A case of advanced gastric cancer with abdominal paraaortic lymph node swelling successfully resected following neoadjuvant chemotherapy of TS-1 and low-dose cisplatin

A 63-year-old man who had suffered from anorexia and body weight loss was admitted to the hospital. Upper GI series and an endoscopic examination revealed type 3 cancer in the posterior wall of the cardia. Abdominal CT scan showed enlargement of No. 16 lymph nodes. Preoperative diagnosis was stage IV gastric cancer (T3 (SE) H0 P0 N3), and we considered a curative operation impossible. Therefore, neoadjuvant chemotherapy with TS-1 and low-dose cisplatin (CDDP) was planned. After 4 weeks of administration, the primary lesion was reduced in size and the No. 16 lymph nodes were shrunken remarkably. Therefore, a total gastrectomy with a splenectomy, a distal pancreatectomy, and D3 lymph node dissection was performed. Histological findings demonstrated the degeneration of cancer cells and fibrosis in the primary tumor and metastatic regional lymph nodes. There were no viable cancer cells in the No. 16 lymph nodes. The histological changes against neoadjuvant chemotherapy were judged to be Grade 1b for the main tumor and Grade 3 for the No. 16 lymph nodes. Neoadjuvant chemotherapy with TS-1 and low-dose cisplatin is so effective in a short period that can be adapted to advanced gastric cancer for downstaging.     

Factor VIII contributes to platelet-fibrin thrombus formation via thrombin generation under low shear conditions

Introduction

Thrombus growth under low blood flow velocity plays an important role in the development of deep venous thrombosis (DVT). Increased plasma levels and activities of coagulation factor VIII (FVIII) comprise risk factors for DVT and pulmonary thromboembolism.

Objective

To localize FVIII in human venous thrombi of DVT and to determine whether FVIII contributes to thrombus formation under low shear conditions.

Methods

The localization of FVIII in venous thrombi obtained from patients with DVT was examined by immunohistochemistry. The role of FVIII in thrombus formation was investigated using a flow chamber system. Venous blood from healthy volunteers were incubated with an anti-FVIII monoclonal antibody (VIII-3776) or non-immunized mouse IgG₁. Blood samples were perfused on immobilized type III collagen at wall shear rates of 70/s and 400/s and then the surface area covered by platelets and fibrin was morphometrically evaluated. Prothrombin fragment 1+2 (PF1+2) generation was measured before and after perfusion.

Results

Venous thrombi of DVT comprised a mixture of platelets, fibrin and erythrocytes. Factor VIII appeared to be colocalized with glycoprotein IIb/IIIa, fibrin and von Willebrand factor in the thrombi. VIII-3776 specifically recognized the light chain of FVIII and prolonged the activated partial thromboplastin time (aPTT), but not prothrombin time (PT). The antibody significantly reduced platelets and fibrin covering, as well as PF1+2 generation at wall shear rates of 70/s and 400/s.

Conclusions

These results suggest that FVIII contributes to platelet aggregation and fibrin formation via thrombin generation under low shear conditions.     

Functional mechanism underlying cyclooxygenase-2 expression in rat small intestine following administration of indomethacin: relation to intestinal hypermotility

BACKGROUND AND AIM: We recently reported that cyclooxygenase (COX)-2 is upregulated in the rat small intestine after administration of indomethacin, and this may be the key to non-steroidal anti-inflammatory drug (NSAID)-induced intestinal damage. The present study investigated the mechanism for COX-2 expression induced in the rat small intestine by indomethacin, in relation with ulcerogenic processes. METHODS: Animals were given indomethacin or SC-560 p.o., and the intestinal mucosa was examined 24 h later. RESULTS: Indomethacin caused hemorrhagic lesions in the small intestine, accompanied with an increase in intestinal motility, bacterial invasion and inducible nitric oxide synthase (iNOS) activity, as well as the expression of COX-2 mRNA in the mucosa. Although SC-560 did not cause any damage, this agent caused intestinal hypermotility, the bacterial invasion and the upregulation of COX-2 expression. The mucosal PGE2 content was decreased by SC-560 at 3 h but recovered 12 h later, and this recovery of PGE2 was attenuated by both atropine and ampicillin, in addition to rofecoxib. The intestinal hypermotility response to indomethacin was prevented by both 16,16-dimethyl PGE2 and atropine, but not ampicillin. Yet all these agents inhibited not only the bacterial invasion but also the expression of COX-2 and iNOS activity in the intestinal mucosa following indomethacin treatment, resulting in the prevention of intestinal lesions. CONCLUSION: These results suggest that COX-2 expression in the intestinal mucosa following the administration of indomethacin is associated with intestinal hypermotility and bacterial invasion. The intestinal hypermotility caused by COX-1 inhibition may be a key to COX-2 expression after administration of NSAIDs and their intestinal ulcerogenic properties.     

