Anti-citrullinated protein antibody titre as a predictor of abatacept treatment persistence in patients with rheumatoid arthritis: a prospective cohort study in Japan.

Objective: Successful rheumatoid arthritis (RA) outcome depends on treatment efficacy in the early stages of the disease and its sustainability. It is thus critical to identify factors predicting treatment persistence with biological agents, such as abatacept. We compared clinical profiles, including early changes in autoantibody titres at 3 months, between patients with RA demonstrating sustained persistence and those discontinuing abatacept treatment.Method: We prospectively enrolled 71 and 78 active RA patients treated with abatacept and tumour necrosis factor inhibitors (TNF-Is), respectively, who had previous disease-modifying anti-rheumatic drug) failure. Clinical characteristics were compared between non-continuation and continuation groups stratified according to abatacept or TNF-I persistence for at least 12 months from treatment initiation.Results: Significantly larger decreases in rheumatoid factor titre and anti-citrullinated protein autoantibody (ACPA) titre were observed in the continuation group of abatacept therapy at 3 months, and early reduction in ACPA titre remained a significant and independent predictor of sustained persistence with abatacept in multivariate analysis. In addition, we obtained the area under the receiver operator characteristics curve of 0.904 from a model including baseline ACPA titre and reduction of ACPA titre at 3 months. Sustained reduction of RA disease activity score at 12 months was significantly and independently associated with reduced ACPA titre at 3 months.Conclusions: Persistence with abatacept and sustained therapeutic response are associated with an early reduction in ACPA titre. Prediction of abatacept continuation and efficacy will facilitate the optimal design of therapy in the early stages of RA.

Long-term skeletal stability in the treatment of mandibular prognathism with a physiological positioning strategy.

Our aim was to evaluate the long-term skeletal stability of the mandible in 21 patients after orthognathic surgery with physiological positioning. The measurement points SNB, B point (X, Y), Pog (X, Y), and the angle of the ramus were measured on cephalometric photographs to assess skeletal stability preoperatively, immediately after operation, and one and two years postoperatively. In addition, we evaluated the clinical symptoms of disorders of the temporomandibular joint (TMJ). The analysis of the cephalometric photographs showed that SNB, B point X, and Pog X showed no significant differences among the postoperative time points. On the other hand, B point Y and Pog Y showed no significant differences throughout the study period. We compared the angle of the ramus before operation and two years postoperatively, and no significant difference was found. In addition, no cases showed any pathological symptoms of disorders of the TMJ two years postoperatively. The long-term stability after orthognathic surgery with physiological positioning was confirmed, and it seems to be a reliable orthognathic treatment in patients with mandibular prognathism.

Complete renal response at 12 months after induction therapy is associated with renal relapse-free rate in lupus nephritis: a single-center, retrospective cohort study.

BACKGROUND: Lupus nephritis (LN) is a major risk factor for overall morbidity and mortality in systemic lupus erythematosus (SLE). METHODS: We retrospectively analyzed cases of proliferative and membranous LN patients who underwent a renal biopsy at our hospital in 1993-2016. We analyzed the association between complete renal response (CR) rates at 12 months after induction therapy and predictive factors for CR and their association with renal flares. RESULTS: Of the 95 cases analyzed, we were able to track the therapeutic responses of 81 patients at 12 months after their induction therapy. The median follow-up duration after renal biopsy was 51 months (interquartile range: 16.5-154.5 months). The Cox proportional hazards model showed that, compared to not attaining CR at 12 months, the attainment of CR at 12 months was correlated with being free from renal flares. The multivariate logistic analysis revealed that the predictive factors for CR at 12 months were the anti-La/SSB antibodies (U/ml) (odds ratio (OR) 1.22, 95% confidence interval (CI) 1.01-1.63, p = 0.0220), blood urea nitrogen (BUN) (OR 0.68, 95% CI 0.44-0.90, p = 0.00048) and serum ß2 microglobulin (MG) (OR 0.26, 95% CI 0.06-0.74, p = 0.00098) levels. CONCLUSIONS: Among LN patients, being free from renal flares was associated with attaining CR at 12 months after induction therapy. Anti-La/SSB antibodies were a positive predictive factor, and BUN and serum ß2MG levels were negative predictive factors of CR at 12 months.

