The Clinical Outcomes after Total Pancreatectomy.

BACKGROUND: Total pancreatectomy (TP) is not more beneficial than less aggressive resection techniques for the treatment of pancreatic neoplasms and is associated with high morbidity and mortality. However, with advances in surgical techniques and glycemic monitoring, and the development of synthetic insulin and pancreatic enzymes for postoperative treatment, TP has been increasingly indicated. This is a review of the recent literature reporting the clinical outcomes after TP. METHODS: We reviewed the publications reporting the use of TP starting 2007. The clinicophysiological and survival data were analyzed. RESULTS: Few studies evaluated the differences in clinical outcomes between TP and pancreaticoduodenectomy (PD) with inconsistent results. It was reported that while the perioperative morbidity did not decrease, the mortality decreased compared to previous literature. All patients who underwent TP required insulin and high dose of pancreatic enzyme supplements. The 5-year survival rates after TP and PD for pancreatic cancer were similar. CONCLUSION: The perioperative mortality decreased in patients who underwent TP with advances in the operative procedures and perioperative care. The long-term survival rates were similar for TP and PD. Therefore, treating pancreatic neoplasms using TP is feasible. Patients undergoing TP should receive adequate treatment with synthetic insulin and pancreatic enzyme supplements.

Heterotopic Ossification in Rectal Carcinoma: Report of a Case and Review of the Literature.

Heterotopic ossification in colorectal carcinoma is extremely rare. This report presents the case of a 57-year-old male who had undergone a low anterior resection following a diagnosis of rectal carcinoma. Histological examination showed heterotopic ossification in the tumor. The patient was referred to Ibaraki Medical Center, Tokyo Medical University, with a diagnosis of rectal carcinoma by a local physician. Abdominal computed tomography revealed thickening of the rectal wall with calcified deposits, and virtual colonoscopy showed stenosis with a mass in the rectum. The patient underwent a low anterior resection and diverting ileostomy in May 2014. Histological examination of the excised tumor showed moderately differentiated adenocarcinoma and an infiltration of spindle cells with numerous foci of osteoid and ossification, with osteoblastic rimming in the stroma. Immunohistochemical analysis of these spindle cells and osteoblasts revealed negative staining for AE1/AE3, suggesting a reactive change. There was metastasis in 1 of the 12 lymph nodes, and the tumor was diagnosed as stage IIIB (T4a, N1a, M0) rectal carcinoma. The patient had an uneventful recovery and was followed up at our outpatient clinic. In conclusion, the malignant potential of heterotopic ossification in rectal carcinoma has not been determined. However, heterotopic ossification is induced by tumor progression in a microenvironment, suggesting a high tumor malignity. The patient should be carefully monitored after surgery in terms of improved patient outcome.

Emergency surgery for hemorrhagic shock caused by a gastrointestinal stromal tumor of the ileum: A case report.

In this report, a case of hemorrhagic shock caused by a gastrointestinal stromal tumor (GIST) of the ileum, which was successfully treated by emergency surgery, is presented. A 67-year-old male patient presented to the Ibaraki Medical Center, Tokyo Medical University (Ami, Japan) in July 18, 2014, with dizziness and blood in the stool. Upper endoscopy and colonoscopy failed to reveal the source of the hemorrhage, although abdominal contrast-enhanced computed tomography revealed extravasation of the contrast medium into the small intestine. The patient developed hemorrhagic shock; thus, double-balloon enteroscopy (DBE) was performed, which revealed a Meckel's diverticulum and a submucosal tumor with excessive bleeding at 60 and 100 cm proximal to the ileocecal valve, respectively. Subsequent emergency partial resection of the ileum, including the tumor and the Meckel's diverticulum, was performed in July 20, 2014. Histological examination of the excised tumor revealed proliferation of spindle-shaped cells, and immunohistochemical staining of the tumor was positive for CD34, KIT and α-smooth muscle actin, but negative for S-100 protein. These immunohistological results supported the diagnosis of GIST of the ileum. The patient had an uneventful recovery and has been monitored at our outpatient clinic for 14 months after surgery. This case demonstrated the efficacy of DBE for the diagnosis of small intestinal bleeding, and immediate emergency surgery should be considered for cases of small intestinal GISTs with excessive bleeding.

Synchronous ovarian metastasis from colorectal cancer: A report of two cases.

