Voriconazole-associated salt-losing nephropathy

A 74-year-old man was diagnosed with nephrotic syndrome due to focal segmental glomerulosclerosis, and steroid therapy was initiated. Subsequently, he was affected by deep mycosis, and hence, voriconazole (VRCZ) was administered. On the 16th day, he was transferred to our hospital because of somnolence and malaise. His systolic blood pressure was approximately 80 mmHg, and he showed decreased skin turgor, indicating volume depletion. Laboratory analysis revealed hyponatremia and liver dysfunction. Discontinuation of VRCZ and drip infusion of normal saline improved the consciousness disorder, hyponatremia, and liver dysfunction. The levels of antidiuretic hormone (ADH) and plasma renin activity were elevated. This patient showed high excreted urine sodium, despite volume depletion and low serum osmolality. Therefore, this patient was diagnosed with salt-losing nephropathy (SLN). SLN should be considered for treatment of VRCZ-associated hyponatremia, together with syndrome of inappropriate secretion of ADH.     

Torsades de Pointes induced by a combination of garenoxacin and disopyramide and other cytochrome P450, family 3, subfamily A polypeptide-4-influencing drugs during hypokalemia due to licorice

We report an 82-year-old man who developed ventricular tachycardia and Torsades de Pointes (TdP) after oral administration of garenoxacin, a novel quinolone antibiotic agent that differs from the third-generation quinolones, for pneumonia. He had hypokalemia (K 2.3 mmol/L) induced by licorice and also had received disopyramide for arrhythmia, bicalutamide for prostate cancer, and silodosin for prostate hypertrophy. After taking him off all drugs and administering spironolactone supplemented with potassium, his low serum potassium level was ameliorated. Therefore, although garenoxacin reportedly causes fewer adverse reactions for cardiac rhythms than third-generation quinolone antibiotics, one must be cautious of the interference of other drugs during hypokalemia in order to prevent TdP.     

Obestatin in human neuroendocrine tissues and tumours: expression and effect on tumour growth

The hormone obestatin, which is derived from the same precursor as ghrelin and whose receptor(s) is still unrecognized, possesses a variety of metabolic/modulatory functions mostly related to food intake suppression and reduction of gastrointestinal motility. The distribution of obestatin in normal and neoplastic human tissues is poorly understoood. We report that in fetal tissue samples, obestatin peptide was detected in the thyroid, pituitary, lung, pancreas and gastrointestinal tract, usually being co‐localized with chromogranin A. In adult tissues, obestatin protein expression was restricted to pituitary, lung, pancreas and gastrointestinal tract and was co‐localized strictly with ghrelin. By contrast, in endocrine tumours obestatin was expressed in a small fraction of thyroid, parathyroid, gastrointestinal and pancreatic neoplasms, in most cases with a focal immunoreactivity and co‐localized with ghrelin. Messenger RNA levels of the specific fragments of ghrelin and obestatin were comparable in both normal and tumour samples, confirming that post‐translational mechanisms rather than alternative splicing events lead to ghrelin/obestatin production. Finally, in TT and BON‐1 cell lines obestatin induced antiproliferative effects at pharmacological doses, opposite to those observed with ghrelin. In summary, our data demonstrate that obestatin is produced by the same endocrine cells that express ghrelin in normal tissues from fetal to adult life, whereas, as compared to ghrelin, in neoplastic conditions it is down‐regulated by post‐translational modulation and shows potential antiproliferative properties in vitro. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

c‐Jun activating binding protein 1 binds to the IgA receptor and modulates protein levels of FcαRI and FcRγ‐chain

The receptor for IgA, FcαRI or CD89, is expressed on myeloid cells and can trigger phagocytosis, tumor cell lysis, and release of inflammatory mediators. These functions critically depend on the associated FcR γ‐chain; however, some biological functions, like receptor internalization, are solely mediated by FcαRI α‐chain. Little is known as to how FcαRI regulates these processes and the FcαRI intracellular domain does not contain recognized signalling motifs. We searched for associating proteins and identified c‐Jun activating binding protein 1 (JAB1) as a binding partner specifically for FcαRI. We found increased FcαRI surface expression after ectopic expression of JAB1 as well as diminished protein levels of total FcR γ‐chain levels after JAB1 knock‐down. These data functionally link JAB1 with controlling protein expression levels of FcαRI‐FcR γ‐chain protein complex.     

Comparison between single antiplatelet therapy and combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome

Satisfactory results have not yet been obtained in therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome (APS). We therefore compared single antiplatelet therapy and a combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with APS.The subjects were 20 ischemic stroke patients with antiphospholipid antibody, 13 with primary antiphospholipid syndrome and 7 with SLE-related antiphospholipid syndrome. Diagnosis of APS was based on the 2006 Sydney criteria. Eligible patients were randomly assigned to either single antiplatelet therapy (aspirin 100 mg) or a combination of antiplatelet and anticoagulation therapy (target INR: 2.0-3.0; mean 2.4±0.3) for the secondary prevention of stroke according to a double-blind protocol. There was no significant difference between the two groups in age, gender, NIH Stroke Scale on admission, mRS at discharge, or rate of hypertension, diabetes mellitus, hyperlipidemia, or cardiac disease. We obtained Kaplan-Meier survival curves for each treatment. The primary outcome was the occurrence of stroke. The mean follow-up time was 3.9±2.0 years. The cumulative incidence of stroke in patients with single antiplatelet treatment was statistically significantly higher than that in patients receiving the combination of antiplatelet and anticoagulation therapy (log-rank test, p-value=0.026). The incidence of hemorrhagic complications was similar in the two groups. The recent APASS study did not show any difference in effectiveness for secondary prevention between single antiplatelet (aspirin) and single anticoagulant (warfarin) therapy. Our results indicate that combination therapy may be more effective in APS-related ischemic stroke.     

