-term cure of patients with BCC. We enrolled 290 patients with primary BCC who underwent SE during 1998-2006. The prognosis of treated patients was subsequently investigated using data obtained through our hospital cancer registration section. In total, 205 patients (70.7%) were treated for BCC lesions located on the face. The mean tumor diameter of excised lesions was 12.8 mm. A majority of patients in the study (256 patients, 88.3%) had pigmented BCC. The mean surgical margin at SE was 3.8 mm. Two patients developed local recurrence during the postoperative course of 290 patients (mean duration, 80 months). One patient developed recurrent disease 21 months after surgery, and the other developed recurrence at 66 months after surgery. The 5- and 10-year cumulative recurrence rates were 0.4% and 0.8%, respectively. In conclusion, this study demonstrated that long-term high cure rates of BCC in Japanese patients may be achieved through conventional SE. A better prognosis was obtained in this study compared with similar studies reported previously in Caucasians. This may be related to the predominance of pigmented versus non-pigmented lesions in the Japanese population., (© 2013 Japanese Dermatological Association.)

It is very important to clarify the relationship between a dentofacial structure and a temporomandibular joint (TMJ) structure in orthognathic surgery. Recently, it was reported that the skeletal and occlusal patterns were associated with the TMJ morphology, including the disk position. In orthognathic surgery, some surgeons state that alterations in the condylar position from surgery can lead to malocclusion associated with the risk of early relapse, and also favor the development of temporomandibular disorders. For these reasons, several positioning devices have been proposed and applied, but now there is no scientific evidence to support the use of condylar positioning devices. There are some reasons why scientific evidence cannot be obtained; however, it also includes the question of whether the preoperative position of the condyle is the desired postoperative position. The purpose of this study was to verify the desired condylar position in orthognathic surgery, based on literature on the postoperative condylar position in orthognathic surgery. From the studies reviewed, it was suggested that the preoperative position of the condyle was not the desired postoperative position in orthognathic surgery., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Toll-like receptors (TLRs) that initiate an innate immune response contain an extracellular leucine rich repeat (LRR) domain and an intracellular Toll IL-receptor (TIR) domain. There are fifteen different TLRs in vertebrates. The LRR domains, which adopt a solenoid structure, usually have higher rates of evolution than do the TIR globular domains. It is important to understand the molecular evolution and functional roles of TLRs from this standpoint. Both pairwise genetic distances and Ka/Ks's (the ratios between non synonymous and synonymous substitution rates) were compared between the LRR domain and the TIR domain of 366 vertebrate TLRs from 96 species (from fish to primates). In fourteen members (TLRs 1, 2, 3, 4, 5, 6, 7, 8, 9, 11/12, 13, 14, 21, and 22/23) the LRR domains evolved significantly more rapidly than did the corresponding TIR domains. The evolutionary rates of the LRR domains are significantly different among these members; LRR domains from TLR3 and TLR7 from primates to fishes have the lowest rate of evolution. In contrast, the fifteenth member, TLR10, shows no significant differences; its TIR domain is not highly conserved. The present results suggest that TLR10 may have a different function in signaling from those other members and that a higher conservation of TLR3 and TLR7 may reflect a more ancient mechanism and/or structure in the innate immune response system. Gene conversions are suggested to have occurred in platypus TLR6 and TLR10. This study provides new insight about structural and functional diversification of vertebrate TLRs., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Various types of granulocyte colony-stimulating factor (G-CSF)-producing malignant tumors have been reported. However, a G-CSF-producing colorectal cancer is rare. We present a case of G-CSF-producing ascending colon cancer. An 81-year-old man was referred to our hospital with right lower abdominal pain. A colon fiberscopy revealed an ascending colon tumor, and histological examination revealed tubular adenocarcinoma. He was admitted due to worsening abdominal pain. Although laboratory data showed an elevated white blood cell (WBC) count of 17000/mm3 with 77.8% neutrophils, elevated C-reaction protein (CRP) was insignificant (1.06 mg/dL), and he was afebrile. Because computed tomography indicated that the tumor penetrated into surrounding tissue, a semi-urgent ileocecal resection was performed. An abscess was not located. The tumor was staged as T3N2aM0 and as stage IIB according to the TNM classification. Microscopically, significant neutrophil infiltration between cancer cells was observed, suggesting the presence of a G-CSF-producing tumor. Immunohistochemical staining using a G-CSF antibody revealed cytoplasmic staining in cancer cells. The serum concentration of G-CSF upon admission was 334 pg/mL. After surgical resection, the WBC count decreased to within a normal range. These findings confirmed the diagnosis of G-CSF-producing ascending colon cancer. The prognosis of G-CSF-producing tumors is considered to be poor. Early diagnosis and surgical treatment are needed for patients with G-CSF-producing tumors, and continuous careful follow-up is required.