Ovarian metastasis of colorectal cancer is relatively rare. The present study reports two cases of synchronous ovarian metastasis from colorectal cancer, which were managed by cytoreductive surgery. In case one, a 60-year-old female patient presented with a multilocular pelvic tumor and ascites. Virtual colonoscopy revealed a mass in the sigmoid colon; however, no tumor cells were identified on histological examination. Ovarian metastasis from sigmoid colon cancer was suspected and adnexectomy was subsequently performed. Histological examination of the excised tumor revealed adenocarcinoma. Immunohistochemical analysis of the resected tumor revealed positive staining for cytokeratin (CK)20 and caudal-type homeobox 2 (CDX2), and negative staining for CK7, estrogen receptor, progesterone receptor and inhibin. The immunohistological results supported the diagnosis of ovarian metastasis from sigmoid colon cancer. In case two, a 56-year-old female patient presented with a multilocular pelvic tumor and ascites. Colonoscopy identified a rectal tumor, and histological examination revealed moderately-differentiated adenocarcinoma, which was confirmed by cytological analysis of ascites. Subsequently, ovarian metastasis from rectal cancer with peritoneal dissemination was diagnosed, and left ovariectomy and transverse colostomy were performed. Histological examination of the excised tumor revealed moderately-differentiated adenocarcinoma, and immunohistochemical investigation revealed positive staining for CK20 and CDX2, but negative staining for CK7. These immunohistological results indicated ovarian metastasis from rectal cancer. Both patients recovered well and are currently undergoing regular follow-up examinations. The observations from the two cases indicate that ovarian metastases of primary colorectal cancer may present as pelvic tumors and, thus, preoperative examination of the gastrointestinal tract is required. Furthermore, even in cases of widespread colorectal cancer metastases, excision of the ovarian tumor is required to establish a histological diagnosis for the selection of appropriate treatments.

Intracavity absorption spectroscopy with a tunable multimode traveling-wave ring Ti:sapphire laser.

A tunable multimode unidirectional traveling-wave Ti:sapphire laser was developed to measure in situ the atmospheric absorption spectra using intracavity absorption spectroscopy. The effective absorption path length was 2100 km. O2 and H2O vapor lines in atmosphere with absorption coefficients of 10(-6)-10(-8) cm(-1) were measured with uncertainties <5%, and the absorption coefficients were in agreement with those estimated from the HITRAN database. By tuning the wavelength, a weak absorption line with an absorption coefficient of 10(-9) cm(-1) was measured with a sensitivity of 2×10(-10) cm(-1). The sensitivity was limited by the residual parasitic variation that appeared in the spectrum.

Enhancement of cytotoxic and pro-apoptotic effects of 2-aminophenoxazine-3-one on the rat hepatocellular carcinoma cell line dRLh-84, the human hepatocellular carcinoma cell line HepG2, and the rat normal hepatocellular cell line RLN-10 in combination with 2-deoxy-D-glucose.

The cytotoxic and pro-apoptotic effects of a single dose of 2-aminophenoxazine-3-one (Phx-3) or 2-deoxyglucose (2-DG) or of a combined dose of Phx-3 and 2-DG were studied in the rat hepatocellular carcinoma cell line dRLh-84, the human hepatocellular carcinoma cell line HepG2 and the rat normal hepatocellular cell line RLN-10. The number of viable cells decreased in a dose-dependent manner, when dRLh-84, HepG2 or RLN-10 cells were treated with 2-DG (0.5-20 mM) or Phx-3 (1-50 µM) alone at 37˚C for 48 h. When these cells were treated with 10 mM 2-DG and different concentrations of Phx-3, the number of viable cells decreased dose-dependently and in an additive manner for these agents. A single dose of 2 or 10 µM Phx-3 induced apoptotic morphology characterized by nuclear condensation and cell shrinkage in dRLh-84, HepG2 and RLN-10 cells, while a single dose of 10 mM 2-DG did not. When Phx-3 (2 or 10 µM) treatment was combined with 2-DG (10 mM) treatment in these three cell lines, the cells with apoptotic morphology increased extensively, which was confirmed by flow cytometric analysis. In addition, autophagic morphology characterized by cytosolic vacuole formation was significantly increased in the hepatocellular carcinoma cell lines dRLh-84 and HepG2 but not in the normal hepatocellular cell line RLN-10 after a single dose of Phx-3 or 2-DG or a combined dose of Phx-3 and 2-DG. Furthermore, when dRLh-84 and HepG2 cells were treated with Phx-3 alone or a combined dose of Phx-3 and 2-DG, depolarization of the mitochondria was extensive, but that of the normal cell line RLN-10 was not. These results may imply that the mechanism for the apoptosis of hepatocellular carcinoma cells caused by Phx-3 alone or a combined dose of Phx-3 and 2-DG differs from that of the normal cell line RLN-10. The present results demonstrate that Phx-3 alone may be beneficial for targeting liver cancer and that its anticancer activity may be enhanced by 2-DG. However, a combined dose of Phx-3 and 2-DG may exert adverse effects on normal liver cells, as evidenced by the cytotoxic and pro-apoptotic effects of the combined treatment in the rat normal hepatocellular cell line RLN-10.

