[A Long-Term Survival Case of Gastric Cancer with Pyloric Stenosis and Peritoneum Dissemination That Received Intravenous and Intraperitoneal Paclitaxel Combined with S-1 Therapy after Bypass Surgery].

Although a 74-year-old man with gastric cancer with pyloric stenosis(cT4aN[+]M0, Stage Ⅲ)had undergone surgery, he was diagnosed with peritoneum dissemination. He received bypass surgery, and an intraperitoneal access port was implanted in his subcutaneous space. Postoperatively, he received 4 courses of SOX therapy. In treatment effect, the primary tumor showed no change, and ascites developed. Therefore, we changed the chemotherapy regimen in intravenous and intraperitoneal paclitaxel combined with S-1 therapy. After starting this regimen, the primary tumor decreased in size, and the pyloric stenosis improved. Currently, the patient is alive without recurrence for 5 years and 8 months after intravenous and intraperitoneal paclitaxel combined with S-1 therapy and receiving this treatment regularly.

Liposarcoma of the pleural cavity.

Liposarcoma rarely occurs in the pleura or thoracic cavity, and few reports appear in the literature. We hypothesized that combining clinicopathologic, immunohistochemical, and fluorescence in situ hybridization methods would allow definite diagnoses. Using formalin-fixed, paraffin-embedded blocks, we examined 6 atypical lipomatous tumor/well-differentiated liposarcomas (ALT/WDLPS), 5 dedifferentiated liposarcomas (DDLPSs), 2 pleomorphic liposarcomas, and 1 myxoid liposarcoma (MLPS). We used the Kaplan-Meier method and the Wilcoxon test for survival analysis for prognostic factor evaluation. Histologically, ALT/WDLPS was composed of a relatively mature adipocytic proliferation, accompanied by some lipoblasts. DDLPS exhibited round-to-oval tumor cells with a high nucleus-to-cytoplasm ratio that had proliferated in nests, accompanied in case 10 by some giant cells but no fatty cells. The pleomorphic type contained a varying proportion of pleomorphic lipoblasts. MLPS displayed uniform round- to oval-shaped cells and small signet-ring lipoblasts in a myxoid stroma. Immunohistochemically, 11 (79%), 11 (79%), and 10 (71%) of 14 cases were positive for S-100, p16, and CDK4, respectively. Six of the 14 cases (43%) were positive for MDM2 and adipophilin. One case of ALT/WDLPS and 3 cases of DDLPS exhibited MDM2 amplification by fluorescence in situ hybridization (Vysis LSI MDM2 SpectrumGreen Probe plus Vysis CEP 12 SpectrumOrange probe). ALT/WDLPS was the most favorable type for survival, while adipophilin tended to be a negative prognostic factor for pleural liposarcoma. For a firm diagnosis of liposarcoma in the pleura, immunohistochemistry for CDK4, MDM2, and adipophilin together with MDM2 gene amplification by fluorescence in situ hybridization may be an important diagnostic tool.

Analysis of entropy production in finitely slow processes between nonequilibrium steady states.

We investigate entropy production in finitely slow transitions between nonequilibrium steady states in Markov jump processes using the improved adiabatic approximation method, which has a close relationship with the slow driving perturbation. This method provides systematic improvement of the adiabatic approximation on infinitely slow transitions from which we obtain nonadiabatic corrections. We analyze two types of excess entropy production and confirm that the leading adiabatic contribution reproduces known results, and then obtain nonadiabatic corrections written in terms of thermodynamic metrics defined in protocol parameter spaces. We also numerically study the resulting excess entropy production in a two-state system.

Sternal Metastasis of Brain Meningioma - A Case Report.

BACKGROUND: Metastases of meningiomas are infrequent and the site of extracranial metastasis such as the bone is extremely rare. CASE REPORT: A 75-year-old male had a history of five sessions of surgery and gamma-knife treatment for brain meningioma over a period of 29 years. He visited our hospital because he noticed a swelling in his anterior chest 2 years and 6 months after the final treatment. After an open biopsy, histopathological analysis revealed the mass to be a metastatic grade II meningioma. We resected the tumor along with the sternum, ribs, pleura, and pericardium. The patient had recurrences in the thoracic cavity and pericardium postoperatively and received radiation therapy. He also had metastasis in the abdominal cavity, which spread rapidly. CONCLUSION: We report on a rare instance of metastasis to the sternum in a case of atypical meningioma, showing rapid growth and invasion after long-term treatment.