Factors predictive of long-term mortality in lupus nephritis: a multicenter retrospective study of a Japanese cohort.

BACKGROUND: Lupus nephritis (LN) is a major determinant of mortality in systemic lupus erythematosus (SLE). Here we evaluated the association between complete renal response (CR) and mortality in LN. METHODS: We retrospectively analyzed the cases of 172 of 201 patients with LN for whom data on the therapeutic response at 6 and 12 months after induction therapy were available. The patients underwent a renal biopsy at Nagasaki University Hospital and community hospitals in Nagasaki between the years 1990 and 2016. We determined the CR rates at 6 and 12 months after induction therapy initiation and evaluated the predictive factors for CR and their relationship with mortality. We performed univariate and multivariable competing risks regression analyses to determine the factors predictive of CR. The patients' survival data were analyzed by the Kaplan-Meier method with a log-rank test. RESULTS: The median follow-up duration after renal biopsy was 120 months (interquartile range: 60.3-191.8 months). The 5-, 10-, 15- and 20-year survival rates of our cohort were 99.3, 94.6, 92.0 and 85.4%, respectively. During follow-up, nine patients (5.2%) died from cardiovascular events, infection, malignancy and other causes. The multivariate analysis revealed that the following factors were predictive of CR. At 6 months: male gender (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.08-0.65, p = 0.0028), proteinuria (g/gCr) (OR 0.83, 95% CI 0.71-0.97, p = 0.0098) and index of activity (0-24) (OR 0.84, 95% CI 0.71-0.99, p = 0.0382). At 12 months: male gender (OR 0.25, 95% CI 0.09-0.67, p = 0.0043) and index of activity (0-24) (OR 0.82, 95% CI 0.69-0.98, p = 0.0236). The Kaplan-Meier analysis showed that compared to not achieving CR at 12 months, achieving CR at 12 months was significantly correlated with the survival rate (OR 0.18, 95% CI 0.04-0.92, p = 0.0339). CONCLUSIONS: Our results suggest that the survival rate of patients with LN is associated with the achievement of CR at 12 months after induction therapy, and that male gender and a higher index of activity (0-24) are the common predictive factors for failure to achieve CR at 6 and 12 months.

Clinical application of autogenous partially demineralized dentin matrix prepared immediately after extraction for alveolar bone regeneration in implant dentistry: a pilot study.

The aim of this study was to examine the efficacy and safety of autogenous partially demineralized dentin matrix (APDDM) prepared onsite, for clinical application in bone regeneration procedures related to implant dentistry, including socket preservation, alveolar ridge augmentation, and maxillary sinus floor augmentation. In this study, 16 patients underwent dental implant placement using APDDM transplantation. There were no systemic or local complications (including surgical site infection) in any of the cases, and oral rehabilitation using dental implants was successful in all cases for at least 2 years after attachment of the suprastructure. This report describes the clinical application of APDDM prepared immediately after tooth extraction to bone augmentation, taking advantage of the relatively short preparation time due to partial demineralization. APDDM, as introduced in this study, is an efficient, safe, and reasonable bone substitute. Consequently, this material has the potential to become one of the options as a bone substitute in implant dentistry.

Adipogenesis of the mesenchymal stromal cells and bone oedema in rheumatoid arthritis.