Gastric tube perforation after esophagectomy for esophageal cancer.

We searched for cases of perforation of the gastric tube after esophagectomy for esophageal cancer by reviewing the literature. Only 13 cases were found in the English literature, and serious complications were seen in all cases, especially in cases of posterior mediastinal reconstruction. However, in the Japanese literature serious complications were also frequently seen in retrosternal reconstruction. Gastric tubes are at a higher risk of developing an ulcer than the normal stomach, including an ulcer due to Helicobacter pylori infection, insufficient blood supply, gastric stasis, and bile juice regurgitation. H. pylori eradication and acid-suppressive medications are important preventive therapies for ordinary gastric ulcers, but for gastric tube ulcers the effects of such treatments are still controversial. We tried to determine the most appropriate treatment to avoid serious complications in the gastric tubes, but we could not confirm an optimal route because each had advantages and disadvantages. However, at least in cases with severe atrophic gastritis due to H. pylori infection or a history of frequent peptic ulcer treatment, the antesternal route is clearly the best. Many cases of gastric tube ulcers involve no pain, and vagotomy may be one of the reasons for this absence of pain. Therefore, periodic endoscopic examination may be necessary to rule out the presence of an ulcer.

It is possible that tumour-infiltrating granulocytes promote tumour progression.

Several lines of evidence indicate that tumour-infiltrating granulocytes (TIGs) promote tumour growth and progression. However, the prognostic significance of TIGs, the relationship between TIGs and Fas ligand (FasL) expressed on tumour cells remains unclear and warrants investigation. Using immunnostaining, we retrospectively investigated TIGs and FasL in 130 tissue specimens from gastric carcinoma. We analyzed the correlation among these markers, their association with clinicopathologic features and prognosis. The number of TIGs was significantly associated with FasL-expression (P=0.002). Further, TIGs were significantly associated with depth of tumour invasion, lymph node metastasis and tumour stage. Calculating the prognostic relevance, in multivariate analysis, TIGs [relative risk (RR)=1.014; 95% CI=1.002-1.027; P=0.015] and tumour stage were statistically significant factors for survival. Our results suggest that TIGs are conveniently measured by the immunostaining method, and possibly serve as an independent factor of prognosis in patients with gastric carcinoma. This is based on the fact that TIGs were significantly associated with tumour stage and shorter survival time.

Identification of degradation products in loxoprofen sodium adhesive tapes by liquid chromatography-mass spectrometry and dynamic pressurized liquid extraction-solid-phase extraction coupled to liquid chromatography-nuclear magnetic resonance spectroscopy.

Rapid and unambiguous identification of three degradation products (DP-1, DP-2 and DP-3) found in heat-stressed loxoprofen sodium adhesive tapes (Loxonin tapes) was achieved by LC-MS and dynamic pressurized liquid extraction (PLE)-solid-phase extraction (SPE) coupled to LC-NMR without complicated isolation or purification processes. The molecular formulae of the degradation products were determined by accurate mass measurements and product ion analyses and on-line hydrogen/deuterium (H/D) exchange experiments provided information about changes in the degradation of loxoprofen. To compensate for the low sensitivity of NMR, on-line dynamic PLE-SPE was employed and higher concentrations of degradation products trapped on the SPE column were afforded in a shorter time than they would be in such time-consuming sample preparations as pre-concentration after extraction. The loop-storage procedure was used in the LC-NMR analysis to allow the acquisition of the (1)H spectra of the three degradation products in one chromatographic run without affecting the peak separation and to avoid the carry-over of previously eluted DP-1 of high concentration by washing the NMR detection cell prior to the measurement of the DP-2 spectrum. Based on the resulting (1)H NMR spectra in combination with the MS results, DP-1 was successfully identified as an oxidation product having an oxodicarboxylic acid structure formed by the cleavage of the cyclopentanone ring of loxoprofen, DP-2 as a cyclopentanone ring-hydroxylated loxoprofen and DP-3 as a loxoprofen l-menthol ester.

