Predictors of the response to treatment in acute lupus hemophagocytic syndrome.

OBJECTIVE: The objective of this paper is to identify predictors for the response to treatment of acute lupus hemophagocytic syndrome (ALHS). METHODS: We reviewed seven cases with ALHS admitted to our hospital and published ALHS cases identified in the 2001-2014 Medline database, and then conducted univariate and multivariate analyses to identify predictors for the response to treatment. RESULTS: Review of our cases showed a significant and negative correlation between serum ferritin and anti-DNA antibody (p = 0.0025). All three patients treated with cyclosporine A (CsA) were considered responders despite high serum ferritin and corticosteroid resistance. We also reviewed 93 patients with ALHS identified in 46 articles. Multiple logistic regression analysis identified C-reactive protein (CRP) (OR 0.83, p = 0.042) and hemoglobin (OR 1.53, p = 0.026) measured at diagnosis of ALHS as significant predictors of the response to corticosteroid monotherapy. Moreover, among 32 patients treated with CsA, serum ferritin was significantly higher in CsA responders (12163 ± 16864 µg/l, n = 22) than in non-responders (3456 ± 6267/µg/l, p = 0.020, n = 10). Leukocyte count was significantly lower in the CsA responders (1940.0 ± 972.3/µl) than in the non-responders (3253 ± 2198/µl, p = 0.034). CONCLUSION: Low CRP and high hemoglobin can predict a positive response to corticosteroid monotherapy while high serum ferritin and low leukocyte count can predict a positive response to CsA in patients with ALHS and therefore, when corticosteroid monotherapy is not effective in such cases, CsA could be the first choice of an additional immunosuppressive agent.

Septic shock caused by Klebsiella oxytoca: An autopsy case and a survival case with driving Extracorporeal Membrane Oxygenation.

We report two cases of Klebsiella oxytoca bacteremia. Case 1 was a 56-year-old man who was transferred to our hospital by ambulance due to diarrhea and general fatigue. On arrival, he was clearly conscious. However he was in septic shock. We injected broad spectrum antibacterial agents and started intensive care. Though intensive care included continuous hemodiafiltration (CHDF), he died 22 hours after admission. Case 2 was a 69-year-old man with a history of gastrectomy for gastric cancer. He had been admitted to a previous hospital due to ileus. His ileus tube was removed on the eighth day, and he then developed a fever of 38 ºC on the following day. He went into shock and became unconscious; he was therefore transferred to our hospital. We diagnosed septic shock and disseminated intravascular coagulation (DIC). We injected broad spectrum antibacterial agents, and recombinant thrombomodulin alpha (rTM). Although he was started in intensive care, his hemodynamics were unstable on the day following admission. Extracorporeal membrane oxygenation (ECMO) and intra-aortic balloon pumping (IABP) were started to maintain his hemodynamics. His condition gradually improved, and he was transferred to the previous hospital for rehabilitation on the 28(th) day. ECMO for septic shock in adults is unusual; however ECMO can be introduced even in patients with severe sepsis under careful monitoring. The new anti-DIC agent rTM is useful for safe driving of ECMO in patients with DIC.

Activation of JNK and high expression level of CD133 predict a poor response to sorafenib in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer deaths worldwide. While sorafenib, a multikinase inhibitor targeting the Raf/extracellular signal-regulated protein kinase (ERK) pathway, has been shown recently to provide a survival advantage to patients with advanced HCC, a predictive biomarker has not been developed. We studied whether c-Jun N-terminal kinase (JNK), which promotes liver carcinogenesis in mice, affects therapeutic response to sorafenib in HCC patients. METHODS: We collected pathological specimens from 39 patients with advanced HCC before starting sorafenib treatment, and measured JNK activity in HCCs. RESULTS: In patients treated with sorafenib, the expression of phospho-c-Jun in HCC, as a read out of JNK activity, was significantly higher (P<0.001) in the non-responder group than in the responder group. c-Jun N-terminal kinase activation in HCC was associated with a decreased time to progression and a poor overall survival (P=0.0028 and P=0.0008, respectively). CONCLUSION: In addition, JNK activity was significantly correlated with CD133 expression level. Correspondingly, high expression level of CD133 was linked to a poor response to sorafenib. Furthermore, D-JNKi, a specific JNK inhibitor, reduced the growth of xenografted CD133(+) cells in athymic mice. In conclusion, JNK activation was positively correlated with CD133 expression level and inversely correlated with the therapeutic response to sorafenib, suggesting that JNK activity may be considered as a new predictive biomarker for response to sorafenib treatment.

