Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis.

BACKGROUND: A phase II study to evaluate the efficacy and tolerability of weekly i.v. and i.p. paclitaxel (PTX) combined with S-1 was carried out in gastric cancer patients with peritoneal metastasis. PATIENTS AND METHODS: Gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered i.v. at 50 mg/m(2) and i.p. at 20 mg/m(2) on days 1 and 8. S-1 was administered at 80 mg/m(2)/day for 14 consecutive days, followed by 7 days rest. The primary end point was the 1-year overall survival (OS) rate. Secondary end points were the response rate, efficacy against malignant ascites and safety. RESULTS: Forty patients were enrolled, including 21 with primary tumors with peritoneal dissemination, 13 with peritoneal recurrence and six with positive peritoneal cytology only. The median number of courses was 7 (range 1-23). The 1-year OS rate was 78% (95% confidence interval 65% to 90%). The overall response rate was 56% in 18 patients with target lesions. Malignant ascites disappeared or decreased in 13 of 21 (62%) patients. The frequent grade 3/4 toxic effects included neutropenia (38%), leukopenia (18%) and anemia (10%). CONCLUSION: Combination chemotherapy of i.v. and i.p. PTX with S-1 is well tolerated and active in gastric cancer patients with peritoneal metastasis.

Selective and sustained delivery of basic fibroblast growth factor (bFGF) for treatment of peripheral arterial disease: results of a phase I trial.

OBJECTIVES: The aim of this study was to evaluate the safety of selective and sustained delivery of basic fibroblast growth factor (bFGF) using acidic gelatine hydrogel microspheres (AGHMs) for the treatment of peripheral arterial disease (PAD). MATERIALS AND METHODS: We conducted a non-randomised and uncontrolled trial involving prospective observation of eight patients (eight limbs) with PAD - five limbs with arteriosclerosis obliterans and three limbs with thromboangiitis obliterans, five limbs (three arms and two legs) with critical limb ischaemia (CLI) and three limbs with intermittent claudication (IC) - who were followed up for 6 months or more. AGHM suspension containing 100 microg bFGF was infused into the artery of the affected limb. Besides evaluation of safety and changes in symptoms, resting ankle-brachial pressure index measurement and transcutaneous PO(2) (tcPO(2)), angiography were conducted at baseline and then at various time points. Skin perfusion pressure as an index of CLI and claudication distance as an index of IC were also used to assess clinical improvement and limb perfusion. RESULTS: No serious adverse events were observed. All cases showed improvement in symptoms, although this was temporary in some patients. CONCLUSION: Selective delivery of bFGF using AGHMs was suggested to be safe and well-tolerated in patients with PAD.

Angleplasty in gastric tube reconstruction after esophagectomy.

Anastomotic leakage after radical esophagectomy is mostly caused by the hypoxia and high tension at the esophagogastric anastomotic site. Here, we introduce a new surgical technique, 'Angleplasty,' to enable the tensionless anastomosis at a highly oxygenic site of gastric conduit. In short, the seromuscular layer is cut for a perpendicular direction against a lesser curvature at a gastric angle and the gastric wall is carefully divided between the muscular and submucosal layers for longitudinal direction for 4-5 cm in length. Then, the wound is closed with seromuscular sutures for longitudinal direction. With this maneuver, the lesser curvature of the gastric roll is significantly elongated and the anastomosis site of the gastric conduit can be moved more distal on the greater curvature of the stomach where it is expected to receive more oxygen supply. This technique takes only several minutes, but provides highly favorable conditions for esophagogastric anastomosis and thus is clinically useful to reduce the risk of anastomotic leakage after esophagectomy.

Preoperative evaluation of enterovesical fistula using magnetic resonance imaging: case report.

We report a case of sigmoido-vesical fistula due to sigmoid diverticulitis. Magnetic resonance imaging enabled us to visualize the fistula itself in the bladder wall. Magnetic resonance imaging was highly effective in making a precise diagnosis and also provided important additional information for the preoperative work-up of the patient.

