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Immunotherapy with nivolumab for patients with recurrent/metastatic oral squamous cell carcinoma has not been evaluated. Here, we aimed to examine the efficacy, safety, and prognostic factors of nivolumab in these patients.This multicentre retrospective observational study involved patients who received nivolumab between April 2017 and June 2019. The patient characteristics were evaluated for association with progression-free and overall survival. Progression-free and overall survival rates were calculated; parameters that were significant in the univariate analysis were used as explanatory variables. Independent factors for progression-free and overall survival were identified using multivariate analysis.Totally, 143 patients were included. The overall response and disease control rates were 27.3% and 46.2%, respectively. The median, 1-year, and 2-year progression-free survival rates were 2.7 months, 25.4%, and 19.2%, respectively; those for overall survival were 11.2 months, 47.3%, and 33.6%, respectively. The independent factors affecting progression-free survival were performance status and immune-related adverse event occurrence, whereas those affecting overall survival were performance status, target disease, and number of previous lines of systemic cancer therapy. Eight patients reported grade ≥3 immune-related adverse events.Nivolumab was effective for recurrent/metastatic oral squamous cell carcinoma treatment and was well tolerated by patients.

It is widely accepted that cellular processes are controlled by protein phosphorylation and has become increasingly clear that protein degradation, localization and conformation as well as protein-protein interaction are the examples of subsequent cellular events modulated by protein phosphorylation. Enamel matrix proteins belong to members of the secretory calcium binding phosphoprotein (SCPP) family clustered on chromosome 4q21, and most of the SCPP phosphoproteins have at least one S-X-E motifs (S; serine, X; any amino acid, E; glutamic acid). It has been reported that mutations in C4orf26 gene, located on chromosome 4q21, are associated with autosomal recessive type of Amelogenesis Imperfecta (AI), a hereditary condition that affects enamel formation/mineralization. The enamel phenotype observed in patients with C4orf26 mutations is hypomineralized and partially hypoplastic, indicating that C4orf26 protein may function at both secretory and maturation stages of amelogenesis. The previous in vitro study showed that the synthetic phosphorylated peptide based on C4orf26 protein sequence accelerates hydroxyapatite nucleation. Here we show the molecular cloning of Gm1045, mouse homologue of C4orf26, which has 2 splicing isoforms. Immunohistochemical analysis demonstrated that the immunolocalization of Gm1045 is mainly observed in enamel matrix in vivo. Our report is the first to show that FAM20C, the Golgi casein kinase, phosphorylates C4orf26 and Gm1045 in cell cultures. The extracellular localization of C4orf26/Gm1045 was regulated by FAM20C kinase activity. Thus, our data point out the biological importance of enamel matrix-kinase control of SCPP phosphoproteins and may have a broad impact on the regulation of amelogenesis and AI.

BackgroundMaxillary gingival squamous cell carcinoma (MGSCC) occurs rather infrequently, compared to tongue and mandibular gingival carcinomas, among the cancers of the oral cavity. Therefore, significant numbers of MGSCC cases have not been statistically analysed. The aim of this study is to clarify the prognostic factors for MGSCC. MethodsWe performed the statistical analysis of 90 MGSCC cases primarily treated in our department from 1999 to 2014. ConclusionsThe patients (male: 36, female: 54) were aged between 38 and 93 years, and the mean age was 68.7 years. The number of patients in each tumour stage according to the TNM classification was as follows: T1: 15 cases, T2: 32 cases, T3: 13 cases, and T4: 30 cases. Forty-two patients were treated only by surgery, 5 only by radiotherapy, 3 by preoperative radiotherapy and surgery, and 40 patients were treated by combination therapy with preoperative chemoradiotherapy and surgery. Neck dissections were performed in 40 cases including 29 cases (11 primary and 18 secondary cases) of histopathologically diagnosed lymph node metastases. Extranodal extension was found in 74.3% cases with metastatic lymph nodes. The 5-year overall survival rate was 81.9%. In univariate analysis, the site of occurrence, stage of tumour, lymph node metastasis, and treatment contributed to the 5-year survival rate. Multivariate analysis demonstrated that the site of occurrence (posterior region) was an independent prognostic factor. Seventeen deaths occurred due to the primary disease, while three deaths were caused by other diseases. ConclusionThe posterior region cancers, according to the classification based on site of occurrence, were independent predictors of poor 5-year overall survival rate.

BackgroundDown syndrome is characterized by a variety of dysmorphic features and congenital malformations, such as congenital heart disease, gastrointestinal disease, and other conditions like leukemia and autoimmune disorders. Patients with Down syndrome are highly prone to respiratory tract infections, which might be fatal to them. However, there are only few available data on patients diagnosed with Down syndrome and agammaglobulinemia. In this report, we describe a case of successful prevention of post-dental treatment complications (e.g., pneumonia and other bacterial infections) in a patient with Down syndrome and agammaglobulinemia.Case presentationA 43-year-old man with Down syndrome, untreated agammaglobulinemia, and a history of recurrent pneumonia, was referred to our clinic for tooth mobility. To reduce the risk of post-operative infections, gammaglobulin treatment and prophylactic administration of antibiotics was scheduled before the dental procedure. Furthermore, the dental treatment, which included a filling and extractions, was conducted under general anesthesia and with the supervision of a hematologist. The dental procedures were successfully performed without any post-operative infection, and the patient is undergoing follow-up care.ConclusionsThe purpose of this case report was to recommend a close liaison between physicians and dentists who may encounter a similar case, and to emphasize the importance of improving oral health of immunodeficient patients to prevent infections caused by oral microbial flora.