Processing of CD109 by furin and its role in the regulation of TGF-beta signaling.

CD109 is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, whose expression is upregulated in squamous cell carcinomas of the lung, esophagus, uterus and oral cavity. CD109 negatively regulates transforming growth factor (TGF)-beta signaling in keratinocytes by directly modulating receptor activity. In this study, we further characterized CD109 regulation of TGF-beta signaling and cell proliferation. We found that CD109 is produced as a 205 kDa glycoprotein, which is then processed in the Golgi apparatus into 180 kDa and 25 kDa proteins by furin (furinase). 180 kDa CD109 associated with GPI-anchored 25 kDa CD109 on the cell surface and was also secreted into the culture medium. To investigate whether furinase cleavage of CD109 is necessary for its biological activity, we mutated arginine 1273 in the CD109 furinase cleavage motif (amino acid 1270-RRRR-1273) to serine (R1273S). Interestingly, CD109 R1273S neither significantly impaired TGF-beta signaling nor affected TGF-beta-mediated suppression of cell growth, although it was expressed on the cell surface as a 205 kDa protein. Consistent with this finding, the 180 kDa and 25 kDa CD109 complex, but not CD109 R1273S, associated with the type I TGF-beta receptor. These findings indicate that processing of CD109 into 180 kDa and 25 kDa proteins by furin, followed by complex formation with the type I TGF-beta receptor is required for the regulation of TGF-beta signaling in cancer cells and keratinocytes.

Neutrophil elastase inhibitor (sivelestat) reduces the levels of inflammatory mediators by inhibiting NF-kB.

OBJECTIVE: Sivelestat sodium hydrate (sivelestat) is a specific synthetic inhibitor of neutrophil elastase (NE). Various studies suggest that sivelestat treatment reduces inflammation. In this study, we tested the hypothesis that sivelestat acts as an inhibitor of inflammatory mediators and prevents nuclear factor-kB (NF-kB) activation. METHODS: In the presence and absence of sivelestat, the mouse macrophage cell line RAW 264.7 was stimulated with lipopolysaccharide (LPS) and the levels of inflammatory mediators (TNF-alpha, IL-6 and high mobility group box 1 (HMGB1)) and nitrite in the cell supernatant were measured, along with inducible nitric oxide synthase (iNOS) expression. RESULTS: While LPS administration increased the secretion of inflammatory mediators and nitric oxide (NO), sivelestat decreased the secretion of these mediators. Cell signaling studies demonstrated that sivelestat decreased NF-kB activation by inhibiting IkB phosphorylation. CONCLUSION: Sivelestat may inhibit the various inflammatory mediators through NF-kB inhibition.

Evaluation of the therapeutic results of epiduroscopic adhesiolysis for failed back surgery syndrome.

BACKGROUND: No data for patients with failed back surgery syndrome (FBSS) based on the location of adhesions separated by epiduroscopic adhesiolysis have been reported. METHODS: We performed epiduroscopic adhesiolysis on 28 FBSS patients to examine the impact of differences in the locations of the separated regions on the treatment results. We performed fluoroscopic imaging through the sacral hiatus to assess the condition of adhesions in the epidural space during the post-adhesiolysis observation period. RESULTS: In patients in whom only the epidural space was separated by adhesiolysis, there was a significant improvement in the Roland-Morris disability questionnaire (RDQ) score until 12 weeks after adhesiolysis, but the score gradually returned to the preoperative value thereafter. Among patients in whom the nerve root responsible for radicular pain was separated, there was a long-term improvement in the RDQ, Oswestry disability index 2.0 (ODI), and Japanese Orthopedic Association Assessment of Treatment (JOA) scores. Among patients in whom both the epidural space and the nerve root responsible for pain were separated, there was a 12 week improvement in the RDQ score and 24 week improvements in the ODI and JOA scores. CONCLUSIONS: Progressive epidural imaging after adhesiolysis suggested that pain was caused by re-adhesion around the nerve root. Since re-adhesion of the nerve root required some time, the effect of adhesiolysis was maintained for extended periods in these cases. We suggest that epiduroscopic adhesiolysis is an effective therapy for FBSS patients, and that adhesiolysis of the nerve root may exhibit the long-term (24 weeks) efficacy in patients with pain.

Combination therapy with PEG-IFN-alpha and 5-FU inhibits HepG2 tumour cell growth in nude mice by apoptosis of p53.

