The induced RNA-binding protein, HuR, targets 3'-UTR region of IL-6 mRNA and enhances its stabilization in periodontitis.

RNA-binding proteins (RBPs) regulate mRNA stability by binding to the 3'-untranslated region (UTR) region of mRNA. Human antigen-R (HuR), one of the RBPs, is involved in the progression of diseases, such as rheumatoid arthritis, diabetes mellitus and some inflammatory diseases. Interleukin (IL)-6 is a major inflammatory cytokine regulated by HuR binding to mRNA. Periodontal disease (PD) is also an inflammatory disease caused by elevations in IL-6 following an infection by periodontopathogenic bacteria. The involvement of HuR in the progression of PD was assessed using in-vitro and in-vivo experiments. Immunohistochemistry of inflamed periodontal tissue showed strong staining of HuR in the epithelium and connective tissue. HuR mRNA and protein level was increased following stimulation with Porphyromonas gingivalis (Pg), one of the periodontopathogenic bacteria, lipopolysacchride (LPS)-derived from Pg (PgLPS) and tumour necrosis factor (TNF)-α in OBA-9, an immortalized human gingival epithelial cell. The luciferase activity of 3'-UTR of IL-6 mRNA was increased by TNF-α, Pg and PgLPS in OBA-9. Luciferase activity was also increased in HuR-over-expressing OBA-9 following a bacterial stimulation. Down-regulation of HuR by siRNA resulted in a decrease in mRNA expression and production of IL-6. In contrast, the over-expression of HuR increased IL-6 mRNA expression and production in OBA-9. The HuR inhibitor, quercetin, suppressed Pg-induced HuR mRNA expression and IL-6 production in OBA-9. An oral inoculation with quercetin also inhibited bone resorption in ligature-induced periodontitis model mice as a result of down-regulation of IL-6. These results show that HuR modulates inflammatory responses by regulating IL-6.

Updated results from GEST study: a randomized, three-arm phase III study for advanced pancreatic cancer.

PURPOSE: The GEST study showed non-inferiority of S-1 but not superiority of gemcitabine plus S-1 (GS) to gemcitabine alone for overall survival with the data by the cut-off date of 31st July in 2010 for chemo-naïve patients with advanced pancreatic cancer. We considered it important to determine whether S-1 maintains non-inferiority after a long-term follow-up in the GEST study and to obtain a firm positive conclusion. In addition, it may be an interesting challenge to explore the efficacious profile of GS in the long-term follow-up study. Using the data from the follow-up period, background and efficacy in patients from Taiwan and Japan, as well as the rates of tumor shrinkage in locally advanced and metastatic patients (Waterfall plot) were also analyzed. METHODS: The results of the primary analysis were reconfirmed, and subset analysis of overall survival and progression-free survival was performed based on the overall survival data updated by the cut-off date of 31st July in 2011. RESULTS: The median follow-up period was 29.8 months, and 795 deaths occurred (95.6%). The median overall survival was 8.8 months for gemcitabine, 9.7 months for S-1 (hazard ratio [HR], 0.96; 97.5% confidence interval [CI], 0.79-1.17), and 9.9 months for GS (HR 0.91; 97.5% CI 0.75-1.11). In patients with performance status (PS) 0, the median overall survival was 9.8 months for gemcitabine, 10.9 months for S-1, and 10.5 months for GS. In patients with PS 1, the median overall survival was 6.2 months for gemcitabine, 6.3 months for S-1, and 9.6 months for GS. CONCLUSION: Our survey reconfirmed the non-inferiority of S-1 to gemcitabine and showed S-1 can be used as one of the standard treatment options for advanced pancreatic cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00498225.

Systemic effects of surgical intervention on disease activity, daily function, and medication in patients with rheumatoid arthritis.