Chronic expanding hematoma in combination with a pseudoaneurysm: a case report.

After bleeding from trauma or surgery, most of the hematomas undergo spontaneous reabsorption. But, in some rare cases, hematomas persist for long periods as slowly expanding masses for months or years. These hematomas were termed as chronic expanding hematomas. In this report, we describe a case of chronic expanding hematoma with a pseudoaneurysm that underwent surgical biopsy, which led to an increase in its expansion speed.

Overexpression of hRFI inhibits 5-fluorouracil-induced apoptosis in colorectal cancer cells via activation of NF-kappaB and upregulation of BCL-2 and BCL-XL.

Resistance to apoptosis is one of the important determinants of resistance to 5-fluorouracil (5-FU) in colorectal cancer cells. Human Ring-Finger homologous to Inhibitor of apoptosis protein type (hRFI) is a newly discovered gene that has been shown to inhibit death receptor-mediated apoptosis in colorectal cancer cells. However, the molecular mechanism of the inhibition of apoptosis is presently unknown. In order to investigate the molecular function of hRFI in the regulation of 5-FU-induced apoptosis in colorectal cancer cells, HCT116 cells were stably transfected with hRFI or LacZ as a control. hRFI overexpression resulted in cellular resistance to 5-FU through an inhibition of the mitochondrial apoptotic pathway and specific upregulation of Bcl-2 and Bcl-XL. Futhermore, hRFI overexpression resulted in the activation of nuclear factor-kappaB (NF-kappaB). Inhibition of NF-kappaB effectively reversed the resistance to apoptosis as well as the upregulation of Bcl-2 and Bcl-XL in the hRFI transfectant, indicating that the activation of NF-kappaB is the key mechanism for all these findings. Overexpression of hRFI in SW480 and COLO320 colorectal cancer cells similarly resulted in resistance to 5-FU with the activation of NF-kappaB and upregulation of Bcl-2 and Bcl-XL. hRFI might be a novel therapeutic target for gene therapy in colorectal cancer.

Good correlation between cerebral oxygenation measured using near infrared spectroscopy and stump pressure during carotid clamping.

AIM: Intraoperative hypoperfusion ischemia is one factor that leads to perioperative stroke during carotid endarterectomy. Selective shunting is one way to reduce intraoperative hypoperfusion, but to shunt selectively needs a sensitive and simple monitoring system together with the rules for insertion. Near infrared spectroscopy (NIRS) is a monitoring system that can be used throughout the operation, and reflects the cerebral oxygenation instantly, but its value in insertion of shunt tubes is still controversial. The aim of this study was to determine criteria that can be used to insert shunt tubes. METHODS: Forty-three consecutive patients with severe carotid stenosis undergoing carotid artery surgery with NIRS monitoring were enrolled in the study. Under general anesthesia, the optodes of NIRS were placed bilaterally on the forehead. Throughout the operation, regional saturation of the frontal lobe (SdO2) was monitored every 5 s. RESULTS: All operations were performed without any perioperative deaths. NIRS showed that SdO2 fell rapidly as soon as the artery was cross-clamped, and reached the lowest level after 60 s. SdO2 change at 60 s and the stump pressure showed good correlation (r=0.65), and stump pressure of 40 mmHg was almost equivalent to 5% SdO2 decrease in NIRS. CONCLUSION: NIRS monitoring is suitable for monitoring during carotid endarterectomy for selective shunting, because it can be used throughout the operation and shows the immediate change in oxygenation. There is a possibility that a decrease of 5% can be used as a decisive value for shunt insertion.

Vaccines targeting tumour angiogenesis--a novel strategy for cancer immunotherapy.