The granulocyte/lymphocyte ratio as an independent predictor of tumour growth, metastasis and progression: Its clinical applications.

Several investigators have suggested that the granulocyte/lymphocyte (G/L) ratio is a good indicator for the evaluation of the condition of a tumour-bearing host, although its prognotic significance is unclear. To further investigate the clinical applications of the G/L ratio, we injected 1x105 and 1x106 Lewis lung carcinoma cells (3LLc) into the feet of 4-week-old C57BL/6 mice separated into groups A, B, C and D (1x105 cells) and E, F, G and H (1x106 cells). For the observation of tumour metastasis and G/L ratio, the mice in groups A-D were sacrificed on days 11, 14, 17 and 21 after inoculation with the 3LLc cells, and the mice in groups E-H on days 7, 11, 14 and 17. The results suggest that in mice the number of granulocytes increases with time after 3LLc cell injection (P<0.05). We also retrospectively investigated the correlation between G/L ratio, clinicopathologic features and prognosis in 62 patients with gastric carcinoma. There was a significant correlation between the G/L ratio and tumour weight (r=0.746, P<0.05), as well as a significant difference between the G/L ratio and the extent of metastases (P<0.05). Additionally, the G/L ratio was significantly associated with lymph node metastasis and higher tumour stage, tumour progression (P=0.017) and 5-year survival (P=0.013). In conclusion, the G/L ratio is associated with tumour progression and shorter survival. The close correlation between G/L ratio and tumour stage or lymph node status suggests that it could be used to predict tumour metastasis, prognosis and overall survival in patients with gastric carcinoma before they undergo surgical treatment.

Gemcitabine resistance in a highly metastatic subpopulation of a pulmonary adenocarcinoma cell line resistant to gefitinib.

The response rates to combination chemotherapy in metastatic non-small cell lung cancer (NSCLC) cases have been reported to be lower than those to induction chemotherapy in locally advanced cases. To understand the relationship between highly metastatic potential and chemosensitivity, we examined the drug sensitivity of a highly metastatic human lung adenocarcinoma cell subpopulation, PC9/f14, which had been previously established in an experimental metastasis model, to commonly used anti-cancer agents (paclitaxel, SN38, gemcitabine, vindesine, etoposide, cisplatin, and carboplatin) via the 3-(4, 5-dimethylthiazol-2-yl)2, 5-diphenyltetrazolium bromide assay. We found that the PC9/f14 subpopulation, which we previously reported to be resistant to gefitinib, was also resistant to gemcitabine (2',2'-difluoro-2'-deoxy-cytidine), a nucleoside analogue. To clarify the mechanisms of the gemcitabine resistance in this subpopulation, we screened the changes to the protein expression profiles of these cells after exposure to gemcitabine, using a 224-antibody microarray analysis. The exposure to gemcitabine in this subpopulation induced an increase in the expression level of the Bcl-X protein, although this expression remained unchanged in the parent cells. Apoptosis following gemcitabine exposure was depressed in the PC9/f14 subpopulation compared with parent cells, as assessed by flow cytometry and TUNEL assay. In addition, knock-down of Bcl-X by RNA interference methodology induced the recovery of gemcitabine sensitivity in PC9/f14. Phosphorylated Akt, which seems to be involved in the gefitinib resistance of this subpopulation, did not change after gemcitabine exposure. In conclusion, this highly metastatic lung cancer subpopulation had multi-resistant characteristics, to both gemcitabine and gefitinib, which were achieved in different ways, during the process of obtaining its highly metastatic potential. The combination of anti-cancer drugs and inhibition of the molecules related with apoptosis and/or Akt pathway might be beneficial in the treatment of metastatic NSCLC.

Bioaccumulation, temporal trend, and geographical distribution of synthetic musks in the marine environment.

