Wearable Epileptic Seizure Prediction System with Machine-Learning-Based Anomaly Detection of Heart Rate Variability.

A warning prior to seizure onset can help improve the quality of life for epilepsy patients. The feasibility of a wearable system for predicting epileptic seizures using anomaly detection based on machine learning is evaluated. An original telemeter is developed for continuous measurement of R-R intervals derived from an electrocardiogram. A bespoke smartphone app calculates the indices of heart rate variability in real time from the R-R intervals, and the indices are monitored using multivariate statistical process control by the smartphone app. The proposed system was evaluated on seven epilepsy patients. The accuracy and reliability of the R-R interval measurement, which was examined in comparison with the reference electrocardiogram, showed sufficient performance for heart rate variability analysis. The results obtained using the proposed system were compared with those obtained using the existing video and electroencephalogram assessments; it was noted that the proposed method has a sensitivity of 85.7% in detecting heart rate variability change prior to seizures. The false positive rate of 0.62 times/h was not significantly different from the healthy controls. The prediction performance and practical advantages of portability and real-time operation are demonstrated in this study.

Efficacy and safety of perampanel monotherapy in patients with focal-onset seizures with newly diagnosed epilepsy or recurrence of epilepsy after a period of remission: The open-label Study 342 (FREEDOM Study).

OBJECTIVE: Our study assessed perampanel monotherapy in patients (aged ≥12 years) with focal-onset seizures (FOS) with or without focal to bilateral tonic-clonic seizures (FBTCS) in Japan and South Korea. METHODS: Study 342 (NCT03201900; FREEDOM) is a single-arm, open-label, Phase III study. Patients initially received perampanel in a 32-week 4-mg/d Treatment Phase (6-week Titration; 26-week Maintenance Periods). If they experienced a seizure during the 4-mg/d Maintenance Period, they could be up-titrated to 8 mg/d across an additional 30-week Treatment Phase (4-week Titration; 26-week Maintenance Periods). Primary endpoint was the seizure-freedom rate during the Maintenance Period (4 mg/d and last evaluated dose [4 or 8 mg/d]). Secondary endpoints included time to first seizure onset and to withdrawal during Maintenance. Treatment-emergent adverse events (TEAEs) were monitored. RESULTS: At data cutoff (February 28, 2019), 89 patients with FOS (84 [94.4%] with newly diagnosed epilepsy and 5 [5.6%] with recurrence of epilepsy after a period of remission) had received ≥1 perampanel dose; 16 patients discontinued during the 4-mg/d Titration Period, meaning 73 patients entered the 4-mg/d Maintenance Period and were included in the primary analysis set for efficacy. Seizure-freedom rate in the 26-week Maintenance Period was 46/73 (63.0%; 95% confidence interval [CI]: 50.9-74.0) at 4 mg/d and 54/73 (74.0%; 95% CI: 62.4-83.5) at 4 or 8 mg/d. Cumulative probability of seizure-onset and withdrawal rates during Maintenance was 30.8% (95% CI: 21.5-43.0) and 23.7% (95% CI: 15.4-35.3) at 4 mg/d, and 18.2% (95% CI: 11.0-29.3) and 23.3% (95% CI: 15.2-34.8) at 4 or 8 mg/d. Perampanel was generally well tolerated, and the most common TEAE was dizziness. SIGNIFICANCE: Perampanel monotherapy (4 to 8 mg/d) was efficacious and consistent with the known safety profile up to 26 weeks in patients (≥12 years) with primarily newly diagnosed FOS with or without FBTCS.

Association of HLA-A*31:01 Screening With the Incidence of Carbamazepine-Induced Cutaneous Adverse Reactions in a Japanese Population.