OBJECTIVES: Although tight control of rheumatoid arthritis (RA) has been achieved through the development of effective medication, surgical intervention is still required for a certain subpopulation of patients. To examine the systemic effects of orthopaedic surgery, we evaluated improvements in disease activity, daily function, and medication after surgery. METHOD: A prospective cohort study was conducted in 196 cases of elective orthopaedic surgery in 150 patients with RA from January 2011 to March 2014 in our institution. The 28-joint count Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR) and modified Health Assessment Questionnaire (mHAQ) scores just before surgery and at 6 and 12 months after surgery were examined prospectively. Concomitant medications were also investigated. RESULTS: Significant improvement was seen in the DAS28-ESR and mHAQ scores for replacement surgery in both the upper and lower extremities, and for arthroplasty/arthrodesis in the upper extremities at the 12-month follow-up. Partial mHAQ scores for the lower extremities were significantly reduced in lower replacement surgery, and partial mHAQ scores for the upper extremities were significantly reduced in upper arthroplasty/arthrodesis surgery. Although the use of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) did not decrease after surgery, the dose of prednisolone (PSL) decreased significantly at 12 months after surgery, especially in the well-controlled group and in surgical procedures in the lower extremities. CONCLUSIONS: Elective orthopaedic surgery improves both systemic disease activity and general functional impairment. Orthopaedic surgery is effective in reducing the amount of medication required postoperatively.

Combination chemotherapy with bevacizumab and S-1 for elderly patients with metastatic colorectal cancer (BASIC trial).

BACKGROUND: Chemotherapeutic regimens for elderly patients with metastatic colorectal cancer (mCRC), such as bevacizumab combined with 5-fluorouracil (5-FU) and leucovorin, often exclude oxaliplatin and irinotecan owing to the risk of toxicity. However, treatment with infusional 5-fluorouracil and leucovorin requires percutaneous port-catheter placement and other precautions, causing unnecessary stress for patients as well as healthcare workers. METHODS: We conducted a phase II study to evaluate the efficacy and safety of bevacizumab plus S-1 in elderly patients with previously untreated mCRC. Bevacizumab was given intravenously every two weeks, and S-1 was administered orally on days 1-28 of a 42-day cycle. The primary end-point was progression-free survival (PFS). The secondary end-points were time to treatment failure, response rate (RR), overall survival (OS), treatment completion status and safety. RESULTS: From October 2007 through March 2010, 56 patients were enroled. The median PFS was 9.9months, the median OS was 25.0months, and the RR was 57%. The main adverse events of grade 3 or higher were hypertension (11%), diarrhoea (9%) and neutropenia (7%). CONCLUSION: Our results suggest that combination chemotherapy with S-1 and bevacizumab can be administered safely and continuously on an outpatient basis and is therapeutically effective in elderly patients with mCRC.

Randomised phase II trial of S-1 plus oxaliplatin vs S-1 in patients with gemcitabine-refractory pancreatic cancer.

BACKGROUND: This randomised, open-label, multicenter phase II study compared progression-free survival (PFS) of S-1 plus oxaliplatin (SOX) with that of S-1 alone in patients with gemcitabine-refractory pancreatic cancer. METHODS: Patients with confirmed progressive disease following the first-line treatment with a gemcitabine-based regimen were randomised to receive either S-1 (80/100/120 mg day(-1) based on body surface area (BSA), orally, days 1-28, every 6 weeks) or SOX (S-1 80/100/120 mg day(-1) based on BSA, orally, days 1-14, plus oxaliplatin 100 mg m(-2), intravenously, day 1, every 3 weeks). The primary end point was PFS. RESULTS: Between January 2009 and July 2010, 271 patients were randomly allocated to either S-1 (n=135) or SOX (n=136). Median PFS for S-1 and SOX were 2.8 and 3.0 months, respectively (hazard ratio (HR)=0.84; 95% confidence interval (CI), 0.65-1.08; stratified log-rank test P=0.18). Median overall survival (OS) was 6.9 vs 7.4 months (HR=1.03; 95% CI, 0.79-1.34; stratified log-rank test P=0.82). The response rate (RR) was 11.5% vs 20.9% (P=0.04). The major grade 3/4 toxicities (S-1 and SOX) were neutropenia (11.4% and 8.1%), thrombocytopenia (4.5% and 10.3%) and anorexia (12.9% and 14.7%). CONCLUSIONS: Although SOX showed an advantage in RR, it provided no significant improvement in PFS or OS compared with S-1 alone.

Correlation of circulating betatrophin concentrations with insulin secretion capacity, evaluated by glucagon stimulation tests.