Bioaccumulation of synthetic musks in a marine food chain was investigated by analyzing marine organisms at various trophic levels, including lugworm, clam, crustacean, fish, marine mammal, and bird samples collected from tidal flat and shallow water areas of the Ariake Sea, Japan. Two of the polycyclic musks, HHCB and AHTN, were the dominant compounds found in most of the samples analyzed, whereas nitro musks were not detected in any of the organisms, suggesting greater usage of polycyclic musks relative to the nitro musks in Japan. The highest concentrations of HHCB were detected in clams (258-2730 ng/g lipid wt.), whereas HHCB concentrations in mallard and black-headed gull were low, and comparable with concentrations in fish and crab. These results are in contrast to the bioaccumulation pattern of polychlorinated biphenyls; for which a positive correlation between the concentration and the trophic status of organisms was found. Such a difference in the bioaccumulation is probably due to the metabolism and elimination of HHCB in higher trophic organisms. Temporal trends in concentrations of synthetic musks were examined by analyzing tissues of marine mammals from Japanese coastal waters collected during 1977-2005. HHCB concentrations in marine mammals have shown significant increase since the early 1990s, suggesting a continuous input of this compound into the marine environment. Comparison of the time trend for HHCB with those for PCBs and PBDEs suggested that the rates of increase in HHCB concentrations were higher than the other classes of pollutants. To examine the geographical distribution of HHCB, we have analyzed tissues of fish, marine mammals, and birds collected from several locations. Synthetic musks were not detected in a sperm whale (pelagic species) from Japanese coastal water and in eggs of south polar skua from Antarctica. While the number of samples analyzed is limited, these results imply a lack of long-range transportation potential of synthetic musks in the environment.

Prognostic significance of immunohistochemically detected blood and lymphatic vessel invasion in colorectal carcinoma: its impact on prognosis.

BACKGROUND: The prognostic significance of blood vessel invasion (BVI) and lymphatic vessel invasion (LVI) is unclear. Because of the absence of specific markers for venous and lymphatic vessels, earlier studies could not reliably distinguish between BVI and LVI. METHODS: By immunostaining for podoplanin and CD34 antigen, we retrospectively investigated LVI and BVI in 419 tissue specimens of colorectal carcinoma. We performed univariate and multivariate analysis of the clinicopathologic features, frequency of recurrence, and outcome of patients with or without LVI and BVI. RESULTS: The use of hematoxylin and eosin (H&E) staining to identify BVI and LVI yielded a false positive rate of 9.1% and false negative rate of 12.6%. The incidence of BVI was significantly higher among tumors with LVI than tumors without LVI (P <.001). In logistic multivariate analysis, only LVI (P < .001) was associated with lymph node metastasis and BVI (P = .015) was associated with distant recurrence. Calculating the prognostic relevance, both two invasion types correlated with decreased survival in univariate analysis (both P <.001). In multivariate analysis, BVI (P =.024), lymph node status (P =.003) and tumor stage (P <.001) remained statistically significant factors for survival. CONCLUSIONS: Our results suggest that immunohistologic evaluation of BVI and LVI could be useful in colorectal carcinoma indicating the risk of lymph node metastasis and recurrence, thereby contributing to prognostic evaluation.

Acute myelogenous leukemia suddenly developing just after surgery for advanced gastric cancer: report of a case.

We report a case of acute myelogenous leukemia (AML) developing just after surgery for advanced gastric cancer, before adjuvant chemotherapy was started. Immature white blood cells were recognized in the peripheral blood from postoperative day (POD) 1. The patient's clinical status and bone scintigraphy showed no evidence of bone metastasis. Acute myelogenous leukemia was diagnosed by an aspiration biopsy of the bone marrow. If the AML had developed later and had become remarkable during or after adjuvant chemotherapy, the differential diagnosis between de novo and therapy-related leukemia would have been very difficult. Most leukemias that develop during the course of chemotherapy or radiotherapy, or both, are indisputably considered to be therapy-related. Thus, we report the clinical course of this patient with reference to the related literature to warn surgeons of the possibility of this unusual manifestation.

[Our outpatient cases for home anti-cancer chemotherapy].

We report our outpatient cases for home anti cancer chemotherapy. A total of 97 patients with advanced and recurrent cancer (22 with breast, 20 gastric, 29 colonic, 12 rectal, 1 hepatic, 3 cholangio, 4 pancreatic, 2 duodenal, 2 ovarian and 2 malignant lymphomas) were performed at an outpatient clinic or provided home anti-cancer chemotherapy since December 1996. Of these patients, 9 patients were provided home anti-cancer chemotherapy, 56 patients had died, and 41 patients are alive and undergoing continuous therapy. The response rates revealed effective results in these diseases. No severe side effects were seen, and they underwent treatment at an outpatient clinic easily. The treatment of outpatients for home anti-cancer chemotherapy was effective and maintained the patient's QOL. However, it was important to establish early an exclusive therapy room, training of expert nurses and good staff.

[Current status of our home care].