OBJECTIVES: Bone oedema is a pathological change in rheumatoid arthritis (RA) that is detectable by magnetic resonance imaging (MRI). Recent histological analyses revealed that a prominent feature of bone oedema is the replacement of adipose tissue with inflammatory cells. Here, we demonstrate the possible roles of mesenchymal stromal cells (MSCs) in bone oedema formation and the pathogenic potential of the cells in RA. METHODS: Adipogenesis of bone marrow-derived human MSCs was induced by a standard adipogenic induction medium in the presence or absence of cytokines. The cytokine productions from MSCs were screened by an antibody array system and confirmed by ELISA. The migration assay was performed to determine the locomotive abilities of undifferentiated MSCs or MSCs after adipogenesis. The expression of α smooth muscle actin (SMA) and F-actin was examined by immunostaining and phalloidin staining, respectively. RESULTS: TNF-α, interleukin (IL)-1ß, IL-6, and TGF-ß clearly inhibited the adipogenesis of MSCs. Production of IL-6 was markedly reduced, and IL-8 secretion was augmented in MSCs after adipogenesis. The mobility of MSCs after adipogenesis was clearly reduced in migration assays compared to that of undifferentiated MSCs. Consistent with these findings, SMA and F-actin expressions were clearly suppressed in MSCs committed to adipogenesis. CONCLUSIONS: Our data suggest that the inflammatory milieu promotes bone oedema by blocking adipogenesis of MSCs. In bone oedema, the enhanced IL-6 production and the increased mobility of MSCs may contribute to the progression of RA. Therefore, bone oedema may be an important target lesion in the treatment of RA.

Contralateral occurrence after laparoscopic total extraperitoneal hernia repair for unilateral inguinal hernia.

PURPOSE: Although laparoscopic total extraperitoneal repair (TEP) has been reported to have a low recurrence rate and relatively little postoperative pain, there have been few studies reported regarding contralateral occurrence after TEP. Although a high incidence of occult contralateral hernias has been reported in the literature, it is unknown whether occult hernias have any significance in clinical settings. The aim of this study was to evaluate the incidence of contralateral occurrence after TEP for unilateral inguinal hernia. METHODS: We retrospectively reviewed the medical charts of 157 TEPs between April 2003 and May 2009. No patients had undergone contralateral exploration during TEP for unilateral inguinal hernias. RESULTS: Five (3.2%) of 157 unilateral TEPs developed a hernia on the contralateral side. In three patients, the initial hernia was on the right side, and in two it was on the left side. In four patients the initial hernia was indirect, and in one it was direct. The mean duration to contralateral occurrence was 12.2 months. Three patients had contralateral occurrence within 6 months after the primary TEP, while in two over a year passed before contralateral occurrence. All five patients had undergone TEP for contralateral occurrence. The mean operation time was 87.2 min, and there was little intraoperative blood loss. There were no complications during and after the second TEP. CONCLUSIONS: The incidence of contralateral occurrence after TEP was found to be low. TEP is a valuable procedure with a low contralateral occurrence rate, and repeated TEP for contralateral occurrence can be performed easily.

The value of image coregistration during stereotactic radiosurgery.

BACKGROUND: Coregistration of any neuroimaging studies into treatment planning for stereotactic radiosurgery became easily applicable using the Leksell Gamma Knife 4C, a new model of gamma knife. The authors investigated the advantage of this image processing. METHOD: Since installation of the Leksell Gamma Knife 4C at the authors' institute, 180 sessions of radiosurgery were performed. Before completion of planning, coregistration of frameless images of other modalities or previous images was considered to refine planning. Treatment parameters were compared for planning before and after refinement by use of coregistered images. FINDINGS: Coregistered computed tomography clarified the anatomical structures indistinct on magnetic resonance imaging. Positron emission tomography visualized lesions disclosing metabolically high activity. Coregistration of prior imaging distinguished progressing lesions from stable ones. Diffusion-tensor tractography was integrated for lesions adjacent to the corticospinal tract or the optic radiation. After refinement of planning in 36 sessions, excess treated volume decreased (p = 0.0062) and Paddick conformity index improved (p < 0.001). Maximal dose to the white matter tracts was decreased (p < 0.001). CONCLUSION: Image coregistration provided direct information on anatomy, metabolic activity, chronological changes, and adjacent critical structures. This gathered information was sufficiently informative during treatment planning to supplement ambiguous information on stereotactic images, and was useful especially in reducing irradiation to surrounding normal structures.