Amelogenesis Imperfecta (AI) represents a group of hereditary conditions that manifest tooth enamel defects. Several causative mutations in the WDR72 gene have been identified and patients with WDR72 mutations have brown (or orange-brown) discolored enamel, rough enamel surface, early loss of enamel after tooth eruption, and severe attrition. Although the molecular function of WDR72 is not yet fully understood, a recent study suggested that WDR72 could be a facilitator of endocytic vesicle trafficking, which appears inconsistent with the previously reported cytoplasmic localization of WDR72. Therefore, the aims of our study were to investigate the tissues and cell lines in which WDR72 was expressed and to further determine the sub-cellular localization of WDR72. The expression of Wdr72 gene was investigated in mouse tissues and cell lines. Endogenous WDR72 protein was detected in the membranous fraction of ameloblast cell lines in addition to the cytosolic fraction. Sub-cellular localization studies supported our fractionation data, showing WDR72 at the Golgi apparatus, and to a lesser extent, in the cytoplasmic area. In contrast, a WDR72 AI mutant form that lacks its C-terminal region was exclusively detected in the cytoplasm. In addition, our studies identified a putative prenylation/CAAX motif within the last four amino acids of human WDR72 and generated a WDR72 variant, called CS mutant, in which the putative motif was ablated by a point mutation. Interestingly, mutation of the putative CAAX motif impaired WDR72 recruitment to the Golgi. Cell fractionation assays confirmed subcellular distribution of wild-type WDR72 in both cytosolic and membranous fractions, while the WDR72 AI mutant and CS mutant forms were predominantly detected in the cytosolic fraction. Our studies provide new insights into the subcellular localization of WDR72 and demonstrate a critical role for the C-terminal CAAX motif in regulating WDR72 recruitment to the Golgi. In accordance with structural modelling studies that classified WDR72 as a potential vesicle transport protein, our findings suggest a role for WDR72 in vesicular Golgi transport that may be key to understanding the underlying cause of AI.

Previous studies suggest that the nerve to the mylohyoid muscle could have a cutaneous branch. However, its clinical relevance has rarely been discussed because there is insufficient evidence for it. Our aim in this study was to investigate the anatomy of the cutaneous branch of the nerve to the mylohyoid muscle and extend the discussion to surgical management.Twenty sides from ten embalmed cadaveric heads were dissected to identify the cutaneous branch of the nerve to the mylohyoid muscle. The cutaneous branch was traced up to its termination.The cutaneous branch was observed in 90% and classified into types I and II. In type I, the terminal trunk reached the anterior belly of the digastric muscle. In type II there were two types of terminal trunks, superior and inferior branches, which were identified on all sides. The number of the terminal trunk was one in 23.1% (type I; 6/26) and two in 76.9% (type II; 20/26). The terminal points of the cutaneous branch were all located within a 3 cm × 2 cm rectangular segment in the center of the submental area.We propose a new dermatome including the nerve to the mylohyoid muscle in the center. Understanding the cutaneous branch of the nerve could help surgeons to prevent iatrogenic sensory loss of the submental area.

Background The prognosis of advanced oral cancer remains dismal. While multimodal therapy is beneficial, maintaining the quality of life of long-term survivors is important. Therefore, risk-adapted treatment regimens need to be designed. We herein investigated whether pathological responses in oral cancer patients treated with preoperative chemoradiotherapy predict locoregional recurrence. Methods We retrospectively reviewed the data of 51 oral cancer patients who received preoperative radiotherapy and concurrent pepleomycin, followed by curative surgery at our institution between January 2009 and June 2018. Each patient received preoperative external beam irradiation to the primary tumor and lymphatics (2 Gy per day for approximately 3 weeks) concurrent with pepleomycin (2.5 mg/day). Surgery was performed approximately 3–4 weeks after the completion of preoperative chemoradiotherapy. Pathological responses were defined based on the grading system of Oboshi and Shimosato. Results Eight, 22, 16, and 5 patients had Oboshi and Shimosato grades 2a, 2b, 3, and 4, respectively. Favorable pathological responses (grades 3 and 4) were observed in 41.2% of patients (21 out of 51 patients). The pathological response and number of pathological lymph node metastases were identified as significant prognostic factors for locoregional control in the univariate analysis. Three-year locoregional control rates were 100 and 56.6% in patients with favorable and unfavorable pathological responses, respectively. Conclusions The present study demonstrated that pathological tumor responses to preoperative chemoradiotherapy are a useful predictive factor for locoregional control.