Altered expression of microRNAs (miRNA) occurs commonly in human cancer, but the mechanisms are generally poorly understood. In this study, we examined the contribution of epigenetic mechanisms to miRNA dysregulation in colorectal cancer by carrying out high-resolution ChIP-seq. Specifically, we conducted genome-wide profiling of trimethylated histone H3 lysine 4 (H3K4me3), trimethylated histone H3 lysine 27 (H3K27me3), and dimethylated histone H3 lysine 79 (H3K79me2) in colorectal cancer cell lines. Combining miRNA expression profiles with chromatin signatures enabled us to predict the active promoters of 233 miRNAs encoded in 174 putative primary transcription units. By then comparing miRNA expression and histone modification before and after DNA demethylation, we identified 47 miRNAs encoded in 37 primary transcription units as potential targets of epigenetic silencing. The promoters of 22 transcription units were associated with CpG islands (CGI), all of which were hypermethylated in colorectal cancer cells. DNA demethylation led to increased H3K4me3 marking at silenced miRNA genes, whereas no restoration of H3K79me2 was detected in CGI-methylated miRNA genes. DNA demethylation also led to upregulation of H3K4me3 and H3K27me3 in a number of CGI-methylated miRNA genes. Among the miRNAs we found to be dysregulated, many of which are implicated in human cancer, miR-1-1 was methylated frequently in early and advanced colorectal cancer in which it may act as a tumor suppressor. Our findings offer insight into the association between chromatin signatures and miRNA dysregulation in cancer, and they also suggest that miRNA reexpression may contribute to the effects of epigenetic therapy., (©2011 AACR.)

Introduction: Chemokines are regulated by a family of 'atypical' chemokine receptors, D6, DARC and CCX-CKR, each of which efficiently internalizes its cognate chemokine ligands. Development of monoclonal antibodies (MAbs) that would recognize CCX-CKR on the cell surface will be helpful to identify primary CCX-CKR-expressing cell types and analyze the fate of CCX-CKR after ligand binding to the receptor., Methods: We generated IgG MAbs recognizing the cell-surface CCX-CKR by DNA immunization using a molecular adjuvant, and analyzed the epitope recognized by the MAbs. Then, the reactivities of the MAbs with CCX-CKR-transfected cells, and also hepatocytes and hepatic tumor lines were evaluated. Finally, we also tested the ligand-like activities of the MAbs, namely, induction of internalization of CCX-CKR by the MAbs., Results: A panel of MAbs reacting with CCX-CKR expressed on the cell surface was prepared. The panel was a small one, consisting of only ten MAbs, but was rich in terms of diversity of the Ig isotypes and of the epitopes. Epitope analyses revealed that all the 10 MAbs recognized at least three different, although very close, peptide structures of the N-terminal domain. Three MAbs, namely, 2F11, 13E11 and 14F10, were selected to represent the panel. All of the MAbs were applicable for flow cytometry and immunoflurescent assays and immunoprecipitation. The reactivity of the 2F11 MAb was also confirmed by western blotting. Endogenous expression of CCX-CKR on human hepatocytes and hepatic tumor cell lines was demonstrated using the 13E11 MAb. Interestingly, binding of the 13E11 MAb with B300-19 cells expressing CCX-CKR resulted in induction of CCX-CKR internalization., Discussion: This panel of MAbs may be expected to prove valuable for further study of the functions of this silent chemokine receptor, including those related to the homeostasis of lymphoid cells, and to the growth and metastasis of hepatic cancer., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Eight patients with inoperable advanced gastric cancer were treated with combination chemotherapy of S-1, low-dose cisplatin(CDDP)and Lentinan. S-1 80 mg/ m² was orally administered for 2 weeks followed by 1-week rest, CDDP 15 mg/ m² and Lentinan 2 mg/body were given intravenously on day 1 and 8. One complete response and four partial responses were observed for an overall response rate of 63%(5 of 8 patients). Only one patient developed over grade 3 toxicity leukocytopenia. Many patients could be maintained by long-term continuous treatment. Since combination chemotherapy of S-1/low-dose CDDP/Lentinan for advanced gastric cancer was very tolerable, it could be used for a long time.

This study investigated how Japanese-speaking learners of English pronounce the three point vowels /i/, /u/, and /a/ appearing in the first and second monosyllabic words of English noun phrases, and the schwa /ə/ appearing in English disyllabic words. First and second formant (F1 and F2) values were measured for four Japanese speakers and two American English speakers. The hypothesis that the area encompassed by the point vowels in the F1-F2 vowel space tends to be smaller for the Japanese speakers than for the English speakers was verified. The hypothesis that the area formed by the three schwas in chicke_n, spoonfu_l, and Tarza_n is greater for the Japanese speakers than for the English speakers and its related hypothesis were largely upheld. Implications for further research are briefly discussed.