MEFV mutations in Japanese rheumatoid arthritis patients.

OBJECTIVE: Familiar Mediterranean Fever (FMF) is common among Mediterranean populations, while other populations are rarely affected. The aim of this study was to assess the involvement of MEFV gene mutations among Japanese rheumatoid arthritis patients with or without amyloid A (AA) amyloidosis. METHODS: The frequency of the MEFV mutations, which were identified in Japanese FMF patients, was determined in 126 Japanese RA patients and 76 Japanese healthy subjects. RESULTS: The M694I mutation was not observed among RA patients and healthy subjects. Allele frequency of R408Q, P369S, E148Q, L110P mutations account respectively for 3.3%, 3.9%, 23.7%, 9.2% in healthy subjects and 5.6%, 6.7%, 24.2%, 9.5% in RA patients. The overall mutation rate was comparable between the RA patients and healthy subjects, as well as between the RA patients with and without amyloidosis. CONCLUSION: This study shows the high prevalence of mutations of the MEFV genes in Japanese RA patients. However, our data suggest that the MEFV gene mutations may not be a genetic factor affecting the susceptibility of RA or the development of amyloidosis in a Japanese population.

Salvage esophagectomy after definitive chemoradiotherapy for esophageal cancer.

Salvage esophagectomy is performed for esophageal cancer after definitive chemoradiotherapy. The clinical significance and safety of salvage surgery has not been well established. We reviewed 14 cases of salvage esophagectomy following definitive chemoradiotherapy from 1994 through 2005 and investigated complication rates and outcomes. Seven of 14 cases were completely resected with salvage surgery. Operation time and bleeding were greater in patients who experienced incomplete resection (R1/R2). Anastomosis leakage, pulmonary dysfunction and heart failure were recognized in four, two and one patients, respectively. The postoperative complications were more frequent (71.4%) in patients with incomplete resection (R1/R2) than in patients with complete resection (R0) (28.4%). Two patients with complete resection (R0) showed long-term survival. Salvage esophagectomy may be indicated when the tumor can be resected completely after definitive chemotherapy. However, all cases of T4 cancer cannot be resected completely, resulting in a high risk for complications and poor survival.

Expression of insulin-like growth factor-1 receptor, p-AKT and p-ERK1/2 protein in extramammary Paget's disease.

BACKGROUND: The insulin-like growth factor-1 (IGF-1) receptor (R)-induced phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK)/ERK signal transduction cascade, which have critical roles in prevention of apoptosis and regulation of cell cycle progression, plays an important role in tumorigenesis. The expression of IGF-1R, AKT and ERK1/2 has been described in some human malignancies, but not in extramammary Paget's disease (EMPD). OBJECTIVES: To study the expression of IGF-1R, p-AKT and p-ERK1/2 in EMPD and to evaluate the relationships among them. METHODS: Thirty-six tissue samples of 34 patients with primary EMPD were subjected to immunohistochemical staining for IGF-1R, p-AKT and p-ERK1/2. RESULTS: Of thirty-six EMPD tissue samples, 34, 34 and 28 were positive for IGF-IR, p-AKT and p-ERK1/2 expression, respectively; 27, 23 and 17 of the 36 specimens stained positive for IGF-IR, p-AKT and p-ERK1/2 in more than half of Paget's cells, respectively. There were significant correlations between the IGF-1R and p-AKT expression as well as between IGF-1R and p-ERK1/2 expression. Taken together, these results indicate that IGF-1R is overexpressed, and AKT and ERK1/2 are frequently phosphorylated in EMPD. CONCLUSIONS: Our study shows that the expression of IGF-1R and the induction of p-AKT and the p-ERK1/2 pathway may play an important role in the pathogenesis of EMPD. The IGF-IR system might be a potential therapeutic target in EMPD.

Expression of phosphorylated Stat3, cyclin D1 and Bcl-xL in extramammary Paget disease.

