Multifocal lesions with pancreatic atrophy in IgG4-related autoimmune pancreatitis: report of a case

We herein report a case of IgG4-related autoimmune pancreatitis (AIP). A 72-year-old male with jaundice visited our hospital complaining of epigastralgia. A blood chemistry analysis revealed elevated serum levels of total bilirubin and DUPAN-II. Computed tomography (CT) revealed irregularly shaped pancreatic masses with a stricture of the main pancreatic duct (MPD) in the head and tail that were interposed by marked atrophy with MPD dilation in the body. F-18 fluorodeoxyglucose (FDG)-positron emission tomography/CT revealed abnormally intense FDG uptake only at the masses. During surgery, another small tumor was also found in the atrophied body; therefore, a total pancreatectomy was performed under the diagnosis of multiple pancreatic cancers. The histological analysis revealed fibrosis with dense and diffuse infiltrations of lymphocytes and IgG4-positive plasma cells. The pancreatic parenchyma of the body was firmly replaced by fibrosis. AIP can lead to the formation of multiple pancreatic lesions, and thus the correct diagnosis is occasionally difficult to establish in atypical cases.     

Microscopic polyangiitis associated with marked systemic bleeding tendency caused by disseminated intravascular coagulation

A 57-year-old woman was admitted to our hospital because of severe dyspnea due to pulmonary hemorrhage and rapidly progressive renal failure. The patient was positive for perinuclear pattern anti-neutrophil cytoplasmic antibody (p-ANCA) and was manifested with gastrointestinal bleeding and brain hemorrhage. Thus, she was diagnosed as having microscopic polyangiitis (MPA). Laboratory examination demonstrated severe thrombocytopenia, increased prothrombin time and a high concentration of fibrin degradation products. In addition, the elevated plasma levels of D-dimer, thrombin-antithrombin complex and plasmin-plasmin inhibitor complex led us to make a diagnosis of disseminated intravascular coagulation (DIC). Complication of DIC was considered to have caused further deterioration in bleeding tendency due to MPA in the present case. The patient was treated with plasma exchange, hemodialysis, administration of corticosteroid including pulse therapy and cyclophosphamide. Continuous infusion of gabexate mesilate proved effective for improvement of systemic bleeding tendency. However, she finally died of severe infectious diseases. In conclusion, it is suggested that ANCA-associated vasculitis could be accompanied by DIC and gabexate mesilate may be a useful therapeutic agent for these disorders.     

Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis

BACKGROUND & AIMS: The mechanism for development of primary biliary cirrhosis (PBC) remains enigmatic, but molecular mimicry has been implicated because of well-known cross-reactivity of human mitochondrial autoantigens and equivalent bacterial antigens. Virtually all patients with PBC have antimitochondrial autoantibodies (AMA), but, interestingly, approximately 50% also manifest antinuclear antibodies (ANA). METHODS: To determine whether generation of ANA are due to molecular mimicry of mitochondrial peptides, we established 6 T-cell clones selected by a peptide corresponding to the E2 subunit of mitochondrial pyruvate dehydrogenase complex and analyzed for reactivity to mimicry peptides derived from mitochondrial and nuclear autoantigens, including control sequences. RESULTS: For mitochondrial autoantigens, 1 peptide from the E2 subunit of the pyruvate dehydrogenase complex, 1 peptide from the E2 subunit of the oxo-glutarate dehydrogenase complex, 1 peptide from the E2 subunit of the branched-chain 2-oxoacid dehydrogenase complex, and 1 peptide from the E3-binding protein cross-reacted with these T-cell clones. For the nuclear autoantigens, 5 peptides from gp210 and 1 from Sp100 cross-reacted with these clones. Furthermore, 1 of 3 T-cell clones selected by recombinant gp210 protein reacted with a mimicry peptide corresponding to amino acids 188-201 of gp210, indicating that this part of the protein is a naturally processed immunodominant T-cell epitope. CONCLUSIONS: These results demonstrate molecular mimicry between mitochondrial and nuclear autoantigens in PBC and that a mimicry peptide may become an immunodominant T-cell epitope. These data have significance not only for PBC but also for the production of ANA in other disease processes.     