Importance: Carbamazepine, a commonly used antiepileptic drug, is one of the most common causes of cutaneous adverse drug reactions (cADRs) worldwide. The allele HLA-A*31:01 is reportedly associated with carbamazepine-induced cADRs in Japanese and European populations; however, the clinical utility of HLA-A*31:01 has not been evaluated. Objective: To assess the use of HLA-A*31:01 genetic screening to identify Japanese individuals at risk of carbamazepine-induced cADRs. Design, Setting, and Participants: This cohort study was conducted across 36 hospitals in Japan from January 2012 to November 2014 among 1202 patients who had been deemed suitable to start treatment with carbamazepine. Preemptive HLA-A*31:01 genetic screening was performed for 1187 participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for 8 weeks to monitor the development of cADRs. Data analysis was performed from June 8, 2015, to December 27, 2016. Exposures: Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A*31:01 and alternative drugs for those who tested positive for HLA-A*31:01. Main Outcomes and Measures: Incidence of carbamazepine-induced cADRs. Results: Of the 1130 included patients who were prescribed carbamazepine or alternative drugs, the mean (range) age was 37.4 (0-95) years, 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Expert dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cADRs, of which 4 patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for 3 patients, maculopapular eruption for 9 patients, erythema multiforme for 5 patients, and an undetermined type of cADR for 6 patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis. Compared with historical controls, the incidence of carbamazepine-induced cADRs was significantly decreased (for BioBank Japan data: incidence, 3.4%; odds ratio, 0.60; 95% CI, 0.36-1.00; P = .048; for the Japan Medical Data Centre claims database: incidence, 5.1%; odds ratio, 0.39; 95% CI, 0.26-0.59; P < .001). Conclusions and Relevance: Preemptive HLA-A*31:01 genetic screening significantly decreased the incidence of carbamazepine-induced cADRs among Japanese patients, which suggests that it may be warranted in routine clinical practice.

Esophagectomy using a thoracoscopic approach with an open laparotomic or hand-assisted laparoscopic abdominal stage for esophageal cancer: analysis of survival and prognostic factors in 315 patients.

UNLABELLED: Survival and prognostic factors were analyzed in 315 patients with esophageal cancer undergoing thoracoscopic-assisted esophagectomy (TAE). The 5-year survival rate of 57.8% was satisfactory, indicating the oncological feasibility of TAE. Perioperative outcomes affected overall survival in the whole cohort but not in the subgroup treated with 2 endoscopic stages. OBJECTIVE: To estimate the oncological feasibility of thoracoscopic-assisted esophagectomy (TAE) for esophageal cancer and to clarify the prognostic impact of perioperative factors after TAE. BACKGROUND: Favorable perioperative outcomes of TAE versus open surgery have been demonstrated. However, survival data after TAE in a large cohort are limited, and no information on the prognostic influence of perioperative factors after TAE is available. METHODS: Prospectively collected data for 315 patients undergoing TAE for esophageal cancer were analyzed. Survival was compared with the Kaplan-Meier analysis and Cox regression analysis between 2 surgical approaches: thoracoscopic and hand-assisted laparoscopic esophagectomy (THLE) and thoracoscopic and open laparotomic esophagectomy (TOE). Factors affecting overall survival were identified with Cox multivariate regression analysis in the whole cohort and the THLE subgroup. RESULTS: THLE and TOE were performed in 153 and 162 patients, respectively. The overall 5-year survival of the whole cohort was 57.8%, with no difference between the THLE and the TOE group. Multivariate analysis of the 315 patients identified the following prognostic factors: blood loss, blood transfusion, intensive care unit stay, cardiovascular complications, pathological T and N stages, lymphatic invasion, intramural metastasis, and number of metastatic nodes. In the THLE subgroup, cerebral comorbidity, histological subtype, pathological T stage, and number of metastatic nodes were independent prognostic factors. CONCLUSIONS: TAE was oncologically feasible. Perioperative factors affected survival in the whole cohort, but did not in the THLE subgroup. However, the reduced perioperative factor effect in this subgroup would be small because the survival rates of the 2 surgical approaches were equal.

[Surgery for temporal lobe epilepsy: historical review and postoperative results].