A 61-year-old man with esophagus invasive advanced gastric cancer and peritoneum dissemination underwent three courses of S-1/CDDP/Lentinan (LNT) combination neoadjuvant chemotherapies (T3N1P1H0, Stage IV) (It is S-1 80 mg/m2,CDDP 15 mg/m2 and LNT 2 mg/body twice/week for two weeks) since down staging was obtained. We performed the surgery of total gastrectomy, splenectomy, D2 lymph node dissection, and Roux-en Y reconstruction in March 2008. With the surgical examination, there was no ascites and peritoneal dissemination. Although there was serious infiltration, we were able to remove it. In the histopathological effect judgment, it was Grade 1b. We changed the therapy to S-1 alone after the same chemotherapy for six months. One year after the operation, he is still alive one year after the surgery.

We have established a protocol for generating antibodies to native G-protein coupled receptors using genetic immunization with a molecular adjuvant, E. coli Gro-EL. Here, we adapted this protocol for use in transchromosome KM mice, which bear a set of human immunoglobulin genes. The immunization of KM mice using expression plasmids containing genes encoding three different human cytokine receptor genes, CXCR4, CCR3, and CCR5, resulted in significant Ab responses to these receptors. The combination of this DNA immunization protocol and KM mice might be a useful strategy for generating human antibodies to cytokine receptors.

The effect of T-2328 {2-fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl]amino]methyl]-[1,1'-biphenyl]-4-carbonitrile dihydrochloride}, a novel tachykinin NK(1)-receptor antagonist, was examined on cisplatin-induced emesis in ferrets. Cisplatin induced acute emesis in 24 h and delayed emesis during 24 and 72 h, respectively. Ondansetron, a 5-HT(3) antagonist, almost completely blocked the acute emesis and transiently reduced the delayed emesis. In contrast, T-2328 elicited long-lasting anti-emetic effects on both acute and delayed phases by a single intravenous administration. Suppression of delayed emesis was not due to elimination of the acute phase because the delayed emesis was also suppressed by administration after the onset of delayed emesis. Persistent blockade of NK(1) receptors in the brain was demonstrated by inhibition of the NK(1) agonist-induced foot tapping response for over 24 h. An appreciable amount of T-2328 was present in the brain 32 and 72 h after the injection. The NK(1) agonist-induced contractions of isolated ileum in guinea pigs was antagonized with IC(50) values of 1.4 nM in an insurmountable manner. It is likely that T-2328 exerts the long-lasting anti-emetic effect by not only long-term presence in the brain but also its insurmountable inhibition of NK(1) receptors.

The absorption enhancing effects of various combinations of a mucolytic agent and a non-ionic surfactant on the intestinal absorption of poorly absorbed hydrophilic compounds were examined. Fluorescein isothiocyanate-labeled dextran with an average molecular weight of ca. 4.4 kDa (FD-4) was used as a model compound. Cysteine derivatives such as N-acetylcysteine (NAC), S-carboxymethylcysteine (SCMC), S-ethylcysteine (SEC), and S-methylcysteine (SMC) were selected as mucolytic agents. A homogeneous series of single chain polyoxyethylene alkyl ethers were employed as non-ionic surfactants. Various dosing solutions were administered into rat jejunum, and the bioavailability of FD-4 was determined. Unlike NAC, the agents such as SCMC, SEC, and SMC, which do not possess a free thiol group, did not show any apparent enhancement of intestinal FD-4 absorption, when they were co-administered with p-t-octyl phenol polyoxyethylene-9.5 (Triton X-100, TX-100). In addition, the absorption enhancement was dependent on the kinds of polyoxyethylene alkyl ethers used, when used in combination with NAC. For a constant alkyl chain of 12 with a varying polyoxyethylene (POE) chain length, the surfactant with a short to medium POE chain length such as lauryl poly (4.2) oxyethylene ether (BL-4.2) and lauryl poly (9) oxyethylene ether (BL-9) were effective. In addition, for a constant alkyl chain of 18 with a varying POE chain length, the surfactants with a longer POE chain length such as oleyl poly (15) oxyethylene ether (BO-15) and stearyl poly (20) oxyethylene ether (BS-20) showed the effective enhancement. All these results suggest that a mucolytic agent not possessing a free thiol group is not effective for enhancing the intestinal absorption of poorly absorbed hydrophilic compounds. Also, they indicate that the combination of a mucolytic agent possessing a free thiol group and a non-ionic surfactant either with a short to medium POE chain length and a medium alkyl chain length, or with a longer POE chain length and a longer alkyl chain length shows the effective enhancement. This fundamental information might be useful for finding the optimal combination.

