A positive direct Coombs' test in the absence of hemolytic anemia predicts high disease activity and poor renal response in systemic lupus erythematosus.

We determined the clinical utility of the direct Coombs' test in the absence of hemolytic anemia as an indicator of disease activity and therapeutic response in systemic lupus erythematosus (SLE). SLE patients without hemolytic anemia who visited our hospital from January 2016 to November 2016 were retrospectively evaluated with a direct Coombs' test. Clinical features, including SLE disease activity index (SLEDAI), treatment and laboratory findings were analyzed. For patients with lupus nephritis, we additionally evaluated the cumulative complete renal response rate over one year after induction therapy. Among 182 patients evaluated, 10 (5.8%) patients had a positive direct Coombs' test in the absence of hemolytic anemia. They had a higher SLEDAI ( p < 0.01), higher circulating immune complex levels ( p = 0.01), higher anti-DNA titers ( p < 0.01) and a lower complete renal response rate ( p = 0.03) compared with those who were negative. Multivariate analysis indicated that SLEDAI was an independent factor correlated with the direct Coombs' test without hemolytic anemia (odds ratio 2.4, 95% confidence interval 1.66-4.98, p < 0.01). A positive direct Coombs' test in the absence of hemolytic anemia may therefore represent a useful biomarker for assessing disease activity and therapeutic response.

Phase II study of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer.

BACKGROUND: Metformin, widely used in the treatment of type 2 diabetes mellitus, reduces the risk of cancer and relapse after treatment. Fertility-sparing treatment for endometrial cancer (EC) with progestin is associated with a high chance of disease regression, and the high relapse rate continues to be a problem. We assessed the efficacy of metformin in preventing recurrence after medroxyprogesterone acetate (MPA) as fertility-sparing treatment for atypical endometrial hyperplasia (AEH) and EC. PATIENTS AND METHODS: This phase II study enrolled 17 patients with AEH and 19 patients with EC limited to the endometrium (age, 20-40 years). MPA (400 mg/day) and metformin (750-2250 mg/day) were administered for 24-36 weeks to achieve a complete response (CR). Metformin was administered until conception, even after MPA discontinuation. The primary end point was relapse-free survival (RFS) after remission. We analyzed all efficacy end points in the full analysis set. RESULTS: The body mass index was ≥25 kg/m(2) in 27 patients (mean, 31 kg/m(2); range, 19-51 kg/m(2)), and the homeostasis model assessment for insulin resistance index was ≥2.5 in 24 patients (mean, 4.7; range, 0.7-21). Two patients showed progression at 12 weeks [6%; 95% confidence interval (CI) 2-18]. At 36 weeks, 29 (81%; 95% CI 65-90) patients achieved CR, and 5 (14%; 95% CI 6-29) patients achieved partial response. During a median follow-up of 38 months (range, 9-66 months) after remission, relapse was confirmed in three of the patients who had achieved CR (relapse rate, 10%). The 3-year estimated RFS rate was 89%. No patients experienced severe toxicity. CONCLUSIONS: Metformin inhibited disease relapse after MPA therapy. The combination of metformin and MPA in EC treatment should be studied further. TRIAL REGISTRATION NUMBER: UMIN 000002210.

Anti-signal recognition particle antibody in patients without inflammatory myopathy: a survey of 6180 patients with connective tissue diseases.

OBJECTIVES: To clarify the prevalence of anti-signal recognition particle (anti-SRP) antibody in connective tissue diseases (CTDs) and investigate the clinical characteristics of patients without inflammatory myopathy. METHOD: Sera from 6180 patients with CTD were examined by immunoprecipitation (IPP) assays, and the records of patients positive for anti-SRP antibody were reviewed retrospectively. The antibody against the 54-kDa protein of SRP (SRP54) was quantified by enzyme-linked immunosorbent assay (ELISA) in patients with anti-SRP antibody. RESULTS: Of the 28 patients positive for anti-SRP antibody, nine (32.1%) did not have inflammatory myopathy. The clinical diagnoses and characteristics of those patients varied considerably. In patients with inflammatory myopathy, the index of anti-SRP54 was much higher than in those without myopathy (1.15 vs. 0.46; p = 0.036). CONCLUSIONS: The prevalence of anti-SRP antibody was 0.5% in a cohort of Japanese patients with CTD, and one-third of them did not have inflammatory myopathy. Sera from patients with inflammatory myopathy recognized SRP54 more strongly than in those without myopathy.

Vascular endothelial growth factor as a predictive marker for POEMS syndrome treatment response: retrospective cohort study.