Phosphonate O-deethylation of [4-(4-bromo-2-cyano-phenylcarbamoyl) benzyl]-phosphonic acid diethyl ester, a lipoprotein lipase-promoting agent, catalyzed by cytochrome P450 2C8 and 3A4 in human liver microsomes.

NO-1886 ([4-(4-bromo-2-cyano-phenylcarbamoyl) benzyl]-phosphonic acid diethyl ester) increases lipoprotein lipase activity, resulting in a reduction in plasma triglycerides and an increase in high-density lipoprotein cholesterol. The metabolism of NO-1886 in human liver was investigated in the present study. Ester cleavage of NO-1886 from diethyl phosphonate to monoethyl phosphonate was the major metabolic pathway catalyzed by cytochrome P450. In addition, the minor metabolic pathway in human liver was the hydrolysis of the amide bond of NO-1886 by a specific cytosolic esterase. Eadie-Hofstee plots of phosphonate O-deethylation of NO-1886 in human liver microsomes showed a biphasic curve, indicating low- and high-K(m) components. Inhibition experiments with chemical inhibitors and antibodies against various cytochrome P450 isoforms suggested the involvement of CYP2C8 and CYP3A in the phosphonate O-deethylation. Recombinant CYP3A4 and CYP2C8 expressed in baculovirus-infected insect cells and human lymphoblastoid cells exhibited a high activity for phosphonate O-deethylation of NO-1886. The recombinant cytochrome P450 enzymes indicated that CYP2C8 and CYP3A4 were responsible for the low- and high-K(m) components in human liver microsomes, respectively. The selectivity of CYP2C8 in catalyzing phosphonate O-deethylation indicates that coadministration of drugs that are metabolized by the same enzyme requires careful consideration.     

The white blood cell count is an independent predictor of no-reflow and mortality following acute myocardial infarction in the coronary interventional era

BACKGROUND: In the era before the use of coronary reperfusion therapy, an elevated white blood cell (WBC) count was associated with a higher risk of adverse events following acute myocardial infarction (AMI). However, the relationship between WBC count and prognosis after AMI has not been investigated since coronary intervention was introduced. AIM: To evaluate whether a high WBC count within 48 hours of the onset of AMI predicts future adverse events in patients undergoing percutaneous coronary intervention (PCI). METHOD: We evaluated 1,016 patients who underwent PCI in the acute phase of MI using the Japanese Acute Coronary Syndrome Study (JACSS) database. RESULTS. WBC count was significantly associated with smoking, sudden onset AMI, and the no-reflow phenomenon during PCI, as were age, peak creatine kinase level, and Killip class. An elevated WBC count was significantly associated with higher risk of in-hospital mortality. Patients in the highest quartile of WBC count were about three times more likely to have a poor prognosis after AMI compared to those in the lowest quartile. CONCLUSIONS: The WBC count is of great significance for stratifying patient risk and can be used as a universal marker for predicting future adverse events following any treatment for AMI.     

Microbiological and clinical features of nine cases with nocardial infections

Following recent advance in medical technology, the increase of immunocompromised patients results in an increase of opportunistic infections such as nocardiosis. However, little is known about relationships between clinical features of nocardial infections and each Nocardia species, especially newly identified ones. Therefore, we identified clinical isolates of Nocardia species by genetic methods and analyzed clinical features of nocardiosis. Nine clinical isolates were obtained in Kyushu University Hospital from 2005 to 2008. Six different Nocardia species were identified by 16Sr RNA: Nocardiafarcinia (n=2), Nocardia brasiliensis (n=2), Nocardia cyriacigeorgica (n=2), Nocardia transvalensis (n=1), Nocardia araoensis (n=1) and Nocardia testacea (n=1). The underlying diseases of 9 patients were pulmonary diseases(n=5), malignant diseases(n=3), collagen diseases(n=1) or primary immunodeficiency diseases (n=l). According to antimicrobial susceptibility testing, none of them was resistant to minocycline or linezolid. Among seven isolates from respiratory specimens, one was resistant to imipenem, sulfamethoxazole/trimethoprim and amikacin, two were to ciprofloxacin. Three species identified recently (N cyriacigeorgica, N. araoensis and N. testacea) were involved in this study and most of them were considered as infectious pathogens to human. These data suggested the identification of Nocardia to the species level and susceptibility testing were important for diagnosis as infectious diseases and treatments.     

Interleukin-10 correlates with oxidized low density lipoprotein in coronary culprit plaques

Inflammation and oxidation play crucial roles in plaque instability. We immunohistochemically assessed expression of the anti-inflammatory cytokine interleukin (IL)-10, and of oxidized low density lipoprotein (ox-LDL) in coronary atherectomy specimens from 19 and 18 patients with stable and unstable angina, respectively. Immunopositive areas for IL-10 and ox-LDL were significantly greater in the group with unstable angina (p < 0.05, each), and they positively correlated (r = 0.452, p < 0.005). These results suggest that IL-10 plays an anti-inflammatory role in atherosclerotic lesions and modulates the inflammatory process in unstable coronary plaque.

Conflict of interest

None