Improved survival rate by temperature control at compression sites in rat model of crush syndrome

Background

Crush syndrome (CS) has been reported in disasters, terrorist incidents, and accidents, and the clinical and pathologic picture has gradually been clarified. Few lethal and reproducible animal models of CS with use of a quantitative load are available. A new model is needed to investigate pathologic and therapeutic aspects of this injury.

Materials and methods

Using a device built from commercially available components, both hindlimbs of anesthetized rats were respectively compressed for 6 h using 3.6-kg blocks. The effects of trunk warming alone without compressed hindlimbs (Group A), non-warming at room temperature (Group B), whole-body warming including compressed hindlimbs (Group C), or warming of compressed hindlimbs alone (Group D) during compression were examined. Survival rates were compared and hematological and histologic analyses were performed at specific time points after compression release.

Results

Limb or whole-body warming significantly worsened the survival of rats. We found a much lower survival rate of 0%–10% in animals, in which the hindlimbs were warmed during compression (Groups C and D) at 12 h after compression release, compared with 90%–100% in animals without warming of the hindlimbs (Groups A and B). Groups C and D showed significantly enhanced hyperkalemia at ≥4 h after compression release and all blood samples from dead cases showed hyperkalemia (>10 mEq/L).

Conclusions

We developed a new lethal and reproducible rat CS model with a quantitative load. This study found that warming of compressed limbs worsened the survival rate and significantly enhanced hyperkalemia, apparently leading to cardiac arrest.     

Usefulness of gradient tree boosting for predicting histological subtype and EGFR mutation status of non-small cell lung cancer on 18 F FDG-PET/CT

To develop and evaluate a radiomics approach for classifying histological subtypes and epidermal growth factor receptor (EGFR) mutation status in lung cancer on PET/CT images. PET/CT images of lung cancer patients were obtained from public databases and used to establish two datasets, respectively to classify histological subtypes (156 adenocarcinomas and 32 squamous cell carcinomas) and EGFR mutation status (38 mutant and 100 wild-type samples). Seven types of imaging features were obtained from PET/CT images of lung cancer. Two types of machine learning algorithms were used to predict histological subtypes and EGFR mutation status: random forest (RF) and gradient tree boosting (XGB). The classifiers used either a single type or multiple types of imaging features. In the latter case, the optimal combination of the seven types of imaging features was selected by Bayesian optimization. Receiver operating characteristic analysis, area under the curve (AUC), and tenfold cross validation were used to assess the performance of the approach. In the classification of histological subtypes, the AUC values of the various classifiers were as follows: RF, single type: 0.759; XGB, single type: 0.760; RF, multiple types: 0.720; XGB, multiple types: 0.843. In the classification of EGFR mutation status, the AUC values were: RF, single type: 0.625; XGB, single type: 0.617; RF, multiple types: 0.577; XGB, multiple types: 0.659. The radiomics approach to PET/CT images, together with XGB and Bayesian optimization, is useful for classifying histological subtypes and EGFR mutation status in lung cancer.     

Dysregulation of microRNAs and their association in the pathogenesis of T-cell lymphoma/leukemias

MicroRNAs (miRNAs) are non-coding regulatory RNAs consisting of 20–24 nucleotides. Over 4,500 miRNAs have been identified in humans, and it is known that nearly all human protein-encoding genes can be controlled by miRNAs in both healthy and malignant cells. Abnormal miRNA expression is known to occur in many cancers, including in malignant lymphomas (MLs). Detailed genome-wide miRNA expression analysis has been performed in various ML subtypes, and these analyses have led to the discovery of subtype-specific miRNA alterations. Actually, in B-cell lymphomas, several miRNAs have been used as prognostic markers, and their targets are for new agents for ML therapy. Successful studies for delineating miRNA functions in B-cell lymphomas lead us to hypothesize that miRNA dysregulation may also be deeply associated with the pathogenesis of T-cell lymphomas. Indeed, studies for delineating essential miRNAs have been conduced against comparatively well-defined T-cell lymphoma entities. In this review, we describe several key miRNAs and their targets in distinct T-cell lymphoma subsets and their roles in their pathogenesis, studies of which will lead to new therapeutic strategies against T-cell lymphomas.     