Association of time in range with hemoglobin A1c, glycated albumin and 1,5-anhydro-d-glucitol.

AIMS/INTRODUCTION: Hemoglobin A1c (HbA1c), glycated albumin (GA) and 1,5-anhydro-d-glucitol (1,5-AG) are used as indicators of glycemic control, whereas continuous glucose monitoring (CGM) is used to assess daily glucose profiles. The aim of this study was to investigate the relationships between CGM metrics, such as time in range (TIR), and glycemic control indicators. MATERIALS AND METHODS: We carried out retrospective CGM and blood tests on 189 outpatients with impaired glucose tolerance (n = 22), type 1 diabetes mellitus (n = 67) or type 2 diabetes mellitus (n = 100). RESULTS: In type 1 diabetes mellitus and type 2 diabetes mellitus patients, HbA1c and GA were negatively correlated with TIR, whereas 1,5-AG was positively correlated with TIR. In type 1 diabetes mellitus patients, a TIR of 70% corresponded to HbA1c, GA and 1,5-AG of 6.9% (95% confidence interval [CI] 6.5-7.2%), 20.3% (95% CI 19.0-21.7%) and 6.0 µg/mL (95% CI 5.1-6.9 µg/mL), respectively. In type 2 diabetes mellitus patients, a TIR of 70% corresponded to HbA1c, GA and 1,5-AG of 7.1% (95% CI 7.0-7.3%), 19.3% (95% CI 18.7-19.9%) and 10.0 µg/mL (95% CI 9.0-11.0 µg/mL), respectively. TIR values corresponding to HbA1c levels of 7.0% were 56.1% (95% CI 52.3-59.8%) and 74.2% (95% CI 71.3-77.2%) in type 1 diabetes mellitus and type 2 diabetes mellitus patients, respectively. CONCLUSIONS: The results of this study showed that the estimated HbA1c corresponding to a TIR of 70% was approximately 7.0% for both type 1 diabetes mellitus and type 2 diabetes mellitus patients, and that the estimated 1,5-AG calculated from the TIR of 70% might be different between type 1 diabetes mellitus and type 2 diabetes mellitus patients.

Relationships between time in range, glycemic variability including hypoglycemia and types of diabetes therapy in Japanese patients with type 2 diabetes mellitus: Hyogo Diabetes Hypoglycemia Cognition Complications study.

AIMS/INTRODUCTION: Continuous glucose monitoring (CGM) metrics, such as times in range (TIR) and time below range, have been shown to be useful as clinical targets that complement glycated hemoglobin (HbA1c) for patients with type 2 diabetes mellitus. We investigated the relationships between TIR, glycemic variability and patient characteristics in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: We carried out continuous glucose monitoring in 281 outpatients with type 2 diabetes mellitus who participated in a multicenter cohort (Hyogo Diabetes Hypoglycemia Cognition Complications) study. RESULTS: The results are shown as the median (interquartile range). The age, disease duration and HbA1c were 68 years (62-71 years), 13 years (7-23 years) and 6.9% (6.5-7.5%), respectively. TIR and standard deviation obtained by continuous glucose monitoring worsened significantly with increasing disease duration. Multiple regression analyses showed that disease duration (standard partial regression coefficient, ß = -0.160, P = 0.003), diabetic peripheral neuropathy (ß = -0.106, P = 0.033) and urinary albumin excretion (ß = -0.100, P = 0.043) were useful explanatory factors for TIR. In contrast, HbA1c (ß = -0.398, P < 0.001) and the use of antidiabetic drugs potentially associated with severe hypoglycemia (ß = 0.180, P = 0.028), such as sulfonylureas, glinides and insulin, were useful explanatory factors for time below range in the elderly patients with type 2 diabetes mellitus. CONCLUSIONS: The results of this study suggest that disease duration and diabetic complications are associated with TIR deterioration. In addition, low HbA1c levels and the use of antidiabetic drugs potentially associated with severe hypoglycemia might worsen the time below range in the elderly.