Background The prognosis of advanced oral cancer remains dismal. While multimodal therapy is beneficial, maintaining the quality of life of long-term survivors is important. Therefore, risk-adapted treatment regimens need to be designed. We herein investigated whether pathological responses in oral cancer patients treated with preoperative chemoradiotherapy predict locoregional recurrence. Methods We retrospectively reviewed the data of 51 oral cancer patients who received preoperative radiotherapy and concurrent pepleomycin, followed by curative surgery at our institution between January 2009 and June 2018. Each patient received preoperative external beam irradiation to the primary tumor and lymphatics (2 Gy per day for approximately 3 weeks) concurrent with pepleomycin (2.5 mg/day). Surgery was performed approximately 3–4 weeks after the completion of preoperative chemoradiotherapy. Pathological responses were defined based on the grading system of Oboshi and Shimosato. Results Eight, 22, 16, and 5 patients had Oboshi and Shimosato grades 2a, 2b, 3, and 4, respectively. Favorable pathological responses (grades 3 and 4) were observed in 41.2% of patients (21 out of 51 patients). The pathological response and number of pathological lymph node metastases were identified as significant prognostic factors for locoregional control in the univariate analysis. Three-year locoregional control rates were 100% and 56.6% in patients with favorable and unfavorable pathological responses, respectively. Conclusions The present study demonstrated that pathological tumor responses to preoperative chemoradiotherapy are a useful predictive factor for locoregional control.

Ellis-van Creveld (EvC) syndrome is a genetic disorder with mutations in either EVC or EVC2 gene. Previous case studies reported that EvC patients underwent orthodontic treatment, suggesting the presence of craniofacial bone phenotypes. To investigate whether a mutation in EVC2 gene causes a craniofacial bone phenotype, Evc2 knockout (KO) mice were generated and cephalometric analysis was performed. The heads of wild type (WT), heterozygous (Het) and homozygous Evc2 KO mice (1-, 3-, and 6-week-old) were prepared and cephalometric analysis based on the selected reference points on lateral X-ray radiographs was performed. The linear and angular bone measurements were then calculated, compared between WT, Het and KO and statistically analyzed at each time point. Our data showed that length of craniofacial bones in KO was significantly lowered by ∼20% to that of WT and Het, the growth of certain bones, including nasal bone, palatal length, and premaxilla was more affected in KO, and the reduction in these bone length was more significantly enhanced at later postnatal time points (3 and 6 weeks) than early time point (1 week). Furthermore, bone-to-bone relationship to cranial base and cranial vault in KO was remarkably changed, i.e. cranial vault and nasal bone were depressed and premaxilla and mandible were developed in a more ventral direction. Our study was the first to show the cause-effect relationship between Evc2 deficiency and craniofacial defects in EvC syndrome, demonstrating that Evc2 is required for craniofacial bone development and its deficiency leads to specific facial bone growth defect. Anat Rec, 299:1110-1120, 2016. © 2016 Wiley Periodicals, Inc.

Case We report a case of post-traumatic hypopituitarism in a 9-year-old boy who was injured in a car accident. Outcome Post-traumatic hypopituitarism might be caused by moderate to severe head trauma, and while this possibility has recently drawn attention in adults, few reports are available regarding children. Our patient experienced head and facial injury, resulting in post-traumatic hypopituitarism. Six hours after injury he suffered from diabetes insipidus and hormone replacement therapy was started. On day 12 he underwent facial fracture reduction under general anesthesia. On day 24 he was discharged from the hospital. One year after the injury, secretory function and water dehydration tests suggested the possibility of post-traumatic hypopituitarism. Conclusion We experienced a child case of post-traumatic hypopituitarism. Emergency physicians should pay attention to the possibility of post-traumatic hypopituitarism in cases of traumatic brain injury.

Bone and dentin are mineralized extracellular matrices produced by osteoblasts and odontoblasts, respectively, and their major organic portion is type I collagen. Dentinogenesis Imperfecta (DGI) is one of the most common clinically- and genetically-based disturbances of dentin formation, causing irreversible dentin defects. Among several types of DGI, patients with DGI type II exhibit opalescent dentin with partial or complete pulp obliteration. It has been previously reported that the non-sense mutation (c.133C>T) in Dentin Sialophosphoprotein (DSPP) was identified in DGI type II patients at glutamine residue 45, resulting in the premature stop codon (p.Q45X). DSPP is known to be synthesized as a single gene product and further processed at Gly462-Asp463, resulting in the production of Dentin Sialoprotein (DSP) and Dentin Phosphoprotein (DPP). We hypothesized that the shorter form (Q45X) of N-terminal Dentin Sialoprotein (N-DSP) may cause over-production of type I collagen protein as obliterated pulp is occupied by dentin. To test this hypothesis, we generated mouse recombinant Glutathione-S-Transferase (GST)-N-DSP fusion protein, and the effect of GST-N-DSP was investigated in calvarial bone explant culture and MC3T3-E1 osteoblastic culture systems. Here we show that a significant increase in calvarial bone formation is observed by GST-N-DSP. GST-N-DSP accelerates MC3T3-E1 osteoblast cell growth and proliferation and subsequent osteoblast differentiation by inducing the expression of certain osteogenic markers such as type I collagen, Runx2, Osterix and ATF4. Interestingly, GST-N-DSP significantly enhances dentinogenesis marker gene expression including Dspp and Dmp1 gene expression in non-odontogenic MC3T3-E1 cells. To rule out any artificial effect of GST-tag, we also used the synthetic peptide of N-DSP and confirmed the results of N-DSP peptide were essentially similar to those of GST-N-DSP. Taken together, our data suggest that N-DSP promotes bone formation by accelerating osteoblast cell proliferation and subsequent osteoblast differentiation accompanied by marked up-regulation of the dentin matrix markers, such as Dspp and Dmp1 genes., Highlights • Recombinant N-terminal DSP (N-DSP) protein was generated. • N-DSP mimics the non-sense mutation form of Dentinogenesis Imperfecta type II. • N-DSP enhances bone formation in clavarial ex vivo cultures. • N-DSP accelerates osteoblast proliferation. • N-DSP upregulates type I collagen and Dspp expression in non-odontogenic osteoblasts.