When the tumour suppressor p53 is activated by DNA damage, it stimulates the transcription of its target genes, which then induce cell cycle arrest or apoptosis. Here, we examined the role p53 plays in the antitumour effect of combination treatment with pegylated interferon (PEG-IFN)-alpha and 5-fluorouracil (5-FU), which has been shown to effectively treat advanced hepatocellular carcinoma (HCC). Nude mice were injected subcutaneously with cultured HepG2 cells, in which p53 is functional. They were treated a week later with PEG-IFN and/or 5-FU for 7 weeks, after which we measured and examined their tumours. Combination groups showed significantly lower tumour volumes and higher tumour cell apoptosis than the other groups. Combination treatment and PEG-IFN monotherapy also significantly elevated the p53 protein and mRNA levels in the tumour but only combination treatment increased the degree of p53 phosphorylation at serine46 and induced p53-regulated apoptosis-inducing protein 1 (p53AIP1) expression. The antitumour effects of combination treatment is due in part to the elevation by PEG-IFN of p53 protein and mRNA expression and in part to the DNA damage that is generated by 5-FU, which induces p53 serine46 phosphorylation, which in turn upregulates p53AIP1 expression.

Changes in cell culture temperature alter release of inflammatory mediators in murine macrophagic RAW264.7 cells.

OBJECTIVES: To examine whether moderate changes in cell culture temperature influence the production of various cytokines and associated mediators of inflammation. METHODS: We performed lipopolysaccharide (LPS) stimulation of the murine macrophagic RAW264.7 cell line under hyperthermic (40 degrees C), normothermic (37 degrees C) and hypothermic (34 degrees C) conditions. We then measured the levels of heat shock protein 70 (HSP70), heat shock factor protein (HSF) and nuclear factor-kB (NF-kB) dimers (p50 and p65) in the cells, and the levels of high mobility group box 1 (HMGB1) and the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta) and interleukin 6 (IL-6) in the culture supernatants. RESULTS: Levels of HMGB1, IL-1beta, IL-6, and TNF-alpha, as well as NF-kB dimers (p50 and p65), were all reduced following LPS stimulation at 40 degrees C and 34 degrees C compared with those at 37 degrees C. Levels of HSP70 and HSF increased at 40 degrees C and 34 degrees C. CONCLUSIONS: The application of moderate hyperthermia and hypothermia after LPS-induced cell activation attenuated the inflammatory response and reduced the likelihood of cell damage. These findings suggest that moderate temperature changes modulate the inflammatory response and could be a useful therapy against sepsis.

Short-term complications of retrograde transvenous obliteration of gastric varices in patients with portal hypertension: effects of obliteration of major portosystemic shunts.

The type, incidence, and severity of complications of balloon-occluded retrograde transvenous obliteration (B-RTO) for gastric varices should be precisely estimated. Complications were evaluated in 38 patients who had fundic gastric varices and 43 B-RTO procedures during injection of ethanolamine oleate (phase 1), within 4 h after injection (phase 2), 24 h after injection (phase 3), and from 24 h to 10 days after injection (phase 4). Endoscopic evaluation at 8 weeks showed resolution of gastric varices in 35 of 38 patients (92%) and smaller varices in the remaining three (8%). B-RTO caused transient hypertension in 35% of patients, hemoglobinuria in 49%, and fever in 33% during phases 1, 2, and 3, respectively. Pleural effusion, pulmonary infarction, ascites, gastric ulcers with unique appearance, localized mosaic-like change of gastric mucosa, and hemorrhagic portal hypertensive gastropathy were noted in phase 4. There were no fatalities. Lactate dehydrogenase, aspartate aminotransferase, and bilirubin increased on day 1. Each datum was retrieved within 7 days. The severity of lactate dehydrogenase elevation correlated significantly with the volume of infused ethanolamine oleate. Thus, B-RTO is a safe and effective management of fundic varices. However, short-term hemodynamic change after B-RTO may cause gastric mucosal damage. Pulmonary infarction and pleural effusion are potential complications.

Successful treatment of advanced peripheral T-cell lymphoma with an angiocentric growth pattern complicated with hemophagocytic syndrome by high-dose chemotherapy and autologous peripheral blood stem cell transplantation.