BACKGROUND: Stat3 (Signal transducer and activator of transcription-3) is an oncogene that plays a critical role in regulating fundamental processes associated with malignant transformation and cell survival. It participates in oncogenesis through upregulation of genes encoding apoptosis inhibitors (Bcl-xL) and cell cycle regulators (cyclin D1). The expression of Stat3, Bcl-xL and cyclin D1 protein has not been investigated in extramammary Paget disease (EMPD). OBJECTIVES: To study the expression of phosphorylated Stat3 (p-Stat3), Bcl-xL and cyclin D1 protein in EMPD and to evaluate the relationships among them. METHODS: Thirty-six tissue samples from 34 patients with primary EMPD were subjected to immunohistochemical staining for p-Stat3, cyclin D1 and Bcl-xL. RESULTS: Thirty-five of 36 specimens were clearly positive for p-Stat3 in EMPD, while 30 of 36 and 32 of 36 were positive for cyclin D1 and Bcl-xL expression, respectively. In all of four invasive EMPD specimens, strong and frequent expression of these three molecules was evident; moreover, two invasive EMPD specimens with lymph nodal metastasis showed very strong nuclear and membranous p-Stat3 staining. Two metastatic lymph node specimens showed very strong nuclear and local membrane p-Stat3 staining. There were significant correlations between p-Stat3 and cyclin D1 expression and between p-Stat3 and Bcl-xL expression. CONCLUSIONS: Our study shows that the expression of p-Stat3, cyclin D1 and Bcl-xL may play a pivotal role in the pathogenesis of EMPD.

[Prophylactic administration of steroid for interstitial pneumonia after pulmonary resection for lung cancer].

OBJECTIVES: The aim of the present study is to investigate the perioperative management of acute exacerbation of idiopathic interstitial pneumonia (IIP) after pulmonary resection for lung cancer. METHODS AND RESULTS: At first, we reviewed 5 Japanese literatures published from 1992 through 1998. Within 30 days after operation, acute exacerbation of IIP occurred in 24.0% of those cases. Preoperative profiles (gender, age, smoking status, respiratory function, pathologic stage) of the exacerbated cases did not differ from those of non-exacerbated cases. The mean intraoperative PO2 of the exacerbated cases was significantly higher than that of non-exacerbated cases (224 Torr versus 120 Torr, p=0.005). Despite high-dose administration of steroids, mortality rate after acute exacerbation of IIP was 91.7%. Second, in order to investigate both the benefits and adverse effects of prophylactic administration of methylprednisolone for interstitial pneumonia (IP) after pulmonary resection, we reviewed 41 patients with primary lung cancer who underwent complete resection. Of these, 24 patients who had 2 or more risk factors for postoperative IP were given 125 mg of methylprednisolone intravenously just before the thoracotomy. The risk factors included male gender, Brinkmann index > or = 600, and the presence of interstitial changes on chest computed tomography (CT). Otherwise, all patients were followed under our postoperative management without oxygen administration. The serum CRP on the 3rd postoperative day was significantly lower in the steroid group than in control (8.5 mg/dl versus 13.3 mg/dl, p=0.011) while it was not different between those 2 groups on the 7th postoperative day. Both the mean days of postoperative hospital stay and the disease-free survival were not different between the 2 groups. CONCLUSION: Prophylactic administration of methylprednisolone for IP might be effective without significantly adverse effects.

Clinicopathological features of cutaneous lesions of adult T-cell leukaemia/ lymphoma.