Case A 66 year-old woman who presented with sudden lower abdominal pain was transferred to our emergency room. Vital signs were stable on arrival at the hospital, but immediately became unstable. Systolic/diastolic blood pressure and heart rate were 66/33 mmHg and 70 b.p.m., respectively. Computed tomography scanning showed splenic artery aneurysm rupture and extravasation. The patient was treated non-operatively and definitively by endovascular therapy comprising resuscitative endovascular occlusion of the aorta for hemodynamic control, N-butyl cyanoacrylate, and metallic coils as an embolization material. Outcome On admission day 3, she was enrolled in another department and admission day 54, she was discharged. Conclusion Although resuscitative endovascular occlusion of the aorta and N-butyl cyanoacrylate is known to be effective, the use of resuscitative endovascular occlusion of the aorta with transcatheter arterial embolization and N-butyl cyanoacrylate for non-traumatic bleeding has not previously been reported. By combining and adapting these devices, their applications in endovascular management may be increased.

This clinico-statistical study includes 597 cases of oral squamous cell carcinoma treated at the Maxillofacial Surgery Section of Tokyo Medical and Dental University between January 2002 and December 2011. There were 373 male and 224 female patients (male to female ratio, 1.7 : 1), and the median age was 67 years. The tongue (53.3%) was the most commonly affected site. The 5-year disease-specific survival rate was 84.8%. Survival rates by clinical stage were as follows : Stage 1, 92.1% (n=195).; Stage , 86.0% (n = 221) ; Stage III, 77.7% (n=65) ; and Stage IV, 73.8% (n =116). Survival rates by primary site were as follows: tongue, 85.4% (n=318) ; lower gingiva, 82.8% (n =114) upper gingiva, 83.7% (n=59) ; buccal mucosa, 89.1% (n 54) ; oral floor, 81.4% (n=49) ; and hard palate, 100% (n=3). According to clinical growth patterns of Stage I / I tongue cancer cases, the 5-year disease-specific survival rate was significantly higher for patients with the exophytic/superficial type (97.3%, n =173) than for those with the endophytic type (77.5%, n=145). Among Stage I/II tongue cancer cases, the corresponding survival rate was significantly higher for patients who had not previously undergone invasive treatments (n=201), such as tooth extraction, compared to those who had previously done so (n=54) (92.7% and 79.7%, respectively). In addition, the incidence of secondary cervical lymph node metastasis was significantly higher in patients who had previously undergone invasive treatments.

By a bioinformatics approach, we have identified a novel cysteine knot protein member, VWC2 (von Willebrand factor C domain containing 2) previously known as Brorin. Since Brorin has been proposed to function as a bone morphogenetic protein (BMP) antagonist, we investigated the binding of Brorin/VWC2 to several BMPs; however, none of the BMPs tested were bound to VWC2. Instead, the βA subunit of activin was found as a binding partner among transforming growth factor (TGF)-β superfamily members. Here, we show that Vwc2 gene expression is temporally upregulated early in osteoblast differentiation, VWC2 protein is present in bone matrix, and localized at osteoblasts/osteocytes. Activin A-induced Smad2 phosphorylation was inhibited in the presence of exogenous VWC2 in MC3T3-E1 osteoblast cell line and primary osteoblasts. The effect of VWC2 on ex vivo cranial bone organ cultures treated with activin A was investigated, and bone morphometric parameters decreased by activin A were restored with VWC2. When we further investigated the biological mechanism how VWC2 inhibited the effects of activin A on bone formation, we found that the effects of activin A on osteoblast cell growth, differentiation, and mineralization were reversed by VWC2. Taken together, a novel secretory protein, VWC2 promotes bone formation by inhibiting Activin-Smad2 signaling pathway.