AIMS: To review the concept of tumour angiogenesis and anti-angiogenic therapy, limitations of recently used anti-angiogenic therapeutics; provide an up-to-date overview of the growing number of reports on vaccines targeting tumour angiogenesis; and finally discuss potential complications and future directions in the development of more potent and specific vaccines. METHODS: A literature search was carried out from PubMed for indexed articles. The most important articles were analysed and discussed. FINDINGS: The search yielded a large number of important indexed published articles that were reviewed, screened and tracked for other relevant publications. The most relevant articles, including those previously published by authors, were analysed and discussed. CONCLUSIONS: Recently, different vaccine strategies have been reported to inhibit tumour growth and metastasis by induction of specific cellular and/or humoral immunity against angiogenesis-associated antigens in pre-clinical models, suggesting effective combination of anti-angiogenesis and cancer immunotherapy. Evaluation of tumour endothelial cells and clinical phase I study of the vaccines are recently ongoing, and should give us better insight into the possibilities of this novel strategy for cancer immunotherapy.

Popliteal venous aneurysm with repeated episodes of pulmonary embolism. Case report and literature review.

Popliteal venous aneurysm (PVA) is a rare, but a life-threatening, disease causing pulmonary embolism (PE). We experienced a case of primary PVA with repeated PE attacks without intraluminal thrombus. Surgical repair was safely performed with a temporary vena cava filter and an intraoperative external pneumatic compression device to the calf. During the perioperative period, pneumatic compression was continued until the patient returned to a normal ambulatory status. The patient has had no episode of PE for 24 months since the operation.

Carotid endarterectomy may reduce the high stroke rate for patients with the disease of abdominal aorta and peripheral arteries.

AIM: The prevalence of carotid stenosis is reported to be high among patients with arteriosclerosis, but the hazards of carotid stenosis and the benefits of carotid endarterectomy (CEA) on long-term event-free survival are still unknown. The aim of this prospective study was to screen preoperative patients with arterial disease for carotid stenosis, and to determine whether CEA had any effect on stroke during the postoperative follow-up period. METHODS: From 1999 to 2003, 406 consecutive preoperative patients with arterial disease underwent routine carotid duplex scan. Patients with known carotid stenosis and those due to undergo operation in emergency were excluded from the study. CEA was performed before or simultaneously with vascular surgery if necessary. The prevalence and risk factors for carotid stenosis were studied, and the patients were followed up for stroke or death. RESULTS: Among the 406 patients examined, 19.4% had greater than 50% stenosis and 11.3% had greater than 70% stenosis. The risk factors for carotid stenosis were having occlusive arterial disease (P=0.0001), and history of stroke (P=0.0038). Long-term follow-up study revealed that patients with greater than 70% carotid stenosis without CEA had a higher tendency for stroke or death, but the stroke rate in patients with severe stenosis who underwent CEA remained low, as in patients with less than 70% stenosis. CONCLUSIONS: Patients with greater than 70% carotid stenosis, diagnosed before arterial operation who did not undergo CEA, had a higher risk for stroke during the postoperative follow-up period. However, their risk could be reduced by performing CEA before or simultaneously with scheduled vascular surgery.

Reduced vascular reserve measured by stressed single photon emission computed tomography carries a high risk for stroke in patients with carotid stenosis.

AIM: A few studies have observed reduced vascular reserve measured by single photon emission computed tomography (SPECT) to be a risk factor for stroke in patients with carotid artery occlusion, but stenosis has been excluded from these former studies. This study has evaluated the prognosis of reduced vascular reserve in patients with stenosis, and the effect of carotid endarterectomy (CEA) on these patients. METHODS: Forty patients diagnosed as having >70% stenosis of the carotid artery at the University of Tokyo Hospital, between 2001 and 2004, underwent acetazolamide-stress SPECT test first. A resting SPECT study was performed on a different day from the stressed SPECT study. The patients were grouped as having reduced vascular reserve or normal vascular reserve from the SPECT results. Analysis of risk factors and the stroke-free curve analysis for reduced vascular reserve was performed. RESULTS: Of the 40 patients, 24 (60%) had reduced vascular reserve and 18 underwent CEA. The mean follow-up period was 21.5+/-15.5 months (mean+/-SD). Four strokes occurred during follow-up: in 1 patient with CEA and 3 without CEA. All stroke patients had reduced vascular reserve. The patients with reduced vascular reserve without any surgery had a significantly lower stroke-free rate compared with those with normal vascular reserve or reduced vascular reserve, but also receiving CEA. CONCLUSIONS: We propose performing SPECT tests in patients with severe carotid stenosis regardless of symptoms, and performing CEA on those with a reduction in vascular reserve.