AIM: To investigate the relationship between plasma betatrophin concentrations and insulin secretion capacity in people with Type 2 diabetes. METHODS: Glucagon stimulation tests (1 mg) were performed in 70 people with Type 2 diabetes after an overnight fast. Plasma betatrophin concentrations were measured using an enzyme-linked immunosorbent assay. Insulin secretion capacity was evaluated by measuring increments of C-peptide concentration in response to glucagon stimulation, and creatinine clearance was determined by comparing creatinine concentrations in serum and 24-h urine samples. RESULTS: Plasma betatrophin concentrations were positively correlated with duration of Type 2 diabetes (r = 0.34, P = 0.003), and negatively correlated with increments of C-peptide concentration (r = 0.37, P = 0.001) and creatinine clearance (r = 0.37, P = 0.001). The correlation with increments of C-peptide concentration remained significant after adjustment for age and duration of Type 2 diabetes (r = 0.25, P = 0.037). Multivariate analysis identified age and increments of C-peptide concentration as independent factors associated with plasma betatrophin levels. CONCLUSION: Plasma betatrophin levels inversely correlate with insulin secretion capacity, suggesting that betatrophin levels are regulated by insulin secretion capacity in humans.

Impact of excision repair cross-complementing gene 1 (ERCC1) on the outcomes of patients with advanced gastric cancer: correlative study in Japan Clinical Oncology Group Trial JCOG9912.

BACKGROUND: Since the best chemotherapy regimen for each patient with advanced gastric cancer is uncertain, we aimed to identify molecular prognostic or predictive biomarkers from biopsy specimens in JCOG9912, a randomized phase III trial for advanced gastric cancer. PATIENTS AND METHODS: Endoscopic biopsy specimens from primary lesions were collected in 445 of 704 randomized patients in JCOG9912. We measured the mRNA expression of excision repair cross-complementing group 1 (ERCC1), thymidylate synthase, dihydropyrimidine dehydrogenase, and five other genes, then, categorized them into low and high groups relative to the median, and examined whether gene expression was associated with efficacy end point. RESULTS: Multivariate analyses showed that high ERCC1 expression [HR 1.37; 95% confidence interval (CI) 1.08-1.75; P = 0.010], performance status ≥ 1 (HR 1.45; 95% CI 1.13-1.86; P = 0.004), and number of metastatic sites ≥ 2 (HR 1.66; 95% CI 1.28-1.86; P < 0.001) were associated with a poor prognosis, and recurrent disease (versus unresectable; HR 0.75; 95% CI 0.56-1.00; P = 0.049) was associated with a favorable prognosis. None of these molecular factors were a predictive marker for choosing irinotecan plus cisplatin or 5-fluorouracil rather than S-1. CONCLUSION: These correlative analyses suggest that ERCC1 is an independent prognostic factor for overall survival in the first-line treatment of gastric cancer. CLINICAL TRIAL NUMBER: C000000062, www.umin.ac.jp.

Improvement of insulin resistance following transsphenoidal surgery in patients with acromegaly: correlation with serum IGF-I levels.

AIM: The aim of this study was to determine the correlation between the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis and glucose intolerance in acromegaly during the early postoperative period. SUBJECTS AND METHODS: The study included 20 patients with acromegaly caused by GH-secreting pituitary adenoma who received transsphenoidal surgery in our hospital. Glucose tolerance was evaluated with oral glucose tolerance tests (OGTTs) performed during pre- and early postoperative periods (9 [7-18] days after surgery). Homeostasis model assessment of insulin resistance (HOMA-IR) and insulinogenic index (IGI) were calculated, and correlation analyses were performed between these values and the GH-IGF-I axis. Patients were divided according to postoperative changes of the axis, and glucose tolerance was compared between the groups. RESULTS: In preoperative OGTTs, nine patients had impaired glucose tolerance and two had diabetes mellitus patterns. Postoperatively, significant reduction was observed both in fasting plasma glucose levels (p<0.01) and in HOMA-IR (p<0.01), whereas IGI showed no significant change. HOMA-IR was significantly correlated with serum IGF-I levels both before (r=0.83, p<0.01) and after (r=0.57, p<0.01) surgery, although it was not correlated with serum GH levels. Patients who achieved more than 50% postoperative reduction in serum IGF-I levels showed significant improvement in OGTTs results (p<0.05). CONCLUSIONS: In patients with acromegaly, serum IGF-I levels, but not GH levels, were significantly correlated with insulin resistance. Early postoperative improvement of glucose tolerance is observed in patients who achieved postoperative reduction in serum IGF-I levels.