Absorption enhancement of poorly absorbed hydrophilic compounds from various mucosal sites by co-administration of a mucolytic agent and a non-ionic surfactant was examined in rats. Fluorescein isothiocyanate-labeled dextran with average molecular weight of ca. 4.4kDa (FD-4), and salmon calcitonin (SCT) were used as model compounds. N-acetylcysteine (NAC) and p-t-octyl phenol polyoxyethylene-9.5 (Triton X-100, TX-100) were selected as a mucolytic agent and a non-ionic surfactant, respectively. Dosing solutions containing these agents were administered into various mucosal sites including the nose, the lung and the large intestine, and the bioavailabilities were determined. The combination of 5% NAC and 5% TX-100 significantly enhanced the nasal, the pulmonary and the large intestinal absorption of FD-4 compared to the control, and the enhancement ratios relative to the control were 7.2-, 2.8- and 4.5-fold, respectively. The different enhancement ratio among the administration sites explored indicates that the absorption enhancing effect of the combination of NAC and TX-100 is site-dependent. This combination also improved the nasal and the pulmonary absorption of SCT, and the enhancement ratios relative to the control were 6.1- and 8.1-fold, respectively. All these results suggest that the combination strategy of a mucolytic agent and a non-ionic surfactant may be widely applicable to various mucosal deliveries of poorly absorbed hydrophilic compounds.

Objective: To investigate whether matrix metalloproteinases (MMPs) and/or aggrecanase in synovial fluid can be used as biochemical markers in the diagnosis of internal derangement (ID) of the temporomandibular joint (TMJ)., Study Design: Forty-four samples of synovial fluid were obtained from 35 patients with ID and osteoarthritis (OA) and 15 normal samples from 10 asymptomatic volunteers. MMP-2, -9, and aggrecanase in the synovial fluid were examined by immunoblotting., Results: The incidences of MMP-2, -9, and aggrecanase expression in the ID and OA group were significantly higher than those in the normal group (P < .05). Those with anterior disc displacement without reduction and severe OA showed significantly high expression of MMP-9 compared with other disease subgroups (P < .05). Conversely, comparatively high expression of MMP-2 and aggrecanase was shown in the early-stage OA group. However, there was no significant difference in expression of MMP-2 and aggrecanase among disease subgroups., Conclusions: These findings suggested that expression of aggrecanase could be a potential biochemical marker for articular cartilage degradation in ID of the TMJ.

The present study investigated the intestinal absorption enhancement of salmon calcitonin (SCT) and the intestinal mucosal damage when a mucolytic agent and a non-ionic surfactant were administered simultaneously to rats. N-acetylcysteine (NAC) and p-t-octyl phenol polyoxyethylene-9.5 (Triton X -100, TX-100) were chosen as the model mucolytic agent and the non-ionic surfactant, respectively. Dosing solutions containing these agents were administered directly into the rat jejunum, and the bioavailability of SCT up to 2 h was determined. NAC and TX-100, when they were used alone at a dose of 1 mg/head, did not show the apparent enhancement compared to the control. However, simultaneous use of NAC and TX-100 enhanced the intestinal absorption of SCT in a synergistic manner, and absolute bioavailability increased 12.5-fold compared to the control. The effect of NAC and TX-100 on SCT absorption was not dependent on their doses over the range of 0.2-2 mg/head, and the maximum effect was obtained at a dose of 1mg/head. Absorption enhancement of SCT by a combination of NAC and TX-100 was compared to those from the classical absorption enhancers. Absorption-enhancing ability of the combination of NAC and TX-100 was significantly higher than those of sodium deoxycholate, citrate, and the combination of citrate and taurocholate, and was comparable with that of the combination of citrate and taurodeoxycholate. Finally, the intestinal mucosal damage caused by the combination of NAC and TX-100 was assessed using a capsule device. Acute damage on intestinal mucosa was observed when they were exposed into rat intestine, but this morphological damage was found to be reversible. All these results suggest that simultaneous use of a mucolytic agent and a non-ionic surfactant would offer a potentiality for peroral delivery of peptide drugs like SCT.

The aim of this study was to examine the relationship between disc position and stress direction on the condyle by means of stress analysis using the rigid body spring model (RBSM) theory. The material consisted of 88 joints of 44 Class III dentofacial deformity patients, divided into symmetry and asymmetry groups on the basis of the Mx-Md midline position. The asymmetry group was identified by comparison with a reference midline vertical plane passing through a plane from ANS to Me. Asymmetry was diagnosed when the angle between these two planes was greater than 3 degrees. The geometry of the stress analysis model was based on sagittal tomography of the subject. The first molar, gonial angle, and the most anterior, superior, and posterior points on the condyle were plotted on a computer display, and stress angulation on the condyles was calculated with the RBSM program. In addition to anterior displacement with or without reduction, three types of disc position could be identified using magnetic resonance imaging (MRI): anterior, fully covered and posterior. In the asymmetric group, stress angulation was significantly higher (P < 0.05) at the deviation side compared with the non-deviation side. There was also a significant correlation between disc position and stress angulation (P < 0.05). In the asymmetry group, regression analysis indicated a significant correlation (P < 0.001) between the difference in stress angulation (between the deviation side and the non-deviation side) and the degree of asymmetry (measured by the angle of asymmetry). This study demonstrated that temporomandibular joint (TMJ) stress was associated with TMJ morphology in Class III patients whether or not they were asymmetric.

Purpose: The purpose of this study was to clarify the influence of patients age and the degree of dislocation on the healing of mandibular condyle fractures., Material and Methods: Sixty-two Japanese white rabbits (30 adolescent and 30 adult ones) were used. They underwent unilateral condylar neck osteotomy. The proximal fragments were positioned differently. In group I animals, the fragments were reduced into the original position, in group II animals the small fragment was dislocated 55-90 degrees to the ramus. In group III animals the proximal fragment was dislocated 135 degrees to the ramus. Gross and microscopic assessment was performed 4, 6, 8, 12 and 24 weeks postoperatively., Results: In adolescent animals, complete healing of the fracture was observed, irrespective of the degree of dislocation. In the adult animals, there was complete healing of the fractures in groups I and II. In group III animals, there was a decrease of ramus height accompanied by some fibro-cartilaginous changes., Conclusion: Even in rabbits condylar deformation has been found following heavily dislocated artificial condylar fractures in adult animals. This result will help to decide for or against surgical treatment of condylar fractures in humans.

Objective: The purpose of this study was to elucidate causal relationship between disc and condyle range of movement and clinical signs and symptoms in patients with temporomandibular disorders (TMD), using magnetic resonance imaging (MRI)., Study Design: The subjects comprised of a study group of 191 patients with TMD and a control group of 43 asymptomatic patients. The clinical assessment consisted of range of maximum mouth opening (MMO) and preauricular pain during mandibular function. After clinical and radiographic findings assessment, disc and condyle condition were examined by MRI and the range of movement was accordingly classified., Results: Disc displacement was observed in 156/191 (81.7%) of the study group and 9/43 (20.9%) of the control group. When disc and condyle mobility was presented around the eminence, wider MMO range was maintained, P < .05. Presence of osteoarthrosis (OA) was not correlated with preauricular pain, because OA variables were mild in the study group., Conclusion: Maintenance of disc/condyle translation is an important factor in TMJ function, irrespective of disc displacement or arthritis.

A specific and simultaneous assay of morphine, morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G) in monkey and dog plasma has been developed. These methods are based on rapid isolation using solid phase extraction cartridge, and high-performance liquid chromatography (HPLC)-electrospray ionization (ESI)-tandem mass spectrometric (MSMS) detection. Analytes were separated on a semi-micro ODS column in acetonitrile-formic (or acetic) acid mixed solution. The selected reaction monitoring for assay in monkey and dog plasma, as precursor-->product ion combinations of m/z 286-->286 for morphine, m/z 462-->286 for glucuronides and m/z 312-->312 for internal standard (IS, nalorphine) were used. The linearity of morphine, M-3-G and M-6-G was confirmed in the concentration range of 0.5-50, 25-2500, 2.5-250 ng/ml in monkey plasma, 0.5-100, 25-5000, 2.5-500 ng/ml in dog plasma, respectively. The precision of this assay method, expressed as CV, was less than 15% over the entire concentration range with adequate assay accuracy. Therefore, the HPLC-ESI-MSMS method is useful for the determination of morphine, M-3-G and M-6-G with sufficient sensitivity and specificity in pharmacokinetic studies.

Distraction osteogenesis of the maxilla is indicated for jaw deformities in patients with extreme dysgnathia. First, extraoral appliances were introduced, and currently intraoral appliances are in vogue. These have significantly reduced the amount of physical and psychological stress placed on the patients. The direction of force vector may be varied according to the individual patient's requirements. This paper presents positioning devices for bilateral intraoral maxillary distraction plates, which have been developed to place maxillary distraction plates parallel to the direction of lengthening.

Purpose: We sought to assess the relationship of the inferior alveolar nerve to the osteotomy site after bilateral sagittal split osteotomy (BSSO) and to correlate the nerve osteotomy relationship as the cause of long-term postoperative hypesthesia., Patients and Methods: The subjects consisted of 28 patients with mandibular prognathism who underwent BSSO setback surgery. The distance between the ostectomized surface of the mandibular ramus and mandibular canal was measured and scored on a computed tomograph (CT). The relationship between this distance and the presence and degree or absence of trigeminal nerve hypesthesia was objectively evaluated by latency delay of the trigeminal somatosensory evoked potential (TSEP) records., Results: Five of the 56 sides (8.9%) showed latency delays more than 1 year after the operations. Scored CT points between the canal and the split surface strongly correlated with TSEP latency recovery (Y = 1.716X + 41.2)., Conclusions: This relationship between the canal and the osteotomy site is related to long-term hypesthesia in BSSO postoperatively.

Purpose: To examine the results of a polylactic acid/polyglycolic acid copolymer and gelatin sponge complex (PGS) with or without recombinant human bone morphogenetic protein-2 (rhBMP-2) used to treat condylar defects in rabbits., Material and Methods: Adult male Japanese white rabbits (n=60; 3kg; 12-16 weeks old) were divided into three groups of 20 each. All rabbits underwent condylectomy. In the two implanted groups, PGS with or without 5 microg of rhBMP-2 was implanted to the condylar defect without fixation. No material was implanted into the control group. Animals were sacrificed at 2, 4, 8, 12 and 24 weeks postoperatively, and the temporomandibular joints (TMJs) were examined histologically., Results: Four weeks after implantation, growth of bone and cartilage-like tissue was observed in all rabbits that received PGS implants (with and without rhBMP-2). A cartilage-like layer was derived from the bone marrow at the operated surface. There was no growth of bone tissue in the control rabbits, but they also had a cartilage-like layer directly derived from the operated surface., Conclusion: This study demonstrated that PGS with or without rhBMP-2 could induce regeneration of new bone and cartilage-like tissue in the TMJ.

Purpose: The present study establishes a model of reversible anterior disc displacement using the rabbit craniomandibular joint (CMJ) and examines the period required for successful disc repositioning surgery., Materials and Methods: The left CMJ was exposed surgically in 27 animals and a suture positioned at the posterolateral portion of the disc was pulled in an anterior direction causing 7 mm of anterior disc displacement. The suture was then fixed to the zygomatic arch. The changes in the CMJ were observed microscopically in 3 rabbits each at 2, 3, 5, 8, and 24 weeks. Another 12 rabbits underwent secondary disc repositioning surgery either the second and third week after disc displacement, and then 3 rabbits from each group were assessed microscopically at 5 to 6 weeks and 21 to 22 weeks after the first operation. Ten rabbits had a sham operation, and 2 served as unoperated controls. Histomorphometric evaluation included changes in morphology, cartilage, and disc condition., Results: Progressive osteoarthritic change was induced by disc displacement. Articular disc perforation at 5 weeks after the first operation was accompanied by subchondral bone exposure. The CMJ morphology was almost normal in rabbits that underwent secondary disc repositioning 2 weeks after disc displacement. However, osteoarthritic changes and perforated discs similar to those in rabbits that did not undergo secondary disc repositioning were seen in animals in which repositioning was done in the third week., Conclusion: Artificial disc displacement in the rabbit causes osteoarthritic changes are reversible when the displaced disc is restored within after 2 weeks but not at 3 weeks., (Copyright 2001 American Association of Oral and Maxillofacial Surgeons)

Objective: The purpose of this study was to assess the onset period of trigeminal nerve hypoesthesia during bilateral sagittal split osteotomy, with the use of the trigeminal somatosensory-evoked potential (TSEP)., Study Design: Subjects were 10 patients with mandibular prognathism who underwent setback surgery. Intraoperative TSEP was measured 4 times: just before the commencement of the surgery, immediately after the induction of general anesthesia; after the medial periosteal dissection of the alveolar neurovascular bundle; after the sagittal split of bone; and after semirigid fixation with a titanium miniplate with the use of a monocortical screw. Postoperative TSEP was measured after the start of postoperative weeks 2, 4, 12, and 24. Normal records of the TSEP wave comprised peak (13 ms), trough (16 ms), peak (22.7 ms), and trough (36 ms) (N1, P1, N2, P2, respectively). Trigeminal hypoesthesia was assessed by the latency of P1 and N2, because they indicated the most reproducible waveforms., Results: The change in shape of the spectra indicated that prolonged latency was initiated on medial periosteal dissection and was extended further after the sagittal bone split and fixation. However, latency recovery was observed relatively quickly after the start of postoperative weeks 2 and 4., Conclusions: Trigeminal hypoesthesia appeared to be induced by direct injury to the alveolar nerve during the bone split or by compression injury after fixation. Accordingly, the occurrence of a long-lasting postoperative trigeminal sensory hypoesthesia seemed to depend on nervous involvement of the split surface, the manner of fixation, or the intraoperative care.