Suppressive effect of basic fibroblast growth factor on transendothelial emigration of CD4(+) T-lymphocyte.

The effect of basic fibroblast growth factor (b-FGF), one of the commonest angiogenic factors in various cancer types, on lymphocyte adhesion and transmigration across the endothelial cell monolayer was investigated using human umbilical vein-derived endothelial cells (HUVEC) and type I collagen gel. Forty-eight h exposure of HUVEC with 2 ng/ml b-FGF significantly decreased the basal adhesion of lymphocytes to endothelial cells. The decrease ratio is further enhanced by the addition of shear stress in this assay system. When HUVEC was stimulated for the last 24 h with optimal conditions of recombinant interleukin 1 beta, the percentages of transmigration as well as adhesion were also decreased significantly by the presence of b-FGF. The expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 was down-regulated by b-FGF exposure in both resting and activated conditions by recombinant interleukin 1 beta, supposedly the main reason for this phenomenon. The migrating cells across b-FGF-stimulated HUVEC contained a markedly lower percentage of CD4(+) T-cells than those across non-treated HUVEC, although the 4B4(+)/2H4(+) ratio in CD4(+) T-cell populations did not differ significantly. These facts suggest that the presence of b-FGF in the angiogenic area suppresses lymphocyte emigration, especially that of CD4(+) T-cells, and thus causes insufficient helper function in local immune response. This effect of b-FGF was possibly one of the critical mechanisms by which cancer cells escape from the host immune reactions in the angiogenic stage of tumor development.

High hRFI expression correlates with resistance to fluoropyrimidines in human colon cancer cell lines and in xenografts.

We previously reported that the over-expression of hRFI, a protein preferentially expressed in the digestive tract regions of several cancers, exhibited a tendency to inhibit TNF-alpha induced apoptosis. In this study, we sought to determine the potential effect of hRFI expression on the sensitivity to 5-fluorouracil (5-FU) and/or other fluoropyrimidines. For the whole lysates of 8 colon cancer cell lines, we performed Western blotting with anti-hRFI antibody and analyzed the correlations between the expression level of hRFI and the cell lines' sensitivity to 5-FU induced apoptosis. Furthermore, for a tissue microarray consisting of 32 xenograft derived human cancer cell lines, we examined the expression levels of hRFI and survivin by immunohistochemical staining, and analyzed the correlations between the expression of each protein and the sensitivity to several chemotherapeutic agents in the xenografts examined. Both in colon cancer cell lines and in xenografts, the expression level of hRFI was correlated with resistance to 5-FU and its derivatives. This evidence suggests that hRFI may be a marker predicting the response to fluorouracil derived chemotherapeutic agents and that the reduction of the expression level of hRFI might improve the outcome of chemotherapy.

Impaired ambulatory venous function in lymphedema assessed by near-infrared spectroscopy.

AIM: The aim of this study was to investigate venous function in patients with leg lymphedema during exercise using near-infrared spectroscopy (NIRS), compared with that of patients with chronic venous insufficiency (CVI). METHODS: Forty-three legs of 33 patients (5 males, 28 females; mean age: 53 years) with leg lymphedema without varicose veins or deep vein thrombosis underwent a treadmill walking test with simultaneous NIRS. For comparison, 136 legs of 91 patients (35 males, 56 females; mean age: 56 years) with varicose veins as a CVI group and 45 legs of 38 healthy volunteers (23 males, 15 females; mean age: 50 years) were also evaluated in the same method. Deoxygenated hemoglobin (HHb) was continuously measured during exercise, and the ambulatory venous retention index (AVRI) of each leg was obtained from the serial changes in HHb. RESULTS: The mean AVRI of the lymphedema group was significantly higher than that of healthy legs and significantly lower than of legs with moderate or severe CVI. Furthermore, it was similar to that in the mild CVI group. CONCLUSIONS: Venous function is impaired in exercising legs with lymphedema, and corresponds to that in legs with mild venous insufficiency. The treatment of lymphedema should take CVI into consideration.