Primary aldosteronism associated with subclinical Cushing syndrome.

BACKGROUND: Recently, it has been reported that the incidence of primary aldosteronism (PA) among patients with hypertension is much more frequent than previously reported. AIM: In the present study, we investigated the frequency and features of PA associated with subclinical Cushing syndrome (SCS). MATERIAL AND METHODS: Subjects included consecutive patients (no.=39) who were diagnosed as PA and performed adrenal venous sampling between 2003 and 2011 in our institute. RESULTS: In 39 subjects who were diagnosed as PA, 29 patients were operated and 5 cases (12.8%) showed no suppression in low-dose dexamethasone suppression test. Four cases of them were demonstrated to be associated with SCS, and one was associated with overt Cushing syndrome (CS). Post-operatively, 3 cases received replacement therapy of hydrocortisone, while others did not. Pathological findings indicated the diagnosis of aldosterone-producing adenoma in 4 cases associated with SCS, and of idiopathic hyperaldosteronismin in one case associated with overt CS. In all 5 cases, immunohistochemical analysis demonstrated the immunoreactivities of both 3ßHSD and P450c17 in the adrenocortical tumors, the marked cortical atrophy in the zona fasciculata and reticularis, the decreased dehydroepiandrosterone sulfotransferase expression, and suppression of hypothalamo- pituitary-adrenal axis indicating the autonomous secretion of cortisol from the tumor. CONCLUSIONS: The present study suggests that PA is frequently associated with SCS with prevalence of more than 10%, justifying the routine examinations for SCS in PA cases.

Periodontal regeneration of transplanted rat teeth subcutaneously after cryopreservation.

The periodontal regeneration of transplanted teeth after cryopreservation in liquid nitrogen overnight was previously examined using an animal model. The results showed that overnight cryopreservation did not have any severe adverse effects on periodontal healing. For clinical application, it is necessary to make the period of storage longer than in the preliminary study. In this study, the regeneration of periodontal tissues after cryopreservation for 4 weeks was examined. The maxillary molars of 4-week-old Wistar rats were extracted and transplanted into the abdominal subcutaneous tissue either immediately or after cryopreservation in a deep freezer at -80 degrees C. The donor teeth were frozen in a rate-controlling freezer. At 1, 2 and 4 weeks after transplantation, they were excised and observed under light microscopy. The cryopreserved teeth had acellular cementum with a rough surface at 1 week. With an increase in cementoblasts and the appearance of periodontal ligament and alveolar bone, the surface had become smooth at 2 weeks. There was no progressive root resorption. Although the process took somewhat more time, the teeth cryopreserved for 4 weeks showed regeneration that was similar to that of the immediately transplanted teeth.

A rare case of the cutaneous form of adult T-cell leukaemia/lymphoma: assessment of remission by PCR for clonal T-cell receptor gamma gene rearrangements in an electron beam-irradiated cutaneous lesion.

Adult T-cell leukaemia/lymphoma is a lymphoproliferative disorder aetiologically associated with human T-cell lymphotropic virus type I infection. A cutaneous lesion often develops in the disease, and in rare cases, is even the only manifestation. Here we report a rare case of 'cutaneous' adult T-cell leukaemia/lymphoma with neither atypical cells in the peripheral blood nor lymph node involvement. All nodular lesions were completely eliminated after local electron beam irradiation (20 Gy/nodule in total). To evaluate whether or not there were residual lymphoma cells in the skin, we performed PCR to detect clonal T cell receptor gamma gene rearrangements. The sample from the nodule before irradiation showed evidence of a rearranged band, which was not detected at the same site after treatment nor in any peripheral blood. The findings suggest that this procedure is useful for the evaluation of therapeutic effects and the early detection of lymphoma recurrence.

Narrow-band imaging in the diagnosis of colorectal mucosal lesions: a pilot study.

BACKGROUND AND STUDY AIMS: A newly developed narrow-band imaging (NBI) technique, in which modified optical filters were used in the light source of a video endoscope system, was applied during colonoscopy in a clinical setting. This pilot study evaluated the clinical feasibility of the NBI system for evaluating colorectal lesions. PATIENTS AND METHODS: A total of 43 colorectal lesions in 34 patients were included in the study. The quality of visualization of colorectal lesions and the accuracy of differentiation between neoplastic and non-neoplastic lesions using the NBI system were evaluated in comparison with results from conventional colonoscopy and with chromoendoscopy. RESULTS: For pit pattern delineation, NBI was superior to conventional endoscopy (P < 0.001), but inferior to chromoendoscopy (P < 0.05). NBI achieved better visualization of the mucosal vascular network and of the hue of lesions than conventional endoscopy (P < 0.05). However there was no significant difference between NBI and chromoendoscopy in differentiating neoplastic from non-neoplastic lesions (both techniques had a sensitivity of 100 % and a specificity 75 %). This was better than the results of conventional colonoscopy (sensitivity 83 %, specificity 44 %; P < 0.05 for specificity). CONCLUSIONS: These results suggest that in the examination of colonic lesions the NBI system provides imaging features additional to those of both conventional endoscopy and chromoendoscopy. For distinguishing neoplasms from non-neoplastic lesions, NBI was equivalent to chromoendoscopy.

MR and CT findings of craniopharyngioma during and after radiation therapy.

Long-term changes in craniopharyngioma treated with radiation therapy (RT) were investigated by computed tomography (CT) and/ or magnetic resonance (MR) imaging. Eight patients with craniopharyngioma were treated with incomplete resection or conservative surgical intervention followed by postoperative RT. The periods of tumor shrinkage were often long and varied (range: 6-68 months, mean: 29.1 months). Temporary enlargement of the solid component of a tumor usually occurs during RT and does not represent tumor progression. Cystic enlargement also occurs sometimes comparatively early after RT, and enlarged cysts often shrink with no treatment or with conservative treatment. These changes should be differentiated from tumor recurrence, with careful follow-up. After shrinkage, small solid or cystic nodules enhanced with contrast medium often remain. Long-term follow-up is necessary to differentiate uncontrolled tumors from controlled tumors with imaging modalities.

Pseudoankylosis of the mandible as a result of methyl methacrylate-induced inflammatory cicatricial contracture of the temporal muscle after cranioplasty.

Pseudoankylosis of the mandible after intracranial surgical procedure has been widely reported, and is usually caused by fibrosis of the temporal muscle as a result of injury during the operation. We present an unusual case of mandibular pseudoankylosis as a result of methyl methacrylate-induced aseptic inflammatory cicatricial contracture of the temporal muscle after cranioplasty.

[Primary squamous cell carcinoma of the prostate forming a rectourethral fistula: a case report].

Eleven cases of squamous cell carcinoma of the prostate have been previously reported in the Japanese medical literature. Patients with this type of carcinoma have dismal prognoses. Herein, we report a case in a 61-year-old man who was admitted to our hospital and whose chief complaints were dysuria and high fever. Pyuria, bacteriuria, and the results of a digital rectal examination suggested acute prostatitis. Despite the administration of antibiotics, the dysuria did not improve. A transrectal needle biopsy was performed, and histology of the tissue showed squamous cell carcinoma. After chemotherapy using methotrexate, pirarubicin, and cisplatin, total pelvic excentration was performed. At 12 months after the operation, the patient is alive with no evidence of the disease.

Incidence of deep fascial space infection after surgical removal of the mandibular third molars.

Nine hundred and ninety-three patients who underwent surgical removal of the mandibular third molars with oral antibiotic prophylaxis were examined to determine the incidence of postoperative deep fascial space infection and its background factors. Postoperative deep fascial space infection was observed in 8 of the patients (0.8%; 4 males and 4 females), and submandibular spaces were involved in all infected patients. Only 1 of these 8 patients was an immune compromised host. Patients aged 30 years or more had a significantly higher incidence of deep fascial space infection than those aged under 30. Five patients had partial bony impactions and 3 had complete bony impactions. However, the incidence of infection according to the molar positions was not significantly different between partial bony impaction and complete bony impaction. The 8 patients had not had pericoronitis preoperatively. The clinical courses of all were favorable after antibiotics were administered intravenously. In conclusion, the incidence of deep fascial space infection after removal of the mandibular third molars was low, at 0.8%. However, it may be desirable to remove the molars, if applicable, at a younger age because of the higher incidence of infection in patients aged over 30. The results of this study also offer information that will be useful as a basis for obtaining informed consent from patients whose mandibular third molars are to be removed.