Introduction: The purpose of this study was to investigate the relationship between temporomandibular joint (TMJ) morphology, including discal tissue and clinical symptoms in class III dentofacial deformity patients., Material and Methods: Forty-four patients were examined with lateral, frontal and axial cephalograms. They were divided into two groups, consisting of a class III symmetry and a class III asymmetry group. By using magnetic resonance imaging the 88 joints could be classified into four types on the basis of disc position and shape: anteriorly displaced disc, anterior type, fully-covered type and posterior type. Furthermore, TMJ morphology was measured tomographically in the sagittal plane., Results: Anteriorly displaced discs in the asymmetry group (56.8%) occurred significantly more frequently than in the symmetry group (18.2%; p <0.05). TMJ symptoms (clicking, crepitus, closed lock, pain) were seen in 17/44 joints (38.6%) of the symmetry and 24/44 joints (54.5%) of the asymmetry group, for a total of 41/88 joints (46.6%). There were no differences in joint space ratio and condyle ratio. However, the fossa ratio on the deviation side was significantly higher than on the nondeviation side in the asymmetry group (p<0.05)., Conclusion: The incidence of internal derangement in asymmetrical class III patients is higher than in symmetrical mandibular prognathism, and this difference is associated with a difference in TMJ morphology of both sides.

Purpose: To examine changes in condylar cartilage following perforation in the posterolateral region of the articular disk of the craniomandibular joint of a rabbit., Material and Methods: The circular perforation in the left joint of 25 female Japanese white rabbits measured precisely one-sixteenth of a disk. Histological examination, including the immunohistochemical proliferating cell nuclear antigen (PCNA) procedure, was performed on separate sets of five rabbits each 2, 4, 8, 12, and 24 weeks postoperatively., Results: Microscopic examination revealed hypertrophy of the condylar cartilage with osteophyte formation up to 8 weeks after perforation. Proliferative activity then decreased near the condylar surface as the perforation flattened. Twenty-four weeks postoperatively, the condylar surface was found to be fibrous and flattened. Positive PCNA results in cartilage cells indicated proliferation following disk perforation which peaked in the 4th week and then decreased., Conclusion: Disk perforation was followed initially by hypertrophy of condylar cartilage, and later by degeneration of the condylar surface. Although osteoarthritic cartilage was found 24 weeks after perforation, degeneration decreased over time. This suggests that remodelling took place after the perforation.

Following orthognathic surgery undesirable changes in the temporomandibular joints (TMJs) are noted sometimes. Altered stress on the condyle and surrounding tissue frequently causes morphological changes in the TMJ. The purpose of the present study was to assess these morphologic changes in a rabbit following mandibular osteotomy and the resulting mandibular body rotation. Adult male Japanese white rabbits (3 kg, 12-16 weeks old) were applied in this study. An experimental mandibular osteotomy was performed on the right side of the body of the mandible. The surgery includes vertical mandibular body osteotomy 5 mm in width after masseter muscle reflection. Then the anterior and posterior osseous segments were fixed with wire at previously made holes. As a result, the condylar medio-lateral width on the contralateral (left) side was significantly larger than that of the ipsilateral side 2 weeks postoperatively (p < 0.05). There were significant differences in the angle between the right and the left condylar heads 4 weeks postoperatively (p < 0.05). The present experimental study demonstrated morphological changes in the contralateral TMJ caused by unilateral mandibular osteotomy. Postoperative morphological changes implied that there is a process of biological adaptation in the rabbit TMJ.

Objective: This study was designed to test the feasibility of several types of enhancements for cephalometric computed radiographs through use of the Fuji Computed Radiography system (Fuji Photo Film Corp., Tokyo, Japan)., Study Design: The material consisted of four lateral cephalograms made with the Fuji Computed Radiography system that were enhanced by varying the gradient levels before processing by means of both A-type (straight gradation) curves and workstation-type (peaked) curves. The four workstation-type images were set with optical densities at the peak of the curve at 1.5, 1.7, 1.9, and 2.1. Ten observers evaluated eight anatomic landmarks comparing pairs of workstation-type images. The best workstation-type image was then compared with the A-type image for the same landmarks., Results: For the four workstation-type images the best visualization of the anatomic landmarks was seen with workstation-type image 3, which had a maximum optical density of 1.9. Image 3 was also superior to the results of A-type image processing for most of the landmarks., Conclusion: Image enhancement with the application of a computed radiography system is effective for study of lateral cephalograms.

Purpose: The clinical use of auricular cartilage grafting after discectomy has been reported as a treatment in the terminal stage of internal derangement of the temporomandibular joint (TMJ). Although the occurrence of fibrous adhesions has been observed in such grafted joints, the exact tissue reaction to the graft is still not understood. The purpose of this study was to evaluate the histologic changes after discectomy and auricular cartilage grafting in the rabbit craniomandibular joint (CMJ)., Materials and Methods: Unilateral discectomy of the left CMJ was performed in 28 Japanese white rabbits. Auricular cartilage harvested from the ipsilateral ear was grafted as a disc replacement in 14 animals (Group C), and the other 14 underwent wound closure immediately after discectomy (Group B). Two other rabbits (Group A) served as nonsurgically treated controls. Two rabbits from each experimental group were killed at 2, 4, 6, 8, 10, 12, and 24 weeks postoperatively. Microscopic observation of the specimens was performed in the parasaggital plane., Results: Complete resorption of the cartilage layer on the articular surface was observed within 4 weeks postoperatively in group B. Regeneration of a fibrous cartilage layer was observed in this group after 6 weeks, but the postoperative degenerative changes were so severe that the surface of the condyle and eminence was flattened. In contrast, the degenerative changes were milder in group C, although the grafted cartilage showed perforation and fragmentation from the sixth postoperative week onward. The condylar shape and cartilage layer were well preserved at all times., Conclusions: These results suggest that the structure and function of the condyle may be preserved by auricular cartilage grafting after discectomy. However, the problems of adhesion and fragmentation need to be addressed.