Long-term results of combined iliac endovascular intervention and infrainguinal surgical revascularization for treatment of multilevel arterial occlusive disease.

AIM: The purpose of this study was to investigate the long-term results of combined iliac endovascular intervention and infrainguinal surgical revascularization. METHODS: A retrospective review of 39 infrainguinal bypasses combined with iliac endovascular intervention in 35 patients over a 16-year period was performed (Combined group). These results were compared to those of 43 infrainguinal bypasses performed with suprainguinal bypass operation in 39 patients (Surgical group), who had iliac lesions not amenable to angioplasty/stenting. There was no significant difference in the preoperative limb ischemic symptoms between them. RESULTS: Although the proportion of patients with coronary artery disease in the Combined group was significantly higher than that in the Surgical group, there was a trend toward lower morbidity/mortality in the Combined group compared with the Surgical group (8.6% vs 15.4%; P=0.3706). No significant differences in the rates of clinical and hemodynamic improvement and limb salvage rate were observed between the two groups. The primary patency rate of infrainguinal bypass at 1, 3, and 5 years was 83.2%, 80%, and 71.2% in the Combined group, and 97.1%, 89.9%, and 80.5% in the Surgical group, respectively. The secondary patency rate at 1, 3, and 5 years was 91.9%, 91.9%, and 76.3% in the Combined group, and 97.1%, 89.9%, and 84.6% in the Surgical group, respectively. Importantly, there was no significant difference in the primary/secondary patency rates between the two groups (Kaplan-Meier, log-rank test, primary patency, P=0.116; secondary patency, P=0.4407). CONCLUSIONS: Infrainguinal surgical reconstruction combined with iliac endovascular procedure may reduce operative risk, and further, long-term patency is comparable to that in the Surgical group.

Persistent sciatic artery in a patient with extracranial internal carotid artery aneurysm and infrarenal abdominal aortic aneurysm. A case report.

A rare case of a persistent sciatic artery (PSA) in a patient with aneurysms of the internal carotid artery and abdominal aorta is presented. A 70-year-old man was referred with intermittent claudication of the right lower extremity. Angiography and computed tomography demonstrated that this symptom was due to occlusion of the PSA. On preoperative examinations, aneurysms of the extracranial internal carotid artery and abdominal aorta were incidentally discovered, and then surgically treated prior to the management of PSA. Systemic examinations must be performed in patients with PSA in order to scrutinize associated anomalies or vascular disease.

Enhanced metastasis of B16 melanoma cells by unexpected elevated expression of the metastasis-associated TI-241 (LRF-1-, Jun-Fos-related) gene treated with antisense oligonucleotide.

B16-F10 is a B16 mouse melanoma subline that preferentially metastasizes to the lung following intravenous injection. Previously we isolated TI-241 (LRF-1 homologue related to Jun-Fos) gene that was expressed higher in the high metastatic clone B16-F10 than the low metastatic clone F1. Transfection of TI-241 into F1 converted it into a high-metastatic cell. We studied the effect of antisense oligonucleotide designed to reduce the expression of TI-241 in B16-F10 cells, and observed an unexpected increase in the TI-241 level. The increase in the expression was maximal at 30 h, then it decreased during further culture with or without TI-241 antisense oligonucleotide. This increased TI-241 expression by antisense oligonucleotide was also observed in B16-F1 cells whereas sense oligonucleotide did not affect the expression. B16-F10 cells cultured with TI-241 antisense oligonucleotide showed enhanced experimental metastatic potential to the mouse lungs compared with untreated B16-F10 and B16-F10 cultured with TI-241 sense oligonucleotide.

E-selectin can mediate the arrest type of adhesion of colon cancer cells under physiological shear flow.

