Summary Epidemiological studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs), known to inhibit cyclooxygenase (COX), reduce the risk of colorectal cancer. COX is a key enzyme in prostaglandin biosynthesis, and two isoforms of COX, COX-1 and COX-2, have been identified. Recently COX-2 has been reported to frequently overexpress in colorectal neoplasms and to play a role in colorectal tumorigenesis and tumour progression. In this study, using immunohistochemistry, we examined COX-2 expression in advanced human colorectal cancer and its correlation with clinicopathological features. COX-2 expression was observed mainly in the cytoplasm of cancer cells in all the specimens examined, but some stromal cells and endothelial cells were also stained. According to the grade of COX-2 expression of the cancer cells, patients were divided into high-and low-COX-2 expression groups. High-COX-2 expression significantly correlated with tumour recurrence, especially haematogenous metastasis. These results suggest that a selective COX-2 inhibitor can be a novel class of therapeutic agents not only for tumorigenesis but also for haematogenous metastasis of cololectal cancer. To our knowledge, this is the first report on the correlation between COX-2 overexpression and recurrence of colorectal cancer.

IntroductionFever is frequently observed in critically ill patients. An independent association of fever with increased mortality has been observed in non-neurological critically ill patients with mixed febrile etiology. The association of fever and antipyretics with mortality, however, may be different between infective and non-infective illness.MethodsWe designed a prospective observational study to investigate the independent association of fever and the use of antipyretic treatments with mortality in critically ill patients with and without sepsis. We included 1,425 consecutive adult critically ill patients (without neurological injury) requiring > 48 hours intensive care admitted in 25 ICUs. We recorded four-hourly body temperature and all antipyretic treatments until ICU discharge or 28 days after ICU admission, whichever occurred first. For septic and non-septic patients, we separately assessed the association of maximum body temperature during ICU stay (MAXICU) and the use of antipyretic treatments with 28-day mortality.ResultsWe recorded body temperature 63,441 times. Antipyretic treatment was given 4,863 times to 737 patients (51.7%). We found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen independently increased 28-day mortality for septic patients (adjusted odds ratio: NSAIDs: 2.61, P = 0.028, acetaminophen: 2.05, P = 0.01), but not for non-septic patients (adjusted odds ratio: NSAIDs: 0.22, P = 0.15, acetaminophen: 0.58, P = 0.63). Application of physical cooling did not associate with mortality in either group. Relative to the reference range (MAXICU 36.5°C to 37.4°C), MAXICU ≥ 39.5°C increased risk of 28-day mortality in septic patients (adjusted odds ratio 8.14, P = 0.01), but not in non-septic patients (adjusted odds ratio 0.47, P = 0.11).ConclusionsIn non-septic patients, high fever (≥ 39.5°C) independently associated with mortality, without association of administration of NSAIDs or acetaminophen with mortality. In contrast, in septic patients, administration of NSAIDs or acetaminophen independently associated with 28-day mortality, without association of fever with mortality. These findings suggest that fever and antipyretics may have different biological or clinical or both implications for patients with and without sepsis.Trial registrationClinicalTrials.gov: NCT00940654

Background. Degradation of basement membrane and extracellular matrix by matrix metalloproteinases (MMPs) is believed to be an essential step in the complicated process of hematogenous metastasis. MMP-1 is a member of collagenases, a family of MMPs that degrades collagens type I, II, and III, main components of the interstitial stroma.The purpose of this study was to investigate the expression of MMP-1 in colorectal cancer and its correlation with hematogenous metastasis.Patients and Methods. We examined 133 cases of colorectal cancer (Dukes A: 72; Dukes B: 26; Dukes C: 23; Dukes D: 12). Sections were cut from formalin-fixed, paraffin-embedded samples containing the deepest site of cancer invasion and stained immunohistochemically with a monoclonal antibody to MMP-1. According to the area

ngiogenesis, the growth of new blood vessels, is essential for tumor growth and metastasis. [1][2][3] In adults, angiogenesis is infrequent due to the balance between inhibitors and stimulators of angiogenesis. But under conditions of hypoxia, tumor cells turn-on the angiogenic switch by secretion of angiogenic stimulators that activate endothelial cells to proliferate and form new blood vessels. 4,5) Proliferation and expression of antigens critical to angiogenesis are two specific characteristics that distinguish angiogenic endothelial cells from quiescent endothelium of normal vasculature. Monoclonal antibodies and synthetic molecules targeting self-angiogenic antigens have been shown to inhibit tumor growth in animal models and were recently used in clinical trials.6-10) However, relatively high doses of these therapeutics have to be administered for long periods of time due to their short biological half-lives. Furthermore, antigens highly specific for angiogenic endothelium still remain to be isolated. These drawbacks should be overcome by active immunization with whole endothelial cells. Recently, active immunization with xenogeneic, but not autologous, endothelial cells was shown to inhibit the growth of experimental tumors in mice.11) However, from the viewpoint of clinical applicability of endothelial vaccines, the use of autologous endothelial cells would be preferable, since xenogeneic immunization may cause a species-specific immune reaction, with undesirable consequences. In the present study, therefore, we aimed to test the usefulness of autologous endothelial vaccine in the treatment of metastatic lesions that are highly dependent on tumor angiogenesis. For this purpose, we immunized BALB/c mice with a vaccine of glutaraldehyde-fixed murine hepatic sinusoidal endothelial cells (HSEs) in a lung metastasis model of colon cancer. We demonstrated that vaccination with autologous HSEs significantly inhibited the development of metastasis through an autoimmune response that was mediated by antibodies and cytotoxic T lymphocytes specifically reactive with endothelial, but not tumor cells. In addition, a vaccine of xenogeneic human umbilical vein endothelial cells (HUVECs) was tested in the same experimental setting, and the effects of both vaccines were compared, both in the animals and in in vitro immunological assays. Materials and MethodsCell culture. Hepatic sinusoidal endothelial cells (HSEs), a cell line isolated from BALB/c mouse, 12) were kindly provided by Dr. Tatsuro Irimura (Faculty of Pharmacology, the University of Tokyo). HSEs were grown in DMEM supplemented with 10% fetal calf serum (FCS) and 1% antibiotic/antimycotic (i.e., 100 U/ml penicillin G, 100 µg/ml streptomycin sulfate, 250 ng/ml amphotericin B; Life Technologies, Grand Island, NY), in an atmosphere containing 5% CO 2 at 37°C. Human umbilical vein endothelial cells (HUVECs) were isolated from fresh umbilical cords (obtained with patients' informed consent, from the Department of Gynecology and Obstetrics, the University of Tokyo)...

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