OBJECTIVE This study was conducted to determine whether a policy of not attempting to resuscitate patients who are 80 years of age and older with cardiopulmonary arrest on arrival is justifiable. METHODS The protocol of this study was approved without the need for informed consent by the research ethics board of Gunma University Hospital. We prospectively analyzed patients with cardiopulmonary arrest on arrival that was due to an intrinsic reason who were taken to Gunma University Hospital between January 2013 and March 2014. The patients were divided into two groups: patients who were less than 80 years of age (L group) and those aged 80 years and older (H group). We compared the patients' characteristics, including the etiology of cardiac arrest, and the prognosis between the two groups. RESULTS A total of 103 patients with cardiopulmonary arrest on arrival were enrolled. There were no significant differences in the patients' characteristics, such as age, sex, witness and bystander cardiopulmonary resuscitation, and transportation time between the two groups. The return of spontaneous circulation was obtained in 14 patients (25.5%) in the L group and in 9 patients (18.8%) in the H group; however, no significant difference was seen between the two groups. Two patients in the L group were in good neurological condition when they were discharged; however, the other patients did not survive. CONCLUSION Even patients 80 years of age and older can be resuscitated to spontaneous circulation. We do not endorse a policy that recommends not performing cardiopulmonary resuscitation based solely on the age of the patient.

Extracapsular spread (ECS) of metastatic lymph nodes from oral carcinoma is the most significant prognostic predictor of a poor treatment outcome. However, only a few reports on prognostic factors in ECS-positive cases have been investigated. To address this problem, a detailed examination of ECS pathology was conducted to determine the prognostic factors of oral squamous cell carcinoma (OSCC) with ECS of metastatic lymph nodes. This study involved 63 OSCC patients with at least one pathologically metastatic node with ECS. Among the 229 metastatic lymph nodes, 149 exhibited ECS. Univariate analysis revealed that a poor outcome and recurrence were significantly associated with the number of ECS-positive nodes, density of ECS, and the minor axis of the smallest ECS-positive node. However, multivariate analysis identified only small size of ECS-positive nodes as a significant and independent factor predicting recurrence and a poor outcome. Thus, small size of ECS-positive nodes is the most important prognostic indicator for OSCC with ECS in metastatic lymph nodes. The classification of ECS status using the minor axis of ECS-positive nodes may be useful for further prediction of a poorer prognosis in OSCC cases. Standardization of ECS diagnosis and multicenter prospective studies will be required to confirm and refine these findings.

Aim To determine the formula that predicts the injury severity score from parameters that are obtained in the emergency department at arrival. Methods We reviewed the medical records of trauma patients who were transferred to the emergency department of Gunma University Hospital between January 2010 and December 2010. The injury severity score, age, mean blood pressure, heart rate, Glasgow coma scale, hemoglobin, hematocrit, red blood cell count, platelet count, fibrinogen, international normalized ratio of prothrombin time, activated partial thromboplastin time, and fibrin degradation products, were examined in those patients on arrival. To determine the formula that predicts the injury severity score, multiple linear regression analysis was carried out. The injury severity score was set as the dependent variable, and the other parameters were set as candidate objective variables. IBM spss Statistics 20 was used for the statistical analysis. Statistical significance was set at P

Aim We evaluated the usefulness of fibrin degradation products and D-dimer levels in blood to predict return of spontaneous circulation in patients with cardiopulmonary arrest on arrival compared with anion gap and albumin-corrected anion gap. Methods We retrospectively reviewed the medical records of patients with cardiopulmonary arrest on arrival who had been transferred to the emergency department of our hospital in 2012. Patients were divided into two groups: patients with return of spontaneous circulation (ROSC(+) group), and those without (ROSC(−) group). The levels of anion gap, albumin-corrected anion gap, fibrin degradation products and D-dimer measured on arrival were compared between the two groups. Results Fifty-three patients could be analyzed. The anion gap and albumin-corrected anion gap levels were significantly better in the ROSC(+) group than in the ROSC(−) group (anion gap, 28.7 mmol/L [median] versus 39.1 mmol/L; albumin-corrected anion gap, 31.1 mmol/L versus 40.9 mmol/L). The fibrin degradation product and D-dimer levels were significantly lower in the ROSC(+) group than in the ROSC(−) group (fibrin degradation products, 32.1 μg/mL versus 157.4 μg/mL; D-dimer, 9.9 μg/mL versus 37.4 μg/mL). The area under receiver operating characteristic curves to evaluate the relationship with return of spontaneous circulation of anion gap, albumin-corrected anion gap, fibrin degradation products, and D-dimer were 0.664, 0.667, 0.714, and 0.707, respectively. Conclusion Fibrin degradation products and D-dimer levels might be more useful as predictors of return of spontaneous circulation than anion gap and albumin-corrected anion gap.

Dentigerous cysts are one of the most prevalent types of odontogenic cysts and are associated with the crown of an unerupted tooth, especially of the mandibular third molar. In this study, the characteristics of a dentigerous cyst developed around a mandibular third molar on panoramic radiographs were investigated. The panoramic images of 257 consecutive dentigerous cyst cases associated with a mandibular third molar were analyzed. The mean age of the patients was 45.9 &plusmn, 13.3 years. The size of the cyst did not significantly correlate to the age of the patient. The unilocular type (89.1%) and the crown side type (68.5%) were significant. The associated mandibular third molars had a high frequency of class III (64.6%) and position B (48.3%) in Pell and Gregory classification and of horizontal position (36.3%) in angulation. Dentigerous cysts were thought to originate and grow commonly around deeply impacted third molars. The associated third molar with dentigerous cyst tends to have a mesial inclination. Dentigerous cysts do not appear to develop gradually after the crown formation has finished, but arise at various periods randomly.