The aim of this study was to determine whether colon cancer cells flowing in blood exhibit the same adhesion pattern to the vascular bed as leucocytes using a flow adhesion system. In shear flow conditions, five colon cancer cell lines showed less tethering to E-selectin substrates than polymorphonuclear cells (PMN). However, some of the Colo201 cells formed complete arrest on E-selectin in continuous shear flow which was never observed in PMN cells. Colo201 cells expressed both sialyl Le-x and sialyl Le-a at similar levels in flow cytometry. However, the staining pattern showed marked contrast under the fluorescein microscope. The cell membrane of Colo201 cells was uniformly stained with anti-sialyl Le-a MAb, whereas anti-sialyl Le-x MAb only stained in the patchy areas. Pretreatment of Colo201 cells with anti-sLe-a decreased tethering, while anti-sLe-x significantly inhibited the arrest formation. Our data suggest that E-selectin alone can mediate colon cancer cell lodgement and subsequent metastasis without the contribution of integrin molecules and that the different distribution of E-selectin ligands may affect the adhesion behaviour of colon cancer cells in flow conditions.

Inhibitory effects of n-3 polyunsaturated fatty acids on sigmoid colon cancer transformants.

Various types of polyunsaturated fatty acids (PUFAs) have been suggested to exert different effects on the colon in terms of promotion or inhibition of tumor development. Results of in vitro and in vivo studies are, however, inconsistent and it remains unclear whether or not the cellular effects of PUFAs change along with the malignant transformation of colonic cells. In this study, we used the NIH3T3 cell line and its SIC (sigmoid colon cancer) oncogene transformants to compare the effects of PUFAs on the proliferation of non-malignant and malignant cells. We also determined the cellular utilization of fatty acids in media by a high-performance liquid chromatography method. The addition of exogenous arachidonic acid (ARA, an n-6 fatty acid), eicosapentaenoic acid (EPA, n-3), and docosahexaenoic acid (DHA, n-3) exerted different effects on NIH3T3 cells, and on SIC transformants, in which selective inhibitory effects were observed at media concentrations ranging from 10 to 20 microg/ml. In cells cultured in media supplemented with EPA or DHA at a concentration of 2 microg/ml, which had no effect on cell proliferation, the cellular utilization of linoleic acid (n-6), a precursor of n-3 fatty acids, was inhibited. This inhibition was stronger in SIC transformants than in NIH3T3 cells (P < 0.05). There was no difference in the utilization of fatty acids between the two cell lines cultured in media supplemented with ARA. We conclude that the cellular response to exogenous long-chain PUFAs is modified during the course of malignant transformation, and that EPA and DHA (n-3 PUFAs) appear to have specific inhibitory effects on cancer cells and may thus enhance the host defense against colon cancer.

Early feeding after oncological colorectal surgery in Japanese patients.

We aimed to determine the safety and feasibility of an alternative postoperative oral intake protocol for Japanese patients who had had oncological colorectal surgery, with the goal of shortening the length of postoperative stay to the same level as that in Western countries. The subjects of the study were 42 consecutive patients who underwent elective oncological colorectal surgery. Two protocols., Japanese traditional management (TM: n = 20) and alternative management (AM; n = 22), were employed. The two protocols differed in their management of oral intake after surgery. Tolerance of the alternative protocol and the incidence of postoperative complications were determined. The mean length of postoperative stay in the AM and TM groups was 11.5 +/- 1.2 and 24.0 +/- 2.1 days, respectively (P < 0.0001; t-test). Analysis of the patients who underwent open operation also revealed that the length of postoperative stay was less in the AM group than in the TM group (12.3 +/- 1.7 and 24.7 +/- 2.2 days, respectively, P = 0.0003). One patient in the TM group developed small bowel obstruction during the introduction of oral intake. One patient in the AM group also developed small bowel obstruction, after discharge. and was readmitted. Other patients tolerated both the TM and AM protocols. Morbidity in the AM group was 20.0%, and that in the TM group was 30.0% (P = 0.72). The employment of an alternative postoperative oral intake protocol was safe and feasible for Japanese patients. Further investigation is needed to determine the possible benefits, both medical and socioeconomic, of this approach.