BACKGROUND: Adult T-cell leukaemia/lymphoma (ATLL) is a human malignancy associated with human T-cell leukaemia virus type I (HTLV-I). ATLL frequently involves the skin. OBJECTIVES: To correlate the clinicopathological features and prognosis in patients with ATLL and cutaneous lesions. METHODS: We examined the HTLV-I proviral state and the clinicopathological features of the cutaneous lesions in 80 patients with serum anti-ATL antibody, to clarify the correlation between macroscopic/histopathological findings and prognosis. Southern blot analysis was performed in all cases to detect monoclonal HTLV-I proviral DNA integration. RESULTS: The cutaneous lesions of 46 patients were positive for proviral DNA integration. The median survival time of patients with monoclonal proviral DNA integration in cutaneous lesions was 14 months, which was markedly shorter than that of patients negative for proviral DNA integration (72 months). Of the 46 patients with proviral DNA, 21 had solitary or multiple red nodules (including three with subcutaneous induration), eight had multiple red papules and 17 had erythema. Patients with papules and nodules had poorer prognosis than those with erythema. Histopathologically, the prognosis was poorer in patients with nodular or diffuse infiltration of medium-sized to large lymphoma cells, compared with those with perivascular infiltration of small to medium-sized lymphoma cells. CONCLUSIONS: Our results show a close correlation between clinicopathological features of HTLV-I-associated cutaneous lesions and prognosis.

[Pulmonary undifferentiated carcinoma associated with severe inflammatory response; report of 2 cases].

We present 2 cases with pulmonary undifferentiated carcinoma accompanying severe inflammatory responses. Both patients initially complained high-grade fever. Laboratory data on admission showed leukocytosis and elevation of serum CRP level. In both cases, the tumors were characterized by a low-density mass with the enhanced wall on chest computed tomography (CT). The presence of tumor cells could not be identified by bronchoscopical examination. One patient was suffered from left adrenal metastasis at the diagnosis. Both patients underwent pulmonary resection for the primary tumor. The tumors consisted of marked necrotic tissue and were histologically diagnosed as pulmonary undifferentiated carcinoma cells with sarcomatous elements, which was compatible with pleomorphic carcinoma by new World Health Organization (WHO) classification (1999). After operation, systemic inflammatory response such as high-grade fever, leukocytosis, high level of serum CRP continued and progressed. Furthermore, extrathoracic metastatic lesions newly appeared. Both patients died within 100 days after operation.

Basal cell carcinomas in association with basaloid follicular hamartoma.

We describe a unique case of various types of basal cell carcinoma (BCC) associated with basaloid follicular hamartoma (BFH) in a 56-year-old female patient. The lesion consisted of a dark brown and elastic soft nodule and papules within the area of a birthmark on the neck. The lesion was surgically excised. Histological examination of the nodular region revealed aggregations of neoplastic basaloid cells. We diagnosed the nodule as BCC with a racemiform or reticular pattern. In addition, a specimen taken from brownish black papules within the birthmark was found to be composed of anastomosing cords of basaloid cells accompanied by infundibular cystic structures. These features were consistent with an infundibulocystic BCC. In contrast, specimens from a hamartomatous plaque showed distinctive branching strands of basaloid cells that are suggestive of BFH. Therefore, our findings indicate that several types of BCC may develop within a BFH.

Chemical peeling with salicylic acid in polyethylene glycol vehicle suppresses skin tumour development in hairless mice.

BACKGROUND: Chemical peeling with salicylic acid in polyethylene glycol (PEG) vehicle is used clinically to improve the cosmetic appearance of skin that has been damaged by exposure to the sun. It is well known that cancers of the skin such as basal cell carcinoma and squamous cell carcinoma may be induced by the sun. However, the carcinogenic potential of chemical peeling agents has not been studied. OBJECTIVES: To evaluate the effects of chemical peeling with 30% salicylic acid in PEG on skin tumour formation in treated vs. control mice. METHODS: To serve as a model of sun-damaged skin, hairless SKH/hr1 mice were irradiated with ultraviolet (UV) B for 14 weeks, with or without treatment every 2 weeks with 30% salicylic acid in PEG for a total of 18 weeks. RESULTS: Not only was the total number of tumours greatly reduced in the treated vs. the control mice, but skin tumour development was also slower in the treated vs. the control mice. At the final treatment, the fractions of T and B lymphocytes and natural killer cells from spleens of both groups of mice were comparable, and interferon-gamma production did not differ. CONCLUSIONS: Our findings suggest that chemical peeling with salicylic acid in PEG may help to prevent as well as to reduce the number of UVB-induced skin tumours.