Surgery is a better treatment option than prolonged medical therapy for patients with temporal lobe epilepsy. Randomized trials on surgery for epilepsy are feasible and appear to yield precise estimates of the effects of surgical treatment. This study includes 56 patients who underwent anterior temporal lobectomy with a mean follow-up of 11.3 years. The probability of achieving complete seizure freedom at 5 and 10 years is 73% and 69%, respectively. Patients who had discrete abnormalities (i.e., tumors, gliosis, or hippocampal sclerosis) before surgery had a significantly higher probability of achieving seizure freedom than did patients without obvious abnormalities. Of the 32 patients, 30 (94%) had the same seizure status as that after surgery at the-10 year follow-up, and 2 (6%) had recurrent seizures. Of the seizure-free patients, 16 (29%) had ceased taking antiepileptic drugs (AEDs) at the 5-year follow-up, and 8 (25%) had ceased taking the drugs at the 10-year follow-up. In this paper, the evolution of the understanding of temporal lobe epilepsy surgery has been discussed. The efficacy of temporal lobe epilepsy surgery remains controversial with regard to the chois of resection method that would provide the best results for seizure freedom and cognitive function. The seizure outcomes obtained after selective amygdalohippocampectomy were found to be similar to those obtained after temporal lobe resection in several studies, and there is considerable evidence for indicating that the neuropsychological outcomes obtained after selective amygdalohippocampectomy are better than those obtained after temporal lobe resection. No significant relationships were found between objective indices of change and subjective ratings for postoperative memory function. A new surgical method based on multiple subpial transections for the hippocampus was developed in 2006. It remains unclear whether mesial resection involving a larger area leads to better seizure outcomes.

Endothelial nitric oxide synthase mediates lymphangiogenesis and lymphatic metastasis.

Lymphatic metastasis is a critical determinant of cancer prognosis. Recently, several lymphangiogenic molecules such as vascular endothelial growth factor (VEGF)-C and VEGF-D were identified. However, the mechanistic understanding of lymphatic metastasis is still in infancy. Nitric oxide (NO) plays a crucial role in regulating blood vessel growth and function as well as lymphatic vessel function. NO synthase (NOS) expression correlates with lymphatic metastasis. However, causal relationship between NOS and lymphatic metastasis has not been documented. To this end, we first show that both VEGF receptor-2 and VEGF receptor-3 stimulation activate eNOS in lymphatic endothelial cells and that NO donors induce proliferation and/or survival of cultured lymphatic endothelial cells in a dose-dependent manner. We find that an NOS inhibitor, L-NMMA, blocked regeneration of lymphatic vessels. Using intravital microscopy that allows us to visualize the steps of lymphatic metastasis, we show that genetic deletion of eNOS as well as NOS blockade attenuates peritumor lymphatic hyperplasia of VEGF-C-overexpressing T241 fibrosarcomas and decreases the delivery of metastatic tumor cells to the draining lymph nodes. Genetic deletion of eNOS in the host also leads to a decrease in T241 tumor cell dissemination to the lymph nodes and macroscopic lymph node metastasis of B16F10 melanoma. These findings indicate that eNOS mediates VEGF-C-induced lymphangiogenesis and, consequently, plays a critical role in lymphatic metastasis. Our findings explain the correlation between NOS and lymphatic metastasis seen in a number of human tumors and open the door for potential therapies exploiting NO signaling to treat diseases of the lymphatic system.

Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib.

Blood vessels are required for a tumor to grow and functional lymphatic vessels are required for it to disseminate to lymph nodes. In an attempt to eradicate both the primary tumor and its lymphatic metastasis, we targeted both blood and lymphatic vessels using two different tyrosine kinase inhibitors (TKIs): cediranib and vandetanib, which block vascular endothelial growth factor receptor (VEGFR)-2 and -3 in enzymatic assays. We found that although both cediranib and vandetanib slowed the growth rate of primary tumors and reduced blood vessel density, neither agent was able to prevent lymphatic metastasis when given after tumor cells had seeded the lymph node. However, when given during tumor growth, cediranib reduced the diameters of the draining lymphatic vessels, the number of tumor cells arriving in the draining lymph node, and the incidence of lymphatic metastasis. On the other hand, vandetanib had minimal effect on any of these variables, suggesting that vandetanib did not effectively block VEGFR-3 on lymphatic endothelial cells in our animal model. Collectively, these data indicate that the response of lymphatic vessels to a TKI can determine the incidence of lymphatic metastasis, independent of the effect of the TKI on blood vessels.

Magnetoencephalogram in a postoperative case with a large skull defect.

We present a patient in whom magnetoencephalograms were successfully performed in presurgical and postsurgical evaluations. A 12-year-old boy with congenital porencephaly was admitted with refractory adversive seizures and frontal absence seizures. Ictal magnetoencephalographic dipoles with frontal absence seizures were located in the left frontal lobe, anterior to the porencephalic cyst, and concordant with the same area detected by intraoperative electrocorticography. A partial cortical excision was performed, and the patient's cranial bone flap was removed because of an epidural abscess. The frontal absences then disappeared. The magnetoencephalogram revealed that secondary bilateral synchrony of focal discharges from the lesion may have caused the generalized seizures in this patient. Because of residual partial seizures, second and third magnetoencephalograms were performed, and we detected residual spike dipoles clustering in the area posterior to the cavity of cortical excision and anterior to the porencephalic cyst. Another excision of the area between the cavity and frontal edge of the cyst was performed, and seizure frequency diminished dramatically. In this case, despite the failure of dipole estimation by electroencephalogram in the context of a large bone defect, the magnetoencephalogram was useful in detecting the residual epileptogenic zone after failed epilepsy surgery.

Long-term follow-up outcome after surgical treatment for lesional temporal lobe epilepsy.

OBJECTIVES: Lateral or neocortical temporal lobe epilepsy (TLE) is regarded as a distinct clinical entity from medial TLE. Surgery for neocortical TLE can be considered as a viable treatment option; however, there is very limited information available on aspects such as long-term seizure outcome. Thus, we retrospectively reviewed our ten surgical cases of lateral TLE with a minimum 2 year follow-up outcome. METHODS: The series comprised four male and six female patients, ranging in age from 3 to 46 years (mean: 28.8 years). Seven cases were found to be drug-resistant. Invasive pre-surgical evaluation for intractable epilepsy was performed in six patients. RESULTS: The pathologic lesions were removed completely in nine cases. Lesionectomy alone was performed in four cases and total epileptogenic focus resection was confirmed in four cases. The epileptogenic regions within eloquent areas were preserved in two cases. The medial temporal structure was intact and preserved in all cases. Neuropathologic diagnoses were cavernoma in three cases, astrocytoma (grade 2) in two cases, arteriovenous malformation in two cases, gliosis in two cases and ganglioglioma in one case. The mean duration of follow-up was 6.5 years (range: 2.2-9.3 years). Outcomes categorized according to Engel classes were class I (E1) in six cases and class II (E2) in four cases. Patients who had post-operative seizures may also achieve long-term seizure decrease or freedom in three cases: case 5 (E4-E2), case 6 (E4-E2) and case 7 (E3-E1). Thus, worthwhile improvement was achieved in 100% of the cases in this series, with 60% of patients being seizure-free during the followed-up period. CONCLUSIONS: The controlled long-term follow-up results suggested that surgery for lesional TLE can be considered as a viable treatment option to control seizure with a low morbidity rate and good outcomes.

Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications.

Preclinical and clinical studies positively correlate the expression of vascular endothelial growth factor (VEGF)-C in tumors and the incidence of lymph node metastases. However, how VEGF-C regulates individual steps in the transport of tumor cells from the primary tumor to the draining lymph nodes is poorly understood. Here, we image and quantify these steps in tumors growing in the tip of the mouse ear using intravital microscopy of the draining lymphatic vessels and lymph node, which receives spontaneously shed tumor cells. We show that VEGF-C overexpression in cancer cells induces hyperplasia in peritumor lymphatic vessels and increases the volumetric flow rate in lymphatics at the base of the ear by 40%. The increases in lymph flow rate and peritumor lymphatic surface area enhance the rate of tumor cell delivery to lymph nodes, leading to a 200-fold increase in cancer cell accumulation in the lymph node and a 4-fold increase in lymph node metastasis. In our model, VEGF-C overexpression does not confer any survival or growth advantage on cancer cells. We also show that an anti-VEGF receptor (VEGFR)-3 antibody reduces both lymphatic hyperplasia and the delivery of tumor cells to the draining lymph node, leading to a reduction in lymph node metastasis. However, this treatment is unable to prevent the growth of tumor cells already seeded in lymph nodes. Collectively, our results indicate that VEGF-C facilitates lymphatic metastasis by increasing the delivery of cancer cells to lymph nodes and therapies directed against VEGF-C/VEGFR-3 signaling target the initial steps of lymphatