Background:Little is known about the biweekly combined use of cetuximab and chemotherapy as second-line treatment of metastatic colorectal cancer (mCRC). Recently, DNA methylation status has been reported to be a new possible predictor of the efficacy from the anti-epidermal growth factor receptor (EGFR) antibody treatment. The purpose of this study was to examine the efficacy and safety of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as a second-line treatment for KRAS exon 2 wild-type mCRC. We also investigated the predictability of DNA methylation status on the efficacy of the EGFR antibody-containing treatment. Methods:Patients who were refractory or intolerant to the first-line chemotherapy were enrolled and received biweekly cetuximab plus mFOLFOX6 or mFOLFIRI. The primary endpoint was progression-free survival (PFS). Tumor evaluations were performed every 2 months using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. DNA methylation status of colorectal cancer cells was defined by a modified MethyLight assay. Results:Sixty-six cases were enrolled. The median PFS (mPFS) was 5.1 [95% confidence interval (CI), 3.8-7.6] months. The median overall survival (mOS) was 12.7 (95% CI, 7.5-15.3) months. Grade 3 or higher neutropenia occurred in 53.0% of patients, whereas skin disorders with a grade 3 or higher occurred in <15% of patients. In multivariate analysis, DNA methylation status could not be an independent predictor of PFS [hazard ratio (HR), 1.43; P=0.39] and OS (HR, 2.13; P=0.086). However, in RAS/BRAF wild-type patients, the mPFS and mOS in the low-methylated colorectal cancer (LMCC) group was numerically better than those in the highly-methylated colorectal cancer (HMCC) group, although the difference was not statistically significant [mPFS: 8.5 (95% CI, 6.1-10.9) vs. 3.3 (95% CI, 1.2-not reached) months, P=0.79; ΔmPFS, 5.2 months; mOS: 15.3 (95% CI, 11.9-23.5) vs. 6.5 (95% CI, 3.1-not reached) months, P=0.53; ΔmOS, 8.8 months]. Conclusions:Biweekly cetuximab plus mFOLFOX6 or mFOLFIRI is a useful second-line therapy for mCRC. DNA methylation status warrants further exploration as a predictive biomarker for anti-EGFR efficacy in mCRC.

Supportive periodontal therapy (SPT) must take individual patient risk factors into account. We conducted a multicenter joint retrospective cohort study to investigate the value of modified periodontal risk assessment (MPRA) and therapy-resistant periodontitis (TRP) assessment as predictive factors for tooth loss due to periodontal disease in patients with severe periodontitis during SPT.

Diabetes and periodontitis may increase risk of cardiovascular disease. Whether albuminuria, C-reactive protein (CRP), and socioeconomic factors, known as cardiovascular risks in subjects with poorly controlled diabetes, are independently associated with periodontal status in well-controlled diabetes remains to be elucidated. In 503 subjects with type 2 diabetes, the cross-sectional associations of clinical and socioeconomic factors with periodontal parameters were investigated. Periodontal parameters on all teeth included the probing pocket depth at 6 sites per tooth, bleeding on probing, the plaque score, tooth mobility, and the number of teeth. The subjects had a mean HbA1c value of 6.85% and a median CRP value of 0.06 mg/dL, and 27.9% of the subjects had albuminuria. Albuminuria and CRP values had significant associations with several periodontal parameters, whereas other variables including HbA1c did not. Subjects with albuminuria had significantly higher HbA1c, CRP, and % sites of pocket depth ≥ 4 mm than subjects with normoalbuminuria; additionally, those with high CRP (≥ median) had significantly higher body mass index, HbA1c, % sites of pocket depth ≥ 4 mm, and plaque score than those with low CRP. In multiple linear regression analysis, albuminuria, CRP, education, smoking, and dental attendance exhibited significant associations with periodontal parameters, independent of the effect of age, sex, body mass index, and diabetes therapy. Albuminuria, CRP, education, smoking, and dental attendance were independently associated with periodontal parameters even in subjects with a mean of HbA1c of 6.85%, implying the importance of these factors for the prevention of cardiovascular disease.

Atherosclerosis, a chronic inflammatory disease in arterial blood vessels, is one of the major causes of death in worldwide. Meanwhile, periodontal disease is a chronic inflammatory disease caused by infection with periodontal pathogens such as P. gingivalis (Porphyromonas gingivalis). Several studies have reported association between periodontal infection and atherosclerosis, but direct investigation about the effects of periodontal treatment on atherosclerosis has not been reported. We have planned Japanese local clinics to determine the relationship between periodontal disease and atherosclerosis under collaborative with medical and dental care. A prospective, multicentre, observational study was conducted including 38 medical patients with lifestyle-related diseases in the stable period under consultation at participating medical clinics and 92 periodontal patients not undergoing medical treatment but who were consulting at participating dental clinics. Systemic and periodontal examinations were performed before and after periodontal treatment. At baseline, LDL-C (low-density lipoprotein cholesterol) levels and percentage (%) of mobile teeth were positively related to plasma IgG (immunoglobulin) antibody titer against P. gingivalis with multivariate analysis. Corresponding to improvements in periodontal clinical parameters after treatment, right and left max IMT (maximum intima-media thickness) levels were decreased significantly after treatment (SPT-S: start of supportive periodontal therapy, SPT-1y: at 1 year under SPT, and SPT-3y: at 3 years under SPT). The present study has clarified our previous univariate analysis results, wherein P. gingivalis infection was positively associated with progression of atherosclerosis. Thus, routine screening using plasma IgG antibody titer against P. gingivalis and periodontal treatment under collaborative with medical and dental care may prevent cardiovascular accidents caused by atherosclerosis.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that is prevalent worldwide.Non-alcoholic steatohepatitis (NASH) is an advanced form of NAFLD and carries the risk of progression from hepatic inflammation and fibrosis to cirrhosis and hepatocellular carcinoma.Pathological mechanisms of NAFLD have been proposed, such as the two-hit hypothesis and the multiple parallel hit hypothesis.Periodontal disease is a chronic infectious disease of the tissues surrounding the teeth that result in tooth loss.Several reports have indicated that periodontal infection is related to NAFLD.NAFLD and periodontal disease are chronic inflammatory conditions that are known as 'silent diseases'.Therefore, both conditions need to be detected early and treated under collaborative medical and dental care in order to prevent progression to NASH.For this purpose, further investigations in humans on the relationship between NAFLD and periodontal disease and on the effect of periodontal treatment on NAFLD are necessary.In this paper, studies on the relationship between NAFLD and periodontal disease are reviewed and a clinical study investigating the effect of periodontal treatment on NAFLD is introduced.Recent animal and human investigations have indicated that NAFLD/NASH is related to periodontal disease [13,14].As patients with liver or periodontal disease have few subjective and early symptoms, the diseases are often severe when they are discovered at medical institutions.[15,16].Therefore, early detection and treatment under collaborative medical and dental care is important to prevent progression to NASH, which may then develop into cirrhosis or liver cancer.Further investigations in humans on the relationship between NAFLD and periodontal disease and on the effect of periodontal treatment on NAFLD are desired.

【目的】悪性腫瘍による脊髄圧迫の症状出現から治療までの遅延と転帰を検討する．【方法】地域中核病院にて診断された25症例を診療録を元に後方視的に解析した．【結果】脊髄圧迫によりがんの診断となった患者（初診患者）は12例，がんの診断で通院中の患者は13例であった（再来患者）．92％の患者は疼痛が初発症状であり，疼痛から神経障害出現までの期間は約2カ月（中央値56日）であった．症状発現から治療までの期間は，初診患者が中央値79日，再来患者が同41.5日であった．症状発現から病院受診までは各53日，9日．受診から診断までは各5日，8日，診断から治療までは各11日，14日であった．麻痺出現前に治療を行った9例中8例は麻痺が出現しなかったが，麻痺出現後に治療を行い麻痺の改善を認めたものは10例中4例であった．【結論】治療に至る種々の過程で遅延が生じ転帰を悪化させていると考えられた．

It has been revealed that atherosclerosis and periodontal disease may have a common mechanism of "chronic inflammation". Several reports have indicated that periodontal infection is related to atherosclerosis, but none have yet reported such an investigation through the cooperation of local clinics. This study was performed in local Japanese clinics to examine the relationship between periodontal disease and atherosclerosis under collaborative medical and dental care. A pilot multicenter cross-sectional study was conducted on 37 medical patients with lifestyle-related diseases under consultation in participating medical clinics, and 79 periodontal patients not undergoing medical treatment but who were seen by participating dental clinics. Systemic examination and periodontal examination were performed at baseline, and the relationships between periodontal and atherosclerosis-related clinical markers were analyzed. There was a positive correlation between LDL-C level and plasma IgG antibody titer to Porphyromonas gingivalis. According to the analysis under adjusted age, at a cut-off value of 5.04 for plasma IgG titer to Porphyromonas gingivalis, the IgG titer was significantly correlated with the level of low-density lipoprotein cholesterol (LDL-C). This study suggested that infection with periodontal bacteria (Porphyromonas gingivalis) is associated with the progression of atherosclerosis. Plasma IgG titer to Porphyromonas gingivalis may be useful as the clinical risk marker for atherosclerosis related to periodontal disease. Moreover, the application of the blood examination as a medical check may lead to the development of collaborative medical and dental care within the local medical clinical system for the purpose of preventing the lifestyle-related disease.

Tumor lysis syndrome (TLS) is a potential life-threatening complication in cancer therapy, although it is rare in nonhematologic malignancy. Sorafenib, an oral multi tyrosine kinase inhibitor, has demonstrated survival benefit for patients with advanced hepatocellular carcinoma (HCC). A 70-year-old man with massive HCC was treated with sorafenib. Seven days after the start of treatment, he developed acute renal failure and elevation of hepatic enzymes, suggesting TLS. Abdominal CT depicted multiple hemorrhages in his liver. He was treated with emergent hemodialysis. He was discharged from the hospital, but mild renal dysfunction remained. We should pay careful attention to treatment of patients who have large HCC with sorafenib.

KEY CLINICAL MESSAGE:We report a case of Behçet's disease which was aggravated by psychological stress and oral infection. The control of oral infection under medical and dental collaboration is important for providing Behçet's disease patients with the optimal medical care and for facilitating the relief of the primary disease.

ある広汎型侵襲性歯周炎患者（女性）の 24 歳時からの 26 年間に及ぶ歯周治療経過を，臨床的観点と細菌学的・免疫学的な観点から追った。その間，患者には結婚，転居，出産，そして育児といったライフステージの変化があった。そこで，このライフステージによる生活習慣の変化が歯周病の病態に影響を与える可能性を考えて，動的治療期から Supportive Periodontal Therapy（SPT）期に渡って臨床症状が出現する前に病態変化を捉えようと，歯周病原細菌感染度を歯周病原細菌に対する血清 IgG 抗体価を用いてモニタした。この治療経過における患者の病態と SPT 期における継続的な受診支援に関して考察し，10 代後半から 20 代前半に発症する侵襲性歯周炎患者の長期管理法を提案する。この方法は，細菌の持続感染による疾患の活動性を把握するために用いた血清 IgG 抗体価検査による，口腔内の感染管理に注目するものである。 日本歯周病学会会誌（日歯周誌）56(2)：217-226，2014

We recently reported frequent detection of antibiotic-resistant bacteria on the oral mucosa during the period of hematopoietic cell transplantation (HCT) and suggested an association between oral mucositis and antibiotic-resistant bacterial infection. Methicillin-resistant Staphylococcus spp. were frequently detected, and the oral cavity may be a reservoir of the gene mediating methicillin resistance, mecA. Here, we examined the frequency of mecA carriers in patients undergoing HCT.

A 27-year-old woman visited our hospital because of high fever. She had been diagnosed as 22q11.2 deletion syndrome (22q11.2DS) due to her cardiac history (tetralogy of Fallot), thymic hypoplasia and 22q11.2 deletion. She had a normal CD4/CD8 ratio, a slightly decreased lymphocyte count and normal serum immunoglobulin levels. Blood cultures were positive for Staphylococcus lugdunensis (S. lugdunensis). Infection route of S. lugdunensis in this case was unclear. The patient was successfully treated with several intravenous antibiotics. Infection should be considered when managing patients with 22q.11.2DS. regardless of whether their immune system is impaired.

BACKGROUND:Curcumin is known to possess many anti-tumor properties such as inhibition of tumor growth and induction of apotosis. However, limited bioavailability of curcumin prevents its clinical application. A synthesized curcumin analog, 1,5-diaryl-3-oxo-1,4-pentadiene such as GO-Y030, has the improved anti-tumor potential in vitro as well as in mouse model of colorectal carcinogenesis.RESULTS:These compounds were divided into two groups; one is the higher anti-proliferative group, in which 79.7% of 1,5-diaryl-3-oxo-1,4-pentadienes were clustered. One of the 1,5-diaryl-3-oxo-1,4-pentadiene analogs, GO-Y078 has the most enhanced growth inhibition, and its solubility was improved, compared with curcumin. GO-Y078 inhibits NF-κB transactivation, as well as expression of TP53 and DR5 more effectively than curcumin. In a mouse model, GO-Y078 presented 1.4 fold more survival elongation that was not achieved by curcumin and GO-Y030.CONCLUSIONS:The 1,5-diaryl-3-oxo-1,4-pentadiene analogs can yield good lead compounds for cancer chemotherapy, to overcome low bioavailability of curcumin.

Curcumin is a dietary constituent with tumor‐suppressing potential, inhibiting various pathways involved in carcinogenesis. However, because of its low bioavailability, the use of curcumin in in vivo trials has been limited. To overcome this problem, we synthesized more than 50 analogs and identified a monoketone analog, GO‐Y030, which has a 30‐fold higher potential to suppress tumor cell growth compared with curcumin. We investigated the inhibitory effect of GO‐Y030 on NF‐κB activation. In thyroid, pancreatic cancers and cholangiocarcinoma cells, in which NF‐κB is activated, NF‐κB activation was suppressed to 8–62% of the control value following treatment with 1 μM GO‐Y030, an effect comparable to that of 10 μM curcumin. Direct inhibition of IKKβ kinase activity and suppression of nuclear translocation of the NF‐κB p65 subunit were observed. The 50% growth inhibition concentrations of GO‐Y030 ranged from one‐11th to one‐14th of those of curcumin. GO‐Y030 also induced cell death comparable to that induced by curcumin but at a 10‐fold lower concentration. In pancreatic and thyroid cancer cells, the growth‐inhibitory effect of GO‐Y030 was 4‐ and 15‐fold greater, respectively, than that of curcumin. GO‐Y030 was a much stronger inducer of apoptosis compared with curcumin. The enhanced potency of GO‐Y030 may make it more useful than curcumin, which suffers from low bioavailability. GO‐Y030 is a good lead compound for the development of useful compounds for practical cancer chemotherapy. ( Cancer Sci 2011; 102: 1045–1051)

Chronic periodontitis is associated with systemic diseases such as atherosclerosis.In this study, we evaluated the efficacy of serum IgG antibody titer to periodontal bacteria for prognosis of periodontitis recurrence during supportive periodontal therapy (SPT) phase.The 139 patients during SPT phase were selected and divided to two groups as follows: ''Stable'' and ''Recurrence'' group at SPT phase for case-control study: ''High IgG titer'' and ''Normal IgG titer'' group before transition to SPT phase for cohort study.We examined whether clinical findings or serum IgG antibody titers to periodontal bacteria are risk factors for the development of periodontitis recurrence.Case-control study showed that there were significant differences between the stable and recurrence groups in age and number of teeth.The serum IgG antibody titer to Eikenella corrodens FDC1073, Porphyromonas gingivalis SU63, and Campylobacter rectus ATCC33238 was significantly higher in the recurrence group.Next, we found, that the recurrence ratio in the high IgG titer group to Gram-negative obligate anaerobe, Prevotella intermedia, Treponema denticola, and C. rectus was significantly higher than that of the normal IgG titer group.Taken together, serum IgG antibody titer test is useful in the prognosis of periodontitis recurrence during the SPT phase.

BACKGROUND:Multiple myeloma remains an incurable malignancy despite of the recent approval of new molecular-targeted agents. The complex molecular mechanism, composed of various signal networks, including nuclear factor-κB (NF-κB), phosphoinositide 3-kinase (PI3K)/AKT, Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), and interferon regulatory factor 4 (IRF4) pathways, is a major reason for treatment failure. Curcumin can regulate these molecules, but its low bioavailability prevents its clinical application.MATERIALS AND METHODS:Growth-suppressive abilities of newly synthesized analogs, GO-Y030 and GO-Y078 were analyzed. Molecular-targeted abilities of the analogs for NF-κB, PI3K/AKT, JAK/STAT3, IRF4 pathways, as well as inhibition of interleukin-6 (IL-6) production, were also examined.RESULTS:GO-Y030 and GO-Y078 were 7 to 12-fold more potent growth suppressors for myeloma cells, and 6- to 15-fold stronger inhibitors of NF-κB, PI3K/AKT, JAK/STAT3, and IRF4 pathways than curcumin. GO-Y78 also 14-fold more potently inhibited IL-6 production.CONCLUSION:GO-Y030 and GO-Y078 are potential therapeutic candidates with enhanced abilities for multiple myeloma.

A series of novel analogues of 1,5-bis(4-hydroxy-3-methoxyphenyl)-penta-(1E,4E)-1,4-dien-3-one (C5-curcumin), which is a natural analogue of curcumin isolated from the rhizomes of Curcuma domestica Val. (Zingiberacea), were synthesized and evaluated for their cytotoxicities against human colon cancer cell line HCT-116 to conclude the SAR of C5-curcuminoids for further development of their use in cancer chemotherapy: (1) Bis(arylmethylidene)acetone serves as a promising skeleton for eliciting cytotoxicity. (2) The 3-oxo-1,4-pentadiene structure is essential for eliciting cytotoxicity. (3) As for the extent of the aromatic substituents, hexasubstituted compounds exhibit strong activities, in which 3,4,5-hexasubstitution results in the highest potency. (5) The symmetry between two aryl rings is not an essential requirement for bis(arylmethylidene)acetones to elicit cytotoxicity. (6) para-Positions allows the installation of additional functional groups for use as molecular probes. By taking advantage of the SAR diagram, we have elaborated several advanced derivatives having GI50 of single-digit micromolar potencies that will function as molecular probes to target and/or report key biomolecules interacting with curcumin and C5-curcumin.