We first investigated the difference in carbohydrate antigens' expression between primary tumors and matched metastatic liver lesions of colorectal carcinomas, using immunohistochemical methods. Regarding the degree of expression, SLA, SLX and SPan-1 antigens were found to be expressed on a larger proportion of tumor cells in liver metastases than in primary tumors. Second, comparing the expression of carbohydrate antigens on highly metastatic colon cancer cell line to the parental line, the expression of SLA on the surface of highly metastatic variant was increased more intensively than the parental line. Finally, we investigated the contribution of carbohydrate antigens to endothelial E-selectin binding in colon and pancreatic cancer cells, and the results indicated that SLA might play a significant role in this binding. These findings suggest that the expression of carbohydrate antigens on the surface of cancer cells obviously contributed to E-selectin binding and also to metastatic potential.

We investigated the variable adhesiveness of pancreatic cancer cells by glycosylation inhibitor to elucidate the role of carbohydrate antigens in cell-cell and cell to extracellular matrix adhesion. Various carbohydrate antigens were strongly expressed on pancreatic cancer cell (SW1990) by ELISA, and these expression correlated to its in vitro invasiveness and in vivo metastatic potential. Cellular adhesion to Matrigel, laminin and collagen type IV and homotypic cellular aggregation in SW1990 were enhanced by reducing O-linked glycosylation with its inhibitor (Bzl-GalNAc), and these effect were reversed by additional purified mucins. These results suggested that O-linked glycoproteins on SW1990 cell surface may inhibit its adhesiveness to the substratum and aggregation properties by hindering surface receptors, and this variability of adhesiveness induced by altered glycosylation may have an another important role in highly metastatic potential of well glycosylated cancer cells.

Quantification of nuclear DNA content in cancer is considered a prognostic factor, and several investigators have demonstrated that aneuploid tumors are more aggressive than diploid tumors. In this report, we investigated the relationship between metastatic capacity and nuclear DNA content using gastric and colon cancer cell lines. We established a highly peritoneal metastatic cell line (2M-D3) from a gastric cancer cell line (2M) and a highly liver metastatic cell line (LM-H3) from colon cancer cell line (LM) in our laboratory. Both the highly metastatic cell lines have more capacity for growth and metastasis, but lower nuclear DNA content and chromosome numbers than these parental cell lines. The results indicated that metastatic capacity was inversely proportional to nuclear DNA content. We cannot provide a satisfactory explanation for this inverse correlation between metastatic capacity and nuclear DNA content, but it is supposed that each cancer cell may have suitable and stable nuclear DNA content in metastasis.

In this study, the expression of thymidine phophorylase (dThdPase) was investigated immunohistochemically in 73 patients with gastric cancer. dThd Pase was mainly distributed at the apical portion, or cytoplasm of cancer cells and its expression was detected in 52 tumors (71.2%). There were no significant association among the expression of dThdPase, histologic type, depth of invasion, and lymph node metastasis. However, a significant difference was noted with respect to liver metastases. Among 73 patients, liver metastases were observed in 11 patients. dThdPase expression was detected in all of these cases with liver metastases, which was significantly more common than those without such metastases. In relation to the prognosis, patients with dThdPase-positive tumors had a significantly worse prognosis than those with dThdPase-negative tumors. In conclusion, the expression of dThdPase may be useful as a predictor of malignant potential in gastric cancer.

The clinical significance of AgNOR and microvessel quantitation as prognostic indicators in Stage I breast cancer were examined. This study included 99 patients with Stage I breast cancer, with a median follow-up period of 119 months. AgNOR was stained by Crocker's method and microvessels were identified by immunohistochemical staining for Factor VIII-related antigen in formalin-fixed, paraffin-embedded primary tumors. AgNOR score related with tumor size. Microvessel count was related to estrogen receptor status. When patients were classified into two groups by the mean AgNOR score, higher scores had a tendency to be correlated with shorter overall survival. And when classified by microvessel count, higher counts were significantly associated with shorter overall, survival (p < 0.01). The microvessel count might be a useful predictor and the AgNOR score could be used to corroborate predictions for identifying patients at high risk for relapse and death in Stage I breast cancer.