OBJECTIVE: POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes) syndrome is a rare multisystem disease characterised by plasma cell dyscrasia and overproduction of vascular endothelial growth factor (VEGF). VEGF is assumed to be useful in monitoring disease activity, because VEGF levels usually decrease after treatment. However, there is no study to investigate whether the extent of decrease in VEGF correlates with clinical outcome. We tested the predictive efficacy of serum VEGF levels in POEMS syndrome. METHOD: This was an institutional review board approved retrospective observational cohort study of 20 patients with POEMS monitored regularly for more than 12 months (median follow-up, 87 months) after treatment onset using our prospectively accumulated database of POEMS from 1999 to 2015. Patients were treated by autologous peripheral blood stem cell transplantation or thalidomide administration. Serum VEGF was measured by ELISA. Outcome measures included clinical and laboratory findings and relapse-free survival. RESULTS: Serum VEGF levels decreased rapidly after treatment, and stabilised by 6 months post treatment. Patients with normalised serum VEGF levels (<1040 pg/mL) at 6 months showed prolonged relapse-free survival (HR=12.81, 95% CI 2.691 to 90.96; p=0.0001) and greater later clinical improvement. The rate of serum VEGF reduction over the first 6 months post treatment correlated with increased grip strength, serum albumin levels, and compound muscle action potential amplitudes at 12 months. CONCLUSIONS: Serum VEGF level at 6 months post treatment is a predicative biomarker for disease activity and prognosis in POEMS syndrome. Serum VEGF could be used as a surrogate endpoint for relapse-free survival or clinical or laboratory improvement of POEMS syndrome for clinical trials.

Overexpression of CXCR4 on circulating B cells in patients with active systemic lupus erythematosus.

OBJECTIVES: To evaluate the roles of circulating B cells in the pathogenic process of systemic lupus erythematosus (SLE) by measuring the expression of chemokines and their receptors. METHODS: Peripheral-blood mononuclear cells were obtained from 17 active, 21 inactive SLE patients, and 13 healthy controls. The expression of CXCR4, CXCR5, and CCR7 on CD19+ B cells was determined by flow cytometry, serum concentration of CXCL12 was measured by enzyme-linked immunosorbent assay, and the chemotactic responsiveness of B cells toward CXCL12 was evaluated. B or plasma cells expressing CXCR4 in renal biopsy specimens were detected using immnofluorescent staining. RESULTS: Flow cytometric analysis revealed that expression level of CXCR4 on circulating B cells was significantly higher in patients with active disease than in those with inactive disease or controls. Serum CXCL12 concentration was not different between these groups. In addition, the migratory ability of B cells toward CXCL12 was enhanced in active SLE patients. Finally, CXCR4-expressing B cells were more frequently observed in the renal biopsy specimens of lupus nephritis. CONCLUSIONS: Up-regulated CXCR4 expression on circulating B cells in active SLE may enhance their chemotactic response toward CXCL12, which may promote infiltration of these cells into inflamed renal tissue and contribute to the development of SLE.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin compared with α-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on sulfonylurea alone (SUCCESS-2): a multicenter, randomized, open-label, non-inferiority trial.

We assessed the efficacy and safety of sitagliptin compared with α-glucosidase inhibitor (αGI) in 120 of Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on stable ≤2 mg/day glimepiride alone [mean hemoglobin A1c (HbA1c) 7.7%] by the randomized, active-controlled, non-inferiority trial. Patients were randomly assigned to receive additional sitagliptin or αGI for 24 weeks. The primary endpoint was change in HbA1c from baseline to week 12. After 12 weeks, sitagliptin reduced HbA1c by -0.44% (p < 0.001) relative to αGI. At 24 weeks, the reduction was almost identical between the groups (-0.091%, p = 0.47). Gastrointestinal disorders were more common with αGI than with sitagliptin, but only minor hypoglycaemia occurred in both groups at similar frequency. These data suggested that sitagliptin was not inferior to αGI for reduction of HbA1c in Japanese T2DM patients receiving glimepiride alone, and well tolerated with minimum risk of gastrointestinal symptoms and hypoglycaemia.

Circulating anti-double-stranded DNA antibody-secreting cells in patients with systemic lupus erythematosus: a novel biomarker for disease activity.