Clinical Effectiveness of Tolvaptan in Patients with Acute Decompensated Heart Failure and Renal Failure: Design and Rationale of the AQUAMARINE Study

Purpose

Over half of all admitted acute decompensated heart failure (ADHF) patients have renal failure. Although diuretics represent the mainstay of treatment strategy even in this population, there are unmet needs for safer and more effective treatment. Tolvaptan is a vasopressin-2 receptor antagonist, and we hypothesized that adding tolvaptan to standard diuretic therapy would be more effective in ADHF patients with renal function impairment.

Methods

The Answering question on tolvaptan’s efficacy for patients with acute decompensated heart failure and renal failure (AQUAMARINE) is a multicenter, randomized controlled clinical trial, which will enroll 220 patients from 17 hospitals in Japan. ADHF patients whose estimated glomerular filtration rate is above 15 and below 60 mL/min/1.72 m² will be randomly assigned within 6 h after admission to usual care with furosemide or tolvaptan add-on therapy. Primary endpoint is achieved urine output within 48 h. Secondary endpoints include dyspnea relief measured by 7-points Likert scale, incidence of worsening renal function, dose of furosemide used within 48 h, and changes of brain natriuretic peptide.

Conclusion

This study is the first multicenter study in Japan to evaluate clinical effectiveness of tolvaptan add-on therapy in ADHF patients with renal failure. The results of this study address the treatment strategy of this high-risk population (UMIN Clinical Trial Registry Number: UMIN000007109).     

Increasing prevalence of diabetes mellitus in association with fatty liver in a Japanese population

Background

The prevalence of diabetes mellitus (DM) has been increasing. The present study was carried out to examine the relationship between this increase and fatty liver.

Methods

Japanese participants who underwent regular health examinations in 1991, 1996, 2001, 2006, and 2011 were enrolled. Fatty liver was diagnosed using ultrasonography. DM was defined as requiring the use of medication for DM, having a fasting blood glucose level ≥126 mg/dl, or hemoglobin A1c level ≥6.5 %.

Results

Logistic regression analysis on data from 11,235 participants (6,882 men and 4,271 women) in 2011 revealed that the association between fatty liver and DM was independent of age, body composition, and other confounders [odds ratio (OR) 1.97, 95 % confidence interval (95 % CI) 1.66–2.32 in men, and OR, 3.12; 95 % CI, 2.29–4.26 in women]. In 2006, 5,318 participants did not have DM and were able to be followed up in 2011. Fatty liver in 2006 was an independent predictor of DM in 2011 [OR 1.73 (95 % CI 1.20–2.50) in men, 4.13 (2.16–8.10) in women]. The prevalence of DM increased significantly during the 20-year period examined among both men (6.0, 8.9, 10.0, 10.8, 12.0 %, P < 0.001) and women (3.3, 4.5, 4.2, 4.1, 5.1 %, P = 0.004), accompanied with an increased prevalence of fatty liver among both men (10.8, 26.3, 33.8, 36.7, and 38.0 %, P < 0.001) and women (6.5, 16.7, 22.2, 21.3, and 20.8 %, P < 0.001).

Conclusion

Fatty liver independently predicts both present and future DM. Fatty liver may play an important role in the recent increases in the prevalence of DM.     

Influence of the scan time point when assessing hypoxia in 18F-fluoromisonidazole PET: 2 vs. 4 h

European Journal of Nuclear Medicine and Molecular Imaging - 18F-fluoromisonidazole (18F-FMISO) is the most widely used positron emission tomography (PET) tracer for imaging tumor hypoxia. Previous...