We report a current status of our home care cases. Our home care has provided for 76 patients (46 men, 30 women) since July 1996. The average age was 73 (range 32-92) years old. The shortest period of home care was for 1 day, and the longest period of home care was achieved for 5 years and 5 months. 70 of the 76 patients suffered from malignant diseases. Of these patients, 53 patients were terminally ill cancer patients. 63 patients of the 76 had died, and over half of them (35 out of the 63 patients) had died at home. 14 of the 76 patients who were treated by other hospitals and clinics came to our hospital by means of referral, and we provided them our home care with the cooperation of these hospitals and clinics. No problems existed in our hospital with issues regarding discharge planning and nursing cooperation.

[Evaluation of CA72-4 as a tumor marker in patients with gastric cancer].

The clinical efficacy of CA72-4 for gastric cancer was studied in comparison with CEA and CA19-9. These 3 markers were examined simultaneously, preoperatively in 156 cases of gastric cancer. The positive rate of CA72-4 was higher than of CA19-9 and was equivalent to CEA. There was no significant difference between differentiated and undifferentiated carcinoma in these 3 markers. However, the positive rates of CEA and CA72-4 were significant higher in the cases with lymph node metastasis and curative grade B, C. The combination assay of CEA and CA72-4 was valuable because the tumor markers were considered to be independent of each other. Cases positive for both CEA and CA72-4 simultaneous were significantly more frequent among the cases with lymph node metastasis and in the serosa-invasive cases. In conclusion, CA72-4 is more important than CA19-9 as a tumor marker in gastric cancer patients.

Bioaccumulation and toxic potencies of polychlorinated biphenyls and polycyclic aromatic hydrocarbons in tidal flat and coastal ecosystems of the Ariake Sea, Japan.

Sediment and marine biota comprising several species of tidal flat and coastal organisms were analyzed for polychlorinated biphenyls (PCBs) including non- and mono-ortho coplanar congeners and polycyclic aromatic hydrocarbons (PAHs) to examine bioaccumulation profiles and toxic potencies of these contaminants. Concentrations of PCBs in tidal flat organisms ranged from 3.6 ng/g (wet wt) in clams to 68 ng/g (wet wt) in omnivore tidal flatfishes, a discernible trend reflecting concentrations and trophic levels. In contrast, PAHs concentrations were the highest in lower trophic organisms, such as crabs and lugworms from tidal flat, whereas those in coastal fishes, squid, and finless porpoises were less than detection limit. Greater bioaccumulation of PAHs was found in lugworms and crabs, which might be due to their direct ingestion of sediment particulates absorbed with PAHs. TCDD toxic equivalents (TEQs) were calculated for PCBs and PAHs in sediments and biota. PCBs accounted for a greater proportion of total TEQs (sum(TEQs): sum of TEQ(PCB) and TEQ(PAH)) in coastal and tidal flatfishes (>95%), while PAHs occupied a considerable portion of sum(TEQs) in sediment (>97%). Interestingly, TEQ(PAH) accounted for 37% and 81% of the sum(TEQs) in crabs and clams, respectively. Benzo[b]fluoranthene was the dominant contributor to TEQ(PAH) in both the species. Considering these observations, the environmental risks of PAHs may not be ignored in benthic tidal flat organisms due to their greater bioaccumulation through sediments.

A novel matrix metalloproteinase inhibitor, FYK-1388 suppresses tumor growth, metastasis and angiogenesis by human fibrosarcoma cell line.

The matrix metalloproteinases (MMPs) are likely to contribute to tumor cell invasion, metastasis and angiogenesis. Several MMP inhibitors have been developed, recently and their anti-tumor efficacy is being evaluated in clinical trials. FYK-1388 is a novel broad MMP inhibitor which blocks the activity of MMP-1, -2, -3, -7, -9, -13 and -14 (MT-MMP-1). It is especially effective against MMP-2 and -9 more so than other MMP inhibitors such as Marimastat, Ro 32-3555 and D-2163. Here, we investigated the anti-tumor efficacy of FYK-1388 using the human fibrosarcoma cell line HT-1080. These cells produced MMP-2 and -9, which FYK-1388 inhibited at a dose of 10(-8) M. FYK-1388 at 0.2 mg/mouse/day significantly suppressed tumor growth when given by s.c. injection for 22 days, experimental lung metastasis after 5 days s.c. injection and also suppressed tumor-induced angiogenesis in the dorsal air sac assay after 7 days s.c. injection. In the MTT assay, FYK-1388 had no effect on the in vitro growth of HT-1080 cells. These results suggest that FYK-1388 possesses anti-tumor efficacy as a result of inhibiting angiogenesis through the suppression of MMP-2 and -9 activity.