Antibodies against double-stranded DNA (dsDNA) are widely used to diagnose systemic lupus erythematosus (SLE) and evaluate its activity in patients. This study was undertaken to examine the clinical utility of circulating anti-dsDNA antibody-secreting cells for evaluating SLE patients. Anti-dsDNA antibody-secreting cells quantified using an enzyme-linked immunospot assay were detected in the spleen, bone marrow and peripheral blood from MRL/lpr but not in control BALB/c mice. Circulating anti-dsDNA antibody-secreting cells were detected in 29 (22%) of 130 patients with SLE, but in none of 49 with non-SLE connective-tissue disease or 18 healthy controls. The presence of circulating anti-dsDNA antibody-secreting cells was associated with persistent proteinuria, high SLE disease activity index and systemic lupus activity measures, and a high serum anti-dsDNA antibody titre measured with an enzyme-linked immunosorbent assay. The positive predictive value for active disease was 48% for circulating anti-dsDNA antibody-secreting cells versus 17% for serum anti-dsDNA antibodies. A prospective cohort of patients with circulating anti-dsDNA antibodies and inactive SLE showed that the cumulative disease flare-free rate was significantly lower in patients with than without circulating anti-dsDNA antibody-secreting cells (p < 0.001). Circulating anti-dsDNA antibody-secreting cells are a useful biomarker for assessing disease activity in SLE patients.

Paravertebral neurinoma associated with aggressive intravertebral extension.

Neurinomas are relatively common benign tumors thought to arise from nerve sheath cells. Although intraosseous neurinomas may destroy the bone, extraosseous neurinomas with extensive destruction and invasion of bone are considered rare. We present two unusual cases of a benign extraosseous neurinoma that extensively invaded the vertebral body through the nutrient canal.

Pulmonary vein and left atrial invasion by lung cancer: assessment by breath-hold gadolinium-enhanced three-dimensional MR angiography.

PURPOSE: The purpose of this work was to evaluate the ability of breath-hold gadolinium-enhanced three-dimensional (3D) MR angiography to assess the invasion of the pulmonary vein and the left atrium by lung cancer. METHOD: Gadolinium-enhanced 3D MR angiography was performed in 20 consecutive patients with lung cancer. RESULTS: At two sites with left atrial invasion shown by MR angiography, associated partial resection of the left atrium was performed. At five sites with invasion of the proximal pulmonary vein within 1.5 cm from the left atrium on MR, partial resection of the left atrium was performed at one site, and the pulmonary vein was resected at the intrapericardial portion at three sites. At two sites with invasion of the proximal pulmonary vein 1.5 cm more distal to the left atrium, the pulmonary vein was resected at the extrapericardial portion. CONCLUSION: Breath-hold gadolinium-enhanced 3D MR angiography is suitable for assessing invasion of the pulmonary vein and the left atrium by lung cancer.

MRI artifacts of metallic stents derived from imaging sequencing and the ferromagnetic nature of materials.

In vitro and in vivo studies were performed to assess the optimum materials and imaging methods for metallic stents by conducting an in vitro investigation of MRI artifacts arising during imaging by several representative imaging methods using various types of stents and by clarifying the differences occurring with different metals and imaging sequences. We also examined the use of MRCP and MRA in evaluating luminal patency within stented biliary tracts and blood vessels in vivo. In vitro study showed either no artifacts or very slight artifacts created by titanium stents, however, marked image distortion was created by a stainless steel stent. Using SE instead of GRE sequences can minimize these artifacts. Echo planar imaging (EPI) produced severe susceptibility artifacts, resulting in unsatisfactory images. In vitro and in vivo studies indicated that MRCP was an effective method for follow-up studies of bile duct stents, but that MRA is quite limited as a method of follow-up study for currently available vascular stents.

Low-dose cisplatin and 5-fluorouracil in combination can repress increased gene expression of cellular resistance determinants to themselves.

The synergistic mechanism of cisplatin (CDDP) and 5-fluorouracil (5-FU) in combination remains unclear, despite its substantial antitumor activity, which has been demonstrated clinically. To clarify the mechanism(s), we determined the sensitivity or resistance factors to either drug in seven gastrointestinal cancer cell lines and then analyzed the altered gene expression after different exposures to CDDP and 5-FU. At the basal gene expression level, glutathione S-transferase pi (GSTpi) expression correlated with the observed resistance to CDDP, whereas dihydropyrimidine dehydrogenase (DPD) and multidrug resistance-associated protein (MRP) expression was related to 5-FU resistance. GSTpi, DPD, and MRP expression increased in response to the respective drug, but they also increased in response to the other drug as well. Additionally, 5-FU revealed a drastically increased thymidylate synthase (TS) gene expression in 5-FU-resistant cells. However, the increasing actions of CDDP and 5-FU on GSTpi, DPD, MRP, and TS expression varied according to the exposure time, concentration, and schedule. A low concentration of CDDP (1 microg/ml, 30 min) followed by 5-FU (0.5 microg/ml, 72 h) was found to cause a less increased expression of DPD, MRP, GSTpi, and TS than either drug alone, thus resulting in synergistic cytotoxicity in 5-FU-resistant COLO201 and CDDP-resistant HCC-48 cells. The sequential combination of CDDP and 5-FU inhibited the growth of human normal renal proximal tubule cells by less than 20%. Low concentrations of CDDP followed by continuous exposure to 5-FU can repress increased gene expression related to both drug resistances, thereby being synergistically cytotoxic in human gastrointestinal cancer cells.

Regulatory network of mitomycin C action in human colon cancer cells.

A network composed of activation and inactivation pathways to regulate mitomycin C (MMC) action is suggested to exist in human cancer cells. COLO201 colon cancer cells were stably transfected with human NQO1 cDNA that encodes NAD(P)H:quinone oxidoreductase (DT-diaphorase, DTD), and a clonal cell line with about 57-fold elevated DTD activity was obtained. Northern analysis revealed that expression of the NADPH:cytochrome P450 reductase (P450 reductase) gene was decreased in the transfectant, COLO201/NQO1, associated with the increase of NQO1 expression. Biochemical characterization of the cells showed a significant increase of the glutathione (GSH) content concomitantly with the decrease of the P450 reductase activity. As a result of these coordinated modulations, sensitivity of COLO201/NQO1 to MMC was not increased as compared to the parent cells. Analyses of inhibition by specific inhibitors of DTD, P450 reductase and glutathione S-transferase (GST) in 5 human colon cancer cell lines including the transfectant showed that DTD and P450 reductase play significant roles in MMC activation in cells with sufficiently high DTD activity and with marginal DTD activity, respectively. In contrast, GST appeared to participate in MMC inactivation in cells with a high level of GST activity. These results indicated that DTD, P450 reductase, GSH and GST may act together compensatively or competitively, depending on their levels in cells, to determine the cellular sensitivity to MMC.

[Breath-hold MR cholangiopancreatography with 2D and 3D-FASE sequence at 0.5 tesla: evaluation based on measurements of signal intensity ratio and contrast-to-noise ratio].

Single-slice 2D-FASE (more than 2 cm) and 3D-FASE images proved to be reliable techniques by which to create high-resolution MRCP images at 0.5 T. In particular, 3D-FASE sequence can provided MIP and its thin source images with sufficient SIR and CNR of the images, which are useful to evaluate detailed structures. Using 3D-FASE sequence, even the non-dilated pancreatobiliary system can frequently be demonstrated because each source image retains satisfactory SIR and CNR of the images due to 3D acquisition and is not affected by motion artifacts of any kind. The most important problem for 3D-FASE sequence is that view-to view amplitude modulation errors may persist, though gradient moment errors can be reduced because of no actual motion during acquisition, resulting in degraded the MIP images due to the different positions of the source images in a few patients with inconstant respiration.

Diagnosis of anomalous pancreaticobiliary junction: value of magnetic resonance cholangiopancreatography.

BACKGROUND: Anomalous pancreaticobiliary junction (a long common channel), with or without congenital choledochal cyst, is frequently associated with biliary tract carcinoma. We assessed the diagnostic value of magnetic resonance cholangiopancreatography (MRCP) for patients with anomalous pancreaticobiliary junction (PBJ). METHODS: In 159 adult patients with pancreatobiliary disease, breath-hold (1 to 18 seconds) MRCP was performed according to a half-Fourier acquisition single-shot turbo spin-echo sequence. In all patients the length of the common channel demonstrated by MRCP was compared with that demonstrated by endoscopic retrograde cholangiopancreatography. In 11 patients with anomalous PBJ (the common channel > or = 15 mm on endoscopic retrograde cholangiopancreatography), the diagnostic accuracy of MRCP for associated biliary diseases was evaluated. RESULTS: No complications were encountered in performing MRCP. On MRCP, the length of the common channel was calculated to be 15 mm or longer in nine (82%) of 11 patients with anomalous PBJ. In patients with normal PBJ, MRCP identified PBJ with the channel measuring 0 mm in length. MRCP allowed detailed visualization of congenital choledochal cyst (all seven patients) but failed to depict carcinoma (one patient) and mucosal hyperplasia (five patients) of the gallbladder. CONCLUSIONS: MRCP is a noninvasive and accurate imaging method for diagnosing anomalous PBJ and congenital choledochal cyst.