Plasma glucagon levels measured by sandwich ELISA are correlated with impaired glucose tolerance in type 2 diabetes.

Glucagon dysfunction as well as insulin dysfunction is associated with the pathogenesis of type 2 diabetes (T2DM). However, it is still unclear whether the measurement of plasma glucagon levels is useful in understanding the pathophysiology of T2DM. We recently reported that sandwich ELISA provides more accurate plasma glucagon values than conventional RIA in healthy subjects. Here we used sandwich ELISA as well as RIA to assess plasma glucagon levels, comparing them in T2DM patients and healthy subjects during oral glucose (OGTT) or meal tolerance tests (MTT). We confirmed that sandwich ELISA was able to detect more significant difference between healthy subjects and T2DM patients in the fasting levels and the response dynamics of plasma glucagon than RIA. We also found significant differences in the following glucagon parameters: (1) fasting glucagon, (2) the area under the curve (AUC) of glucagon in OGTT, and (3) the change in glucagon between 0 and 30 min (ΔGlucagon0-0.5h) in OGTT or MTT. Among these, the most apparent difference was ΔGlucagon0-0.5h in MTT. When we divided T2DM patients into two groups whose ΔGlucagon0-0.5h in MTT was either below or above the maximum value in healthy subjects, the group with higher ΔGlucagon0-0.5h showed more significant impairment of glucose tolerance. These results suggest that the assessment of plasma glucagon levels by sandwich ELISA might enhance our understanding of the pathophysiology of T2DM.

Xanthine oxidoreductase activity correlates with vascular endothelial dysfunction in patients with type 1 diabetes.

AIMS: Xanthine oxidoreductase (XOR) is an enzyme regulating uric acid synthesis and generation of reactive oxygen species. Several studies suggested relationship between XOR and atherosclerotic diseases; however, few previous studies have directly examined the relationship between XOR and vascular endothelial dysfunction in patients with type 1 diabetes mellitus (T1DM). The aim of this study was to evaluate the relationship between XOR activity and vascular endothelial function in patients with T1DM. METHODS: Seventy-one patients with T1DM participated in the study and underwent assessments, including plasma XOR activity and flow-mediated dilation (FMD), to measure vascular endothelial function. RESULTS: The natural logarithm value of XOR activity (ln-XOR) was 3.03 ± 0.99 pmol/h/mL, and FMD was 5.5% ± 2.4%. FMD was inversely and significantly correlated with ln-XOR (correlation coefficient: r = - 0.396, P < 0.001), UA (r = - 0.252, P = 0.034), and asymmetric dimethylarginine (ADMA) (r = - 0.414, P < 0.001). ln-XOR showed positive correlation with HbA1c (r = 0.292, P = 0.013), ALT (r = 0.658, P < 0.001), and ADMA (r = 0.363, P = 0.002). Stepwise multiple regression analysis showed that ln-XOR (standard partial regression coefficient: ß = - 0.254, P = 0.018) was an independent explanatory variable of FMD. CONCLUSIONS: The results of this study showed for the first time that XOR activity is associated with glycemic control in patients with T1DM and that XOR activity is associated with vascular endothelial dysfunction.

Effect of an intensive conservative therapy with daily teriparatide administration and rehabilitation for osteoporotic delayed vertebral collapse and paralysis.

Although patients with osteoporotic delayed vertebral collapse (ODVC) have frequently been treated surgically, the efficacy and limitation of conservative treatment for it have not yet been reported. The purpose of this study was to investigate the effectiveness and limitation of further intensive conservative treatment for patients with ODVC.Patients treated for ODVC from 2011 to 2014 with a follow-up period of more than 1 year were eligible. The fundamental treatment strategy consisted of surgical treatment following intensive conservative treatment with daily teriparatide and rehabilitation for 3 months. We conducted a surgical treatment for patients who could not keep standing position by themselves because of prolonged leg paralysis or intolerable back pain. We performed a logistic regression model in which surgical treatment was set as an objective variable, and other related factors including sex, age, the level of affected vertebrae, the quality of paralysis, changing rate (δ) of spinal canal encroachment, local kyphotic angle, mobility of collapsed vertebrae, EuroQol questionnaires (EQ5D), numerical rating scale (NRS), and Frankel grade as explanatory variables. We also plotted receiver operating curves (ROCs) to investigate the cutoff values of parameters at the baseline.Thirty patients (6 males and 24 females, mean age 76.7 years) were enrolled. Eventually 12 out of 30 patients avoided surgical treatment because their symptoms were improved. Logistic regression showed that δ of local kyphotic angle (odds ratio: 1.072), P = .01), mobility of collapsed vertebrae (1.063, 0.01), EQ5D (0.98, 0.04), and NRS (1.113, 0.01) were significantly correlated with the need for surgical treatments. Among the factors at baseline, only the mobility of collapsed vertebrae showed a significant value of area under a curve (AUC = 0.727, P = .008).The results that 40% of patients with ODVC did not need further surgical treatment after the intensive conservative treatment was of great significance. Patients with greater mobility of collapsed vertebrae might be treated surgically as quickly as possible.

