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.

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.

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.

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.

Histogenesis of alveolar soft part sarcoma. An immunohistochemical and biochemical study.

In order to clarify the histogenesis of alveolar soft part sarcoma (ASPS), an immunohistochemical and biochemical study was performed on three cases. The immunohistochemical study indicated the presence of actin, desmin, vimentin, and Z-protein in all cases. On the other hand, intermediate filaments other than desmin and vimentin were not detected immunohistochemically. The presence of desmin and Z-protein strongly suggests the myogenic character of this tumor. As to whether ASPS shows striated muscle differentiation or smooth muscle differentiation, the immunohistochemical absence of myoglobin in the three cases suggests that the tumor does not differentiate in the direction of striated muscle. However, biochemical assay of subunits of enolase revealed significantly high amounts of beta-enolase, which is known as a marker for striated muscle, in all three cases. The determined values--735, 426, and 584 ng/mg of protein --are indicative of striated muscle differentiation. In addition, the immunohistochemical study of all cases revealed the presence of beta-enolase in tumor cells. These data definitely show the myogenic character and rhabdomyoblastic differentiation of ASPS.

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.

The fate of hypertrophic chondrocytes of the epiphyseal plate. An electron microscopic study.

An ultrastructural study of the distal femoral epiphyseal-metaphyseal junction of C3H mice revealed that the hypertrophic chondrocytes undergo degenerative changes leading to their death. While most chondrocytes will die before their lacunae are opened to the marrow, others survive for a time in lacunae which communicate with the primary spongiosa, but they also ultimately die. There was no evidence to indicate that hypertrophic chondrocytes survive or are transformed into other cells.

Hydration of fibrinogen, fibrin, and fibrin degradation product (FDP) as estimated by nuclear magnetic resonance (NMR) spectroscopy.

The relaxation times (T1 and T2) of water proton in nuclear magnetic resonance (NMR) were measured with solutions containing bovine fibrinogen (Fbg), fibrin degradation products (FDP) and with fibrin-gel (Gel), at varying protein concentrations (0.7-70 mg/ml). Both T1 and T2 declined exponentially with increasing protein concentration. At a protein concentration of 35 mg/ml, the T1 of Fbg, Gel and FDP were 2.32, 2.12 and 2.82 s and the T2 values were 0.35, 0.17 and 0.70, respectively. The relaxation times for the control samples (0.2 M borate buffer) were 3.41 (T1) and 2.28 (T2). When the relaxation rates (the inverse of T1 and T2), R1 and R2 were plotted against the protein concentration, there were positive linear correlations between them. Using the slopes of the plots, the hydration value of each protein was calculated. The hydration value (g of H2O/g of protein) was 0.24 for Fbg, 0.34 for Gel and 0.14 for FDP.

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.

Hypophosphatemic osteomalacia in von Recklinghausen neurofibromatosis.

Skeletal lesions are not uncommon in von Recklinghausen neurofibromatosis. Most of them are considered to be dysplastic in nature. Association of osteomalacia or rickets with neurofibromatosis has been documented only rarely. Reported herein is a 40-year-old woman with known von Recklinghausen neurofibromatosis who presented with bone pain, multiple pseudofractures, marked increase in osteoid by bone biopsy, and hypophosphatemia with renal phosphate wasting. Treatment with oral phosphate and vitamin D was effective. A survey of the literature revealed that 34 similar cases have been reported in the past. Although the exact pathogenetic mechanism remains to be determined, osteomalacia in neurofibromatosis appears to be distinct from more common dysplastic skeletal affections of this disease, being characterized by later onset in adulthood as a rule, renal phosphate loss with hypophosphatemia, multiple pseudofractures in typical cases, and response to treatment with pharmacological dose of vitamin D with or without phosphate supplement.

Atelectasis as a complication of tracheobronchial stent therapy.

Although insertion of expandable metallic stents in cases of tracheobronchial stenosis is effective as palliation for respiratory distress, the potential risk of creating obstructive atelectasis and aggravating symptoms of patients should be noted. The authors' experience in two cases is presented, and prevention of this potential complication is discussed.

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.

[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.