Expression of adhesion proteins E-cadherin, alpha-catenin, beta-catenin and gamma-catenin is different in T1 and T2 breast tumours

BACKGROUND: Breast cancer is the most common malignancy in women. Although an increasing number of patients with breast cancer are being cured by surgery, a considerable number of patients suffer relapse in the form of metastases after surgery. E-cadherin and catenins have documented roles in breast cancer progression. Mammography is supposed to decrease breast cancer mortality by detecting tumours while they are small and before they have reached a clinically detectable stage.Aim: In the present study, we wanted to evaluate whether there are differences in expression patterns of adhesion proteins, shown to be crucial in the metastatic process, between small tumours detected by mammography and clinically detected large tumours. METHODS: Expression of E-cadherin, alpha-catenin, beta-catenin and gamma-catenin was analysed using immunohistochemistry methods in 86 invasive breast carcinomas detected by mammography and compared with 90 clinically palpable invasive breast carcinomas. RESULTS: In the group of tumours detected by mammography (86 samples), reduced expression of E-cadherin was observed in 12 (14%) samples. Reduced expression of alpha-catenin was observed in four (4.6%) samples, and three (3.5%) samples showed reduced expression of beta-catenin. All samples showed strong expression of gamma-catenin. When expression patterns of these proteins were evaluated in 90 clinically detected tumours, we observed reduced expression of E-cadherin in 58 (64.4%) samples, 12 (13.3%) samples showed reduced expression of alpha-catenin, while nine (10%) samples showed reduced expression of beta-catenin. Strong expression of gamma-catenin was detected in all tumours also in this group.Statistical analyses revealed a highly significant difference in expression of E-cadherin (p<0.001). However, no statistically significant differences were observed in expression of alpha-catenin (p = 0.081) and beta-catenin (p = 0.092) between the two groups of tumours. CONCLUSION: Results indicate that T1 breast tumours harbour less alterations in E-cadherin-catenin complexes and therefore are probably less likely to disseminate, and patients probably have a better prognosis than if tumours are diagnosed as T2.     

A case of recurrent esophageal cancer with lymph node and lung metastases, successfully treated with systemic chemotherapy and radiofrequency-ablation

We report a case of recurrent esophageal cancer with lymph node and lung metastases, successfully treated with systemic chemotherapy and radiofrequency-ablation(RFA). A 45-year-old man was diagnosed with thoracic esophageal cancer.Radical esophagectomy with three-field lymphadenectomy was performed.After 6 months, mediastinal lymph node recurrence occurred.Although the size of the recurrent mediastinal lymph nodes were reduced after 10 courses of systemic chemotherapy, two new lung metastatic nodules appeared in the right segments 8 and 9.CT -guided percutaneous RFA was successfully achieved for the 2 lesions.However, 6 months after the RFA, a local recurrence at the RFA site of segment 9 occurred, and an additional RFA was performed for this tumor.Five years and four months after the first operation, the tumor marker level remained within a normal range, and the patient is doing very well without any signs of recurrence. RFA appears to be an effective and minimally invasive technique for controlling local recurrence of esophageal cancer when combined with systemic chemotherapy.     

Identification of CXCL5/ENA-78 as a factor involved in the interaction between cholangiocarcinoma cells and cancer-associated fibroblasts

Knowledge of tumor-stromal interactions is essential for understanding tumor development. We focused on the interaction between cholangiocarcinoma and cancer-associated fibroblasts (CAFs) in intrahepatic cholangiocarcinoma and reported their positive interaction in vitro and in vivo. The aim of this study is to identify the key protein involved in the interaction between cholangiocarcinoma cells and CAFs and its role on cholangiocarcinoma progression. Using the conditioning medium from cholangiocarcinoma cells, hepatic stellate cells and coculture of them, Protein-Chip analysis with SELDI-TOF-MS showed that the peak of an 8,360-Da protein remarkably increased in the coculture medium. This protein was identified as CXCL5/ENA78, epithelial cell-derived neutrophil-activating peptide-78, by q-TOF/MS/MS analysis. Two cholangiocarcinoma cell lines, HuCCT1 and RBE, produced CXCL5 that promoted their invasion and migration in an autocrine fashion. These effects of CXCL5 significantly decreased by inhibition of CXC-receptor 2, which is the receptor for CXCL5. In addition, IL-1β produced by hepatic stellate cells induced the expression of CXCL5 in cholangiocarcinoma cells. In human tissue samples, a significant correlation was observed between CAFs and CXCL5 produced by cholangiocarcinoma cells in intrahepatic cholangiocarcinoma (p = 0.0044). Furthermore, the high-CXCL5-expression group exhibited poor overall survival after curative hepatic resection (p = 0.027). The presence of tumor-infiltrating neutrophils expressing CD66b was associated with CXCL5 expression in tumor cells (p < 0.0001). These data suggest that CXCL5 is important for the interaction between cholangiocarcinoma and CAFs, and inhibition of tumor-stromal interactions may be a useful therapeutic approach for cholangiocarcinoma.