To evaluate the usefulness of the levels of fibrin degradation products (FDPs) and d-dimer (DD) in blood for reflecting the severity of trauma.We reviewed medical records of trauma patients who were transferred to the emergency department of Gunma University Hospital between January 2010 and December 2010. The relationships among Injury Severity Score, mean blood pressure, heart rate, hemoglobin, hematocrit, platelet count, fibrinogen, international normalized ratio of prothrombin time, activated partial thromboplastin time, FDP, and DD on arrival were examined in those patients.A total of 122 patients were included in this study. The coefficients of correlation of FDP (r = 0.710) and DD (r = 0.636) with Injury Severity Score were higher than those of other parameters. In addition, the areas under the receiver operating characteristic curve of FDP and DD were larger than those of other parameters (0.757 and 0.756, respectively). The cutoff value of FDP from the Youden index was 4.70 μg/mL, and the sensitivity and specificity values were 75.9% and 68.4%, respectively. The cutoff value of DD from the Youden index was 2.55 μg/mL, and the sensitivity and specificity values were 75.9% and 73.7%, respectively. There were four patients requiring more than 10 U of red blood cell transfusion within 24 hours after trauma (a unit of red blood cell transfusion is made from 200 mL of whole blood in Japan). In those four patients, the mean values of FDP and DD were 90.8 μg/mL (range, 5.7-160 μg/mL) and 45.3 μg/mL (range, 3.2-66.4 μg/mL), respectively, and those data were much higher than the mean of all patients. The mean values of FDP and DD in four patients who died were 244.6 μg/mL (range, 158.4-420 μg/mL) and 102.8 μg/mL (range, 32.8-240 μg/mL), respectively. Both FDP and DD in patients who died were remarkably elevated immediately after trauma.FDP and DD levels may be useful parameters for initial evaluation of the severity of trauma, massive blood transfusion, and mortality.

Purpose The reliable parameter, which can be obtained easily and quickly, is necessary to predict the return of spontaneous circulation (ROSC) of patients with cardiopulmonary arrest (CPA) in the emergency situation. In this study, we evaluated the significance of albumin corrected anion gap (ACAG) for the prediction of ROSC in patients with CPA. Patients and methods In 166 patients with CPA between January 2009 and December 2010, 132 patients could be analyzed retrospectively. We compared acute physiology and chronic health evaluation (APACHE) II score, sequential organ failure assessment(SOFA) score, anion gap (AG) and ACAG levels between patients with/without ROSC and evaluated the significance of AG and ACAG to predict ROSC in patients with CPA. Results Both AG and ACAG were significantly lower in patients with ROSC than in patients without ROSC. Both AG and ACAG had the relation with APACHE II and SOFA scores, however, coefficients of correlation with APACHE II and SOFA score were higher in ACAG (r = 0.506) than in AG (r = 0.482). The sensitivity, specificity, positive predictive value, and negative predictive value of ACAG for the prediction of ROSC in patients with CPA were better than those of AG. Conclusion Our study shows that both AG and ACAG have the relation with ROSC and ACAG is better to predict the ROSC following CPR in patients with CPA compared with AG. ACAG can be easily obtained in the emergency situation, and ACAG is a useful parameter to predict ROSC in patients with CPA.

One of the most important prognostic factors in oral squamous cell carcinoma (OSCC) is the presence of lymph node metastasis. Therefore, the early detection of late-presenting cervical lymph node metastasis is important. Although many studies have assessed diagnostic modalities for detecting metastatic cervical lymph nodes, no study has evaluated the process, especially first signs, for detecting late-presenting cervical lymph node metastasis. A retrospective analysis comparing methods for detecting the first signs of late-presenting lymph node metastasis was performed. A total of 65 OSCC patients were assessed. These patients were identified retrospectively as having presented late metastasis during follow-up after initial treatment with curative intent. The findings of four detection methods were analyzed: palpation, ultrasonography, computed tomography, and subjective symptoms. The numbers of cases identified by each method were as follows: palpation, 31 (47.7%); ultrasonography, 17 (26.1%); computed tomography, 12 (18.5%); and subjective symptoms, 5 (7.7%). Palpation played a major role in the discovery of late-presenting lymph node metastasis. In contrast, metastatic lymph nodes were detected by other methods in about half of the cases. The results suggest a possible stratification of the various methods used for metastatic lymph node detection, depending on the characteristics of individual cases.

Objective Our objectives were to determine the expression of EVC2 in craniofacial tissues and investigate the effect of Evc2 deficiency on craniofacial bones using Evc2 knockout (KO) mouse model. Design Evc2 KO mice were generated by introducing a premature stop codon followed by the Internal Ribosomal Entry Site fused to β-galactosidase (LacZ). Samples from wild-type (WT), heterozygous (Het) and homozygous Evc2 KO mice were prepared. LacZ staining and immunohistochemistry (IHC) with anti-β-galactosidase, anti-EVC2 and anti-SOX9 antibodies were performed. The craniofacial bones were stained with alcian blue and alizarin red. Results The LacZ activity in KO was mainly observed in the anterior parts of viscerocranium. The Evc2 -expressing cells were identified in many cartilageous regions by IHC with anti-β-galactosidase antibody in KO and Het embryos. The endogenous EVC2 protein was observed in these areas in WT embryos. Double labeling with anti-SOX9 antibody showed that these cells were mainly chondrocytes. At adult stages, the expression of EVC2 was found in chondrocytes of nasal bones and spheno-occipital synchondrosis, and osteocytes and endothelial-like cells of the premaxilla and mandible. The skeletal double staining demonstrated that craniofacial bones, where the expression of EVC2 was observed, in KO had the morphological defects as compared to WT. Conclusion To our knowledge, our study was the first to identify the types of Evc2 -expressing cells in craniofacial tissues. Consistent with the expression pattern, abnormal craniofacial bone morphology was found in the Evc2 KO mice, suggesting that EVC2 may be important during craniofacial growth and development.