Bizarre parosteal osteochondromatous proliferation of the femur: A case report.

A 54-year-old man initially presented with left distal thigh pain during walking. Imaging analysis revealed a diffuse calcified or ossified mass adjacent to the medial cortex of the distal femur and absence of continuity with the medulla. We performed resection biopsy. Histological examination revealed a large amount of hypercellular cartilage showing transformation to trabecular bone and BPOP was diagnosed. Postoperative course was uneventful and he remained free of recurrence. The method of resection should depend on the stage of reactive proliferation and whether the lesion is pathologically immature or mature. We also provide a brief review of the literature.

Clinical outcomes of limb salvage surgery with postoperative intensity-modulated radiation therapy for soft-tissue sarcoma and metastasis.

OBJECTIVE: The primary aim of intensity-modulated radiation therapy (IMRT) for treating soft tissue sarcoma of an extremity is the reduction of morbidity and maintenance of local control. METHODS: We evaluated the outcomes and toxicity of adjuvant IMRT following function-preserving surgery to treat patients with soft tissue sarcoma and metastasis of the extremities. We retrospectively reviewed prospective databases at Kure Medical Center and Aichi Medical University between 2013 and 2016 and identified 10 patients with lower extremity soft tissue sarcoma who underwent both limb-sparing surgery and postoperative IMRT at one of our institutions. RESULTS: There were 7 men and 3 women (mean age, 67.2 years; range, 48-87 years) included in the study. Of these, four patients were continuously disease-free, two showed no evidence of disease, and four died due to disease. The average functional score was 82% (range, 53-100%). Among the 10 patients, 2 (22%) had grade 1-2 edema and 1 (11%) had grade 2 joint stiffness. Another patient developed grade 2 acute dermatitis. There were no severe complications such as infection, tissue necrosis, fracture, or nerve palsy. CONCLUSION: Although the number of patients in this study was small, our results show that adjuvant IMRT following function-preserving surgery for soft tissue sarcoma of the extremity can be valuable for treating unmanageable tumors.

Inhibitory effects of low-intensity pulsed ultrasound sonication on the proliferation of osteosarcoma cells.

To date, there is limited data on the biological effects of low-intensity pulsed ultrasound (LIPUS) on primary malignant bone tumors. The purpose of the present study was to investigate the antitumor effects of LIPUS on osteosarcoma cells. The effects of LIPUS on cell viability, induction of apoptosis, mitochondrial membrane potential and intracellular signaling molecules in the LM8 osteosarcoma cell line were investigated. LIPUS inhibited cell viability (P=0.0022) and mitochondrial membrane potential (P=0.0019) in LM8 cells. Flow cytometry analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling staining revealed significantly higher numbers of apoptotic (P<0.0001) and necrotic cells (P=0.0091) compared with cells without treatment. LIPUS treatment significantly increased phosphorylated Akt (P<0.0001) and IκBα (P=0.0001) levels, and reduced phosphorylated mitogen-activated protein kinase 7 (P<0.0001) and phosphorylated checkpoint kinase 1 (P=0.0008) levels. These results suggest that LIPUS is a non-invasive adjuvant therapy that is able to inhibit cellular proliferation in osteosarcoma cells.

Xanthine oxidoreductase activity is correlated with insulin resistance and subclinical inflammation in young humans.

BACKGROUND AND AIMS: The enzyme xanthine oxidoreductase (XOR) catalyzes the formation of uric acid (UA) from hypoxanthine and xanthine, which in turn are products of purine metabolism starting from ribose-5-phosphate. Besides the synthesis of UA, basic research has suggested that XOR is involved in the regulation of reactive oxygen species, adipogenesis, and peroxisome proliferator-activated receptor-γ (PPAR-γ). XOR activity has shown to be much lower in humans than in rodents, which makes its accurate measurement difficult. Recently, a novel human plasma XOR activity assay has been established using a combination of liquid chromatography (LC) and triple quadrupole mass spectrometry (TQMS) to detect [13C2,15N2]UA using [13C2,15N2]xanthine as a substrate. Using this novel assay, we for the first time determine plasma XOR activity in humans, and evaluate its association with insulin resistance, high-sensitivity C-reactive protein (hsCRP) levels, and other parameters. METHODS: Of the 29 volunteers who wished to participate in the study, 3 were excluded; of the remaining, 11 were female and 15 were male with a mean age of 25.9±3.3years. Blood samples were collected under fasting conditions in the early morning to measure XOR activity and other parameters. RESULTS: The natural logarithmic value of XOR activity (ln-XOR) in plasma was 3.4±0.8pmol/h/mL. Ln-XOR had a positive correlation with UA and body mass index (BMI) and a negative correlation with quantitative insulin sensitivity check index (QUICKI) and adiponectin. In addition, ln-XOR had a positive correlation with hsCRP levels, which serves as a marker of chronic inflammation. CONCLUSIONS: The present study has shown that XOR activity is correlated with serum UA levels in humans. Furthermore, even in young subjects, XOR activity is correlated with insulin resistance, BMI, and subclinical inflammation. Thus, XOR activity may be potentially involved in adiposity and subclinical inflammation in humans.

Ameloblastin induces tumor suppressive phenotype and enhances chemosensitivity to doxorubicin via Src-Stat3 inactivation in osteosarcoma.

Ameloblastin (AMBN), the most abundant non-amelogenin enamel matrix protein, plays a role in ameloblast differentiation. Previously, we found that AMBN promoted osteogenic differentiation via the interaction between CD63 and integrin ß1, leading to the inactivation of Src; however, how AMBN affects the malignant behavior of osteosarcoma is still unclear. Osteosarcoma affects the bone and is associated with poor prognosis because of the high rate of pulmonary metastases and drug resistance. Here we demonstrated that stable overexpression of AMBN induced apoptosis and suppressed colony formation and cell migration via the inactivation of Src-Stat3 pathway in human osteosarcoma cells. Moreover, AMBN induced chemosensitivity to doxorubicin. Thus, AMBN induced a tumor suppressive phenotype and chemosensitivity to doxorubicin via the AMBN-Src-Stat3 axis in osteosarcoma. Indeed, immunohistochemical expression of AMBN was significantly correlated with better outcome of osteosarcoma patients. Our findings suggest that AMBN can be a new prognostic marker and therapeutic target for osteosarcoma combined with conventional doxorubicin treatment.

An extremely rare case of a glomus tumor in the popliteal fossa.

Glomus tumors are the benign perivascular tumors that typically present with hypersensitivity to cold, paroxysmal severe pain, and pinpoint tenderness. This tumor is usually subungual lesions and accounts for 1.6% of all soft-tissue tumors. However, extradigital glomus tumors are extremely rare and can be difficult to diagnose, as they typically have a diameter of less than about 1 cm. We report a glomus tumor in the popliteal fossa of a 17-year-old male patient who experienced severe posterior knee pain while playing sports. A physical examination did not reveal a mass, although a glomus tumor was identified in the popliteal fossa using magnetic resonance imaging. We successfully performed open excision to remove the tumor, and the patient achieved a restored postoperative gait and could perform sports activities with no pain. These tumors are extremely rare in the knee area, and typically have a diameter of less than about 1 cm, which can complicate their diagnosis and treatment, despite the presence of severe pain. Therefore, we recommend that clinicians be aware of extradigital glomus tumors, as careful imaging can facilitate an early diagnosis and treatment.

Postabsorptive hyperglucagonemia in patients with type 2 diabetes mellitus analyzed with a novel enzyme-linked immunosorbent assay.

AIMS/INTRODUCTION: The aims of the present study were to investigate the performance of a novel sandwich enzyme-linked immunosorbent assay (ELISA) for measuring glucagon (1-29) with monoclonal antibodies against both the C- and N-terminal regions of glucagon (1-29), and to analyze the differences in plasma levels and responses of glucagon (1-29) to oral glucose loading in normal glucose tolerance (NGT) subjects and patients with type 2 diabetes mellitus. MATERIALS AND METHODS: The cross-reactivity against proglucagon fragments using the ELISA kit and two types of conventional radioimmunoassay (RIA) kits was evaluated. A 75-g oral glucose tolerance test was carried out with NGT subjects and patients with type 2 diabetes mellitus, and the glucagon (1-29) concentration was measured using three types of kit. RESULTS: The ELISA kit clearly had the lowest cross-reactivity against miniglucagon (19-29) and glicentin (1-61). The oral glucose tolerance test was carried out with 30 NGT and 17 patients with type 2 diabetes mellitus. The glucagon (1-29) levels measured by the ELISA kit after glucose loading were significantly higher at all time-points in the type 2 diabetes mellitus group than in the NGT group. However, the glucagon (1-29) levels measured by one RIA kit were significantly higher in the NGT group, and those measured with the other RIA kit were approximately the same among the groups. CONCLUSIONS: The novel sandwich ELISA accurately determines plasma glucagon (1-29) concentrations with much less cross-reactivity against other proglucagon fragments than conventional RIA kits.

The prevalence of diffuse idiopathic skeletal hyperostosis in Japan - the first report of measurement by CT and review of the literature.

BACKGROUND: Diffuse idiopathic skeletal hyperostosis (DISH) is prone to be accompanied by a spinal column fracture which is resistant to conservative therapy. This major characteristic of DISH is not recognized adequately by physicians, because the disease's detailed pathological condition has not yet been investigated. Therefore, the purposes of this study were to investigate the prevalence of DISH using computed tomography (CT), and to validate the reliability of CT interpretation. METHODS: Subjects were 558 patients (300 male and 258 female) who underwent both CT of chest to pelvis and x-ray of chest and abdomen from August 2011 to July 2012 at any department other than orthopedic surgery in our institution. The definition of DISH based on x-ray as well as CT was the presence of consecutive fused vertebral bodies according to Resnick's criteria. The prevalence of DISH based on both modalities was calculated in all subjects. For 107 subjects extracted at random, intra- (Cohen kappa) and inter-observer error (Fleiss kappa) were calculated and the levels of fused segments were investigated. RESULTS: Ninety-eight of 558 subjects (17.6%) were diagnosed as DISH by x-ray, and 152 (27.2%) by CT. Among males, 70 of 300 subjects (23.3%) were diagnosed by x-ray, and 116 (38.7%) by CT. Among females, 28 of 258 subjects (10.9%) were diagnosed by x-ray and 36 (14.0%) by CT. The levels of fused segments were presented from thoracic spine to lumbar spine, especially the middle and lower thoracic spine. Cohen kappa of x-ray was 0.587, and that of CT was 0.825. Fleiss kappa of x-ray was 0.552, and that of CT was 0.643. CONCLUSIONS: The prevalence of DISH based on CT was 27.1%, which was higher than that of x-ray. In addition, intra- and inter-observer error by review of CT was less than that of x-ray. CT evaluation would be a better method for precise understanding of the state of DISH.

Effect of Denosumab Administration on Lumbar Vertebral Strength of Patients with Vertebral Bony Metastases: Preliminary Study.

The purpose of this study was to examine the usefulness of administration of denosumab (antibody against tumor necrosis factor superfamily member 11) as a preventative therapy for skeletal-related events (SREs), such as fracture or paralysis, by computed-tomography (CT)-based on the finite element method (FEM). Patients who had undergone treatment for vertebral metastases with denosumab administration from December 2013 to August 2015 at our Institution were reviewed. We investigated patient data at the time before denosumab administration and at 1, 3 and 6 months using CT. A total of six patients were eligible; four males and two females, with ages ranging from 35 to 73 years, with a mean age of 56 years. Repeated measures analysis of variance showed a significant increase (p=0.0055, F=10.67). To our knowledge, this is the first article to substantiate the effects of the SRE-preventative drug denosumab.