Peripheral T-cell lymphomas (PTCL) account for about 10% of all lymphomas in Western countries, respond poorly to therapy, and have short survival with no sustained remission. Furthermore, the complication of hemophagocytic syndrome (HPS) sometimes makes the prognosis of this disease extremely worse. We report here a case of PTCL with an angiocentric growth pattern complicated with HPS successfully treated by high-dose chemotherapy and autologous peripheral blood stem cell transplantation. Our case suggests this approach is an excellent candidate for the treatment of this disease.

A case of true malignant histiocytosis: identification of histiocytic origin with use of immunohistochemical and immunocytogenetic methods.

We report here an autopsy case of true malignant histiocytosis. The patient was a 67-year-old woman who exhibited fever, wasting, hepatosplenomegaly, and progressive pancytopenia. The bone marrow aspiration disclosed hemophagocytosing cells, which resembled histiocytes. The molecular analysis did not show the clonal gene rearrangement of T-cell receptor or immunoglobulin heavy chain. Although the patient had been started on methylprednisolone pulse therapy and chemotherapy with etoposide, she died from cerebral hemorrhage. The autopsy specimens of spleen and liver showed extensive infiltration of atypical cells, for which histiocytic origin was identified with an immunohistochemical method using monoclonal antibodies against CD11c, CD68, macrophage colony-stimulating factor (M-CSF), M-CSF receptor, lysozyme, antitrypsin and alpha1-antichymotrypsin. Recent investigations have disclosed that in most cases diagnosed as malignant histiocytosis, hemophagocytosis was reactive and not evoked by histiocytic malignancy. True malignant histiocytosis, for which histiocytic origin is confirmed, is extremely rare.

Concentrated platelets harvesting before cardiopulmonary bypass improved cardiac and pulmonary function.

BACKGROUND: Sequestration of concentrated platelets (P-con) during cardiopulmonary bypass (CPB) has been performed to preserve platelet function after cardiac surgery. Since P-con also harvests leukocytes simultaneously, there might be a possibility that the inflammatory effects or ischemia-reperfusion injuries associated with CPB, such as a cardiac or pulmonary dysfunction after cardiac surgery, are reduced with its use. METHODS: We retrospectively evaluated 53 patients who underwent cardiac surgery after the introduction of the P-con technique at our institute. There were 20 patients in the P-con group and 33 patients in the control group in whom concentrated platelet were not harvested. RESULTS: The patients characteristics and preoperative cardiac and pulmonary function did not differ between the two groups. The percentages of platelets and leukocytes sequestrated were 20.2+/-5.4% and 8.5+/-3.9% of the total estimated circulating cell counts, respectively. There were no significant differences in the postoperative dose of dopamine used, cardiac index, pulmonary capillary wedge pressure or intubation period between the two groups. However, the stroke volume index (p=0.005), left ventricular stroke work index (p=0.002), and ratio of the arterial oxygen tension to the inspired fraction of oxygen on extubation (p=0.02) were significantly greater in the P-con group as compared with those in the control. CONCLUSIONS: P-con improved cardiac and pulmonary function after CPB. Simultaneous sequestration of platelets and leukocytes by P-con during CPB may contribute to the improvement of cardiac and pulmonary function after cardiac surgery.

Functional, metabolic, and histological changes of vascular tissues after warm ischemia.

We examined functional, metabolic, and histological changes in the aortic tissue of rats after the period of warm ischemia ranging from 0 to 24 hours to determine the window of time in which grafts can be optimally viable for harvest. Sixty aortas from Brown Norway rats obtained after warm ischemia were used and changes in contraction, endothelial-dependent or -independent vasodilatation, cell viability, and histology were examined. Maximal contraction induced by norepinephrine and potassium chloride decreased time-dependently after exposure to warm ischemia. The warm ischemic period when 50% of the maximal contractile response of freshly isolated arteries was preserved, ranged from 6 to 8 hours. Maximal endothelium-dependent relaxation induced by acetylcholine decreased along with the time of warm ischemia. Endothelium-independent relaxation induced by sodium nitroprusside and forskolin was unaltered for up to 9 hours. Cell viability gradually decreased, and a significant negative correlation was found between warm ischemic period (T: hours) and cell viability (V: %) (V=101.9-2.35T; r(2)=0.96; p<0.0001). Cell viability was greater than 70% within 12 hours postmortem. Histologically, after 9-hour-warm ischemia irreversible changes were detected. Results suggest that the period of warm ischemia for up to 6 hours would be acceptable for preservation of tissue viability.

[Simultaneous mitral and aortic valvuloplasty using rasping procedure for combined valvular disease: a case report].