Regressive effect of intralesional injection of a moderate dose of recombinant interleukin-2 on carcinoma erysipeloides from gastric carcinoma.

Cutaneous metastatic diseases remain nearly incurable and a major medical challenge. It has been shown that interleukin-2 (IL-2) has potential as a therapeutic agent for various neoplastic diseases such as melanoma, renal cell carcinoma and myeloid leukaemia. However, IL-2 therapy for metastatic skin lesions has not been established yet. In the present study, we investigated the effect of recombinant IL-2 in a 79-year-old Japanese man with carcinoma erysipeloides, a rare type of cutaneous metastasis from gastric cancer. He was treated with an intralesional injection of rIL-2 (200 000 JRU) daily. Ten days after treatment, an erythematous plaque was eliminated almost completely leaving light brown pigmentation. A skin biopsy from the pigmented area revealed the absence of obvious tumour cells. These findings suggest that this cytokine should be considered for the clinical treatment of several inoperative metastatic cutaneous diseases, including gastric cancer.

[Hyperdense renal cyst associated with papillary adenoma: a case report].

An abnormal shadow in the chest of a 57-year-old male was detected during a medical checkup and careful investigation revealed a left posterior mediastinal tumor (neurinoma) and a clearly demarcated homogenous mass with dimensions of 16 x 12 mm and computed tomographic (CT) value of 79 H.U. in the superior pole of the right kidney. The content solution was sticky and blackish-green. Neoplastic degenerations of 8 x 4 and 5 x 5 mm were seen in the cyst. Partial nephrectomy, which included the cystic section, was conducted and papillary adenoma was pathologically diagnosed. Nine years after the operation, the patient is alive and neither relapse nor other abnormalities were detected.

[A case of ileal conduit stenosis 13 years after construction].

A 63-year-old male was admitted to our hospital with the complaint of bilateral hydronephroses. Total cystectomy and ileal conduit construction were performed because of bladder tumor (TCC, G2, pT2N0M0) in 1985. The patient remained asymptomatic, but bilateral hydronephroses was observed by ultrasonography in 1997. DTPA renogram showed the delayed excretion. Conduitgraphy and antegrade pyelography revealed that the conduit was narrow like a pinhole at 2 cm distal region from the anastomotic site of the urinary duct. The stenotic region was inflated by a 24 Fr inflation-balloon-catheter. Chronic inflammation, which was thought to be caused by infection, was detected at the stenotic conduit by biopsy. Hydronephroses disappeared after the operation and the postoperative course was uneventful.

An immunohistochemical study of cytokeratins in skin-limited amyloidosis.

The frequency of amyloid deposits in cases of seborrheic keratosis was investigated In addition, the origin of amyloid protein(s) in lichen amyloidosis, macular amyloidosis and seborrheic keratosis was studied by immunohistochemical staining using a panel of anti-cytokeratin (CK) monoclonal antibodies. Amyloid deposits were found in 41 of 327 specimens (12.5%) from 301 cases of seborrheic keratosis. Amyloid deposits in seborrheic keratosis reacted with 6 of 12 CK antibodies and in lichen and macular amyloidosis (20 specimens) reacted with 5 of 12 CK antibodies. In seborrheic keratosis, antibody DE-K10 (labeling CK10) reacted with amyloid in 17 of 36 cases, antibody 34betaE12 (labeling CK1, 5, 10, 14) reacted in 33 of 39 cases, and antibody MNF116 (labeling CK5, 6, 8, 17) reacted in 32 of 35 cases. Among 20 specimens from lichen and macular amyloidosis, the three antibodies reacted with amyloid in the following rates: 1 with antibody DE-K10, all 20 with antibody 34betaE12, and 6 with antibody MNF116. These results suggest that amyloid deposits in seborrheic keratosis and lichen and macular amyloidosis may derive from epidermal cytokeratins.