Mutations in the Family with sequence similarity (FAM) 20 gene family are associated with mineralized tissue phenotypes in humans. Among these genes, FAM20A mutations are associated with Amelogenesis Imperfecta (AI) with gingival hyperplasia and nephrocalcinosis, while FAM20C mutations cause Raine syndrome, exhibiting bone and craniofacial/dental abnormalities. Although it has been demonstrated that Raine syndrome associated-FAM20C mutants prevented FAM20C kinase activity and secretion, overexpression of the catalytically inactive D478A FAM20C mutant was detected in both cell extracts and the media. This suggests that FAM20C secretion doesn’t require its kinase activity, and that another molecule(s) may control the secretion. In this study, we found that extracellular FAM20C localization was increased when wild-type (WT), but not AI-forms of FAM20A was co-transfected. On the other hand, extracellular FAM20C was absent in the conditioned media of mouse embryonic fibroblasts (MEFs) derived from Fam20a knock-out (KO) mouse, while it was detected in the media from WT MEFs. We also showed that cells with the conditioned media of Fam20a WT MEFs mineralized, but those with the conditioned media of KO MEFs failed to mineralize in vitro. Our data thus demonstrate that FAM20A controls FAM20C localization that may assist in the extracellular function of FAM20C in mineralized tissues.

Although vascular invasion (VI) is recognized as an important predictor of lymph node metastasis and a significant prognostic factor in head and neck squamous cell carcinoma (HNSCC), there is currently no common definition for the pathological evaluation of VI status. We reviewed the medical records of 63 consecutive resected primary oral tongue SCCs (OTSCCs) without preoperative treatment between June 1999 and April 2008, and evaluated VI status by investigating lymphatic vessel invasion (LVI) and blood vessel invasion (BVI) by using immunohistochemistry (IHC) with monoclonal antibody D2-40 (D2-40) and Elastica van Gieson (EVG) staining, respectively. Subsequently, we analyzed their correlations with cervical lymph node metastasis and prognosis. LVI was found in 16 of the 63 tumors (25.4%) and BVI was in 32 tumors (50.8%). Univariate analysis revealed that the presence of LVI is statistically correlated with lymph node metastasis. Moreover, multivariate logistic regression analysis revealed that LVI is an independent risk factor of nodal metastasis (odds ratio=4.262, 95% confidence interval=1.262-14.397, p=0.020). In contrast, Kaplan-Meier survival analysis revealed that patients with BVI had a significantly shorter disease-free survival (DFS) and overall survival (OS) rates than those without BVI (68.6% versus 90.3%, p=0.028 and 68.6% versus 93.5%, p=0.013, respectively). The present study clearly demonstrated that LVI at primary OTSCC had significant correlation with lymph node metastasis, and that BVI was significantly associated with recurrence and poor prognosis. Evaluation of VI status, as LVI and BVI status separately, using IHC with D2-40 and EVG staining may be useful in predicting lymph node metastasis and poor prognosis in OTSCCs.

In search of new cysteine knot protein (CKP) family members, we found a novel gene called von Willebrand factor C domain-containing protein 2-like (Vwc2l, also known as Brorin-like) and its transcript variants (Vwc2l-1, Vwc2l-2 and Vwc2l-3). Based on the deduced amino acid sequence, Vwc2l-1 has a signal peptide and 2 cysteine-rich (CR) domains, while Vwc2l-2 lacks a part of 2nd CR domain and Vwc2l-3 both CR domains. Although it has been reported that the expression of Brorin-like was predominantly observed in brain, we found that Vwc2l transcript variants were detected in more ubiquitous tissues. In osteoblasts, the induction of Vwc2l expression was observed at matrix mineralization stage. When Vwc2l was stably transfected into osteoblasts, the matrix mineralization was markedly accelerated in Vwc2l-expressing clones compared to that in the control, indicating the modulatory effect of Vwc2l protein on osteoblastic cell function. The mechanistic insight of Vwc2l-modulation was further investigated and we found that the expression of Osterix, one of the key osteogenic markers, was significantly increased by addition of all Vwc2l isoform proteins. Taken together, Vwc2l is a novel secreted protein that promotes matrix mineralization by modulating Osterix expression likely through TGF-β superfamily growth factor signaling pathway. Our data may provide mechanistic insights into the biological functions of this novel CKP member in bone and further suggest a novel approach to enhance osteoblast function, which enables to accerelate bone formation, regeneration and healing.