We reported a case of successful simultaneous mitral and aortic valvuloplasty using rasping procedure. A 55-year-old woman with combined valvular disease received this operation. Postoperatively, the mitral valve area increased from 1.15 cm2 to 2.03 cm2. Mitral regurgitation improved. Aortic valve pressure gradient decreased from 21 mmHg to 0 mmHg. Aortic regurgitation also improved. Cardiac Index (CI) increased from 1.94 l/min./m2 to 2.59 l/min./m2. Ejection fraction (EF) also increased from 60% to 82%. The postoperative course was uneventful. Excellent postoperative results of this procedure may be expected, not only in single valvular disease but also in combined valvular disease.

Tyrosine phosphorylation of proteins in primary human myeloid leukemic cells stimulated by macrophage colony-stimulating factor: analysis by disease type and comparison with normal human hematopoietic cells.

We investigated tyrosine phosphorylation of proteins in primary human leukemic cells stimulated by macrophage colony-stimulating factor (M-CSF) in 60 patients with acute myeloid leukemia (AML) and 5 patients with chronic myelomonocytic leukemia and compared the findings for leukemic cells with those of normal human monocytes and bone marrow immature hematopoietic cells. M-CSF induced tyrosine phosphorylation of p140-200, p110, p60, p44, and p42 frequently, and that of p95 and p55 less frequently, in primary myeloid leukemic cells, whereas M-CSF-induced phosphorylation of proteins was not detected in the normal human hematopoietic cells tested. Of these phosphoproteins, p140-200 was phosphorylated in all patients who responded to M-CSF and was considered to be almost identical to Fms, a product of the c-fms proto-oncogene. M-CSF-induced tyrosine phosphorylation was observed frequently (89%) in AML of French-American-British class M4 and infrequently in all other subtypes of AML, including M5. In chronic myelomonocytic leukemia, M-CSF-induced protein phosphorylation was prominent in blast crisis but was not detected in the chronic phase. Both bone marrow immature cells and mature monocytes showed low responsiveness to M-CSF. These findings for responsiveness to M-CSF were correlated with the amount of Fms in each type of cell. We also identified tyrosine phosphorylation of Vav, Shc, and extracellular signal-regulated kinase by M-CSF in some cases. These findings clarified an M-CSF-specific pattern of protein tyrosine phosphorylation and the responsiveness to M-CSF of primary human myeloid cells. Particularly, enhanced phosphorylation responses to M-CSF and increased amounts of Fms protein were observed in restricted human hematopoietic cells with a premature myelomonocytic character.

Anti-metastatic gene therapy utilizing subcutaneous inoculation of EC-SOD gene transduced autologous fibroblast suppressed lung metastasis of Meth-A cells and 3LL cells in mice.

We have previously reported that superoxide stimulates the motility of tumor cells and the administration of Cu-Zn superoxide dismutase (SOD) significantly suppresses metastasis. However, ideally, anti-metastatic therapy should be long-lasting, systemically effective and have low toxicity. The half-life of Cu-Zn SOD in plasma is so short that it cannot provide long-lasting effects. Therefore, in this study we have developed a gene therapy in a mouse model utilizing extracellular SOD (EC-SOD), which is the most prevalent SOD isoenzyme in extracellular fluids. We retrovirally transfected fibroblasts (syngeneic) with the EC-SOD gene and established EC-SOD-secreting fibroblasts. Inoculation of EC-SOD-secreting fibroblasts suppressed both artificial and spontaneous metastatic lung nodules in mouse metastasis models. These data indicate the feasibility of anti-metastatic gene therapy utilizing the EC-SOD gene.

Consumption coagulopathy associated with aneurysms of the abdominal aorta and the bilateral femoral arteries. Report of a case.

The authors report a case of a 70-year-old man, with repeating episodes of systemic subdermal hematoma due to consumption coagulopathy associated with abdominal aortic aneurysm and the bilateral femoral arterial aneurysms. Prior to the first operation for abdominal aortic repair, anticoagulation therapy was applied to treat thrombocytopenia and hypofibrinogenemia. Five years following the first surgery, the same treatment was required before resection of the femoral lesions. Consumption coagulopathy is seen in approximately 1-4% population of aortic aneurysms, however, repeated appearance of symptomatic coagulopathy is rarely reported. Anticoagulation therapy was effective to normalize the coagulation and fibrinolytic system and followed by uneventful surgical resection of the aneurysms.