Improvement of MR cholangiopancreatography at .5 T: three-dimensional half-averaged single-shot fast spin echo with multi-breath-hold technique.

The purpose of this study was to determine the advantage of a three-dimensional (3D) single-shot fast-spin-echo (SSFSE) sequence to obtain MR cholangiopancreatography (MRCP) with a .5-T MR unit by comparison with a two-dimensional (2D) SSFSE sequence. MRCP with 2D-SSFSE and with 3D-SSFSE with 128 echo train lengths was performed on 15 volunteers and 38 patients with pancreatobiliary disease using a .5-T MR unit. For maximum intensity projection (MIP) reconstruction, the section thickness of source images was 4 mm in the 2D-SSFSE and 3 mm in the 3D-SSFSE. 3D volume data in 3D-SSFSE were obtained using repeated short breath-hold of 2 seconds for every repetition time throughout the examination. The image quality, duct conspicuity, signal-intensity ratio (SIR), and contrast-to-noise ratio (CNR) were evaluated. In 23 of the patients who underwent both MRCP and direct cholangiopancreatography (endoscopic retrograde cholangiopancreatography [ERCP]/percutaneous transhepatic cholangiography [PTC]), a comparison between these two modalities was also conducted. The image quality of the MIP image with 3D-SSFSE (49 of 53, 92.5% graded excellent or good) was superior to that with 2D-SSFSE (31 of 53, 58.4%). Duct conspicuity, SIR, and CNR were significantly higher with 3D-SSFSE than with 2D-SSFSE. 3D-SSFSE also showed a stronger relationship with the ERCP/PTC findings compared to 2D-SSFSE. 3D-SSFSE provided satisfactory quality, SIR, and CNR of MRCP images, even when a .5-T MR unit was used, because the breath-hold technique used during 3D data sampling minimized all types of motion effects.

Reversible intracranial changes in eclampsia demonstrated by MRI and MRA.

CT and MRI allow visualization of eclampsia changes in the brain. Once case with reversible changes is reported.

The effects of high dose of parathyroid hormone on fetal osteoclasts and their precursors in vivo: an ultrastructural-cytochemical study.

BACKGROUND: It is not well known how the immediate precursors of osteoclast develop into osteoclasts in the fetus. This ultrastructural-cytochemical study was designed to clarify the formation process of the osteoclasts and their increased activities in the fetal mouse limb buds after administration of high dose parathyroid hormone (PTH). METHODS: Twenty-four or forty-eight hours after the high doses of PTH were injected into amniotic fluid of the pregnant C3H mice, the femoral limb buds of embryos were dissected out. Tartrate-resistant acid phosphatase (TRAP) reactions were performed while preparing specimens for electron microscopy. RESULTS: Both control and PTH-given preosteoclasts and osteoclasts exhibited TRAP-positivities in dense bodies and vesicles. As effects of PTH, a binucleated preosteoclast of tandem fashion was observed. More osteoclastic hyperactivities were observed in the diaphyseal bone marrow. An osteoclast with a large cytoplasm exhibited two sets of clear zones and ruffled borders. Some osteoclasts demonstrated prominent amoeboid figures, while other osteoclasts developed large cytoplasmic vacuoles, which contained pieces of calcified chondroid bars. CONCLUSIONS: Our results revealed the progression of maturation from young preosteoclasts to osteoclasts. An existence of a peculiar binucleated preosteoclasts suggested one of the processes for multinucleation of the osteoclast. Quite remarkable osteoclastic hyperactivities were obviously the effects of high dose PTH. Our results also indicated the endophagocytic ability of the osteoclast. How PTH affected the osteoclasts and their precursors in the diaphyseal bone marrow can be speculated.

[Clinical application of magnetic resonance angiography for coronary arteries: correlation with conventional angiography and evaluation of imaging time].

Magnetic resonance angiography (MRA) of the coronary arteries is a particularly difficult task because of the small size of the vessels and cardio-respiratory motion. The authors describe a method of performing of ultrafast MRA of the coronary arteries with a standard MR system and body coil. Each image was obtained within a single breath hold by "segmented Turbo FLASH" sequences using an electrocardiography gate. Clinical application was performed in 20 patients with ischemic heart disease, and a comparison was made with conventional coronary angiography. The imaging time was shortened significantly by our methods. The diagnosis was made by at least two different images to avoid false positives. The results indicated a good correlation between MRA and conventional angiography.