Weak pancreatic β-cell function is a cause of type 2 diabetes mellitus. Glucokinase regulates insulin secretion via phosphorylation of glucose. The present study focused on a system for the self-protection of pancreatic cell by expressing heat shock factor (HSF) and heat shock protein (HSP) to improve insulin secretion without inducing hypoglycemia. We previously generated a constitutively active form of human HSF1 (CA-hHSF1). An adenovirus expressing CA-hHSF1 using the cytomegalovirus promoter was generated to infect mouse insulinoma cells (MIN6 cells). An adenovirus expressing CA-hHSF1 using a human insulin promoter (Ins-CA-hHSF1) was also generated to infect rats. We investigated whether CA-hHSF1 induces insulin secretion in MIN6 cells and whether Ins-CA-hHSF1 can improve blood glucose and serum insulin levels in healthy Wister rats and type 2 diabetes mellitus model rats. CA-hHSF1 expression increased insulin secretion 1.27-fold compared with the overexpression of wild-type hHSF1 in MIN6 cells via induction of HSP90 expression and subsequent activation of glucokinase. This mechanism is associated with activation of both glucokinase and neuronal nitric oxide synthase. Ins-CA-hHSF1 improved blood glucose levels in neonatal streptozotocin-induced diabetic rats. Furthermore, Ins-CA-hHSF1 reduced oral glucose tolerance testing results in healthy Wister rats because of an insulin spike at 15 minutes; however, it did not induce hypoglycemia. CA-hHSF1 induced insulin secretion both in vitro and in vivo. These findings suggest that gene therapy with Ins-CA-hHSF1 will be able to be used to treat patients with type 2 diabetes mellitus and impaired glucose tolerance without causing hypoglycemia at fasting.

根治的治療を行った上顎歯肉扁平上皮癌一次症例41例について臨床病理学的検討を行った。性別は，男性15例，女性26例，年齢は38歳から85歳で，平均62歳であった。T分類はT1：8例，T2：13例，T3：10例，T4：10例であった。治療法は，外科療法単独：11例，術前化学放射線療法＋外科療法：26例，その他：4例であった。頸部郭清術は18例20側に施行され，このうち病理組織学的頸部リンパ節転移陽性例は14例16側であった。頸部リンパ節転移のレベルは，Level IIが14例と最も多く，Level IIIより遠位への転移は認められなかった。全症例の5年累積生存率は80.9%であり，前歯部型100%，臼歯部型88.5%，後方進展型52.5%と，後方進展型が臼歯部型に比べ有意に低かった（p < 0.05）。経過不良例の死因は，原病死5例（原発巣死：1例，頸部転移死：1例，遠隔転移死：3例），他癌死1例であった。

A prospective randomized open-labeled study was performed to compare the renoprotective effects of enarapril and losartan on the development of microalbuminuria in type 2 diabetic patients with hypertension. Diabetic patients who have hypertension and microalbuminuria at base line (n=19) were recruited. Enarapril (n=11) or losartan (n=8) was randomly chosen by envelope methods and was prescribed for one year. At the end of this study, the blood pressure of patients in these two groups decreased significantly. Urine albumin-creatinine ratio (U-ACR) also decreased in these two groups, however, U-ACR of enarapril group was not significantly different from that of losartan group at any time of this study. Body mass index, HbA1c, blood pressure, and serum lipid profiles were not significantly different between the two groups. From these results, we conclude that the effects of enarapril and losartan on the development of microalbuminuria in type 2 diabetic patients along with hypertension seem to be equivalent in terms of clinical renoprotection.

【目 的】 紹介状なしで受診する患者の現状を調査し, 患者の大学病院に対するニーズを把握する. 【対象と方法】 1年間に群馬大学医学部附属病院を紹介状なしで初診した患者数を調査. また, 総合診療部を受診した患者について専門科受診希望の有無, 具体的な受診希望専門科, 受診前の状況等を問診表から調査した. 【結 果】 紹介状なしで大学病院を受診した患者の11.6％は専門診療科受診希望を表明せず. 専門科希望者1,104人の内, 具体的に専門科がわからない患者は64.9％であった. 総合診療部初診者2,051人の内, 48.9％は同症状で他医療機関の受診歴があった. 【結 語】 患者はかならずしも専門科希望でなくとも大学病院を受診する. 一方, 専門科希望で受診しても具体的な専門科がわからないことは多い. 受診する前に同じ症状で他の医療施設を受診している患者が相当数おり, 患者からみると紹介機能は必ずしも十分に働いていない.

症例は37歳男性マリ人. 来日後7日目に発熱, 咽頭痛, 水様性下痢にて発症した. 血液検査では貧血と血小板減少を認め, 母国マリ共和国への渡航歴からマラリア感染を疑い, 末梢血塗末標本にて原虫を確認し, 熱帯熱マラリアと診断した. メフロキンを治療薬として選択し, 1,650mgの最大量投与にて治療を開始したところ, 速やかな解熱と全身状態の改善を認めた. 熱帯熱マラリアは容易に重症化や死亡に至る疾患であるため迅速な治療開始が必須であると同時に, 薬剤耐性マラリアを考慮した適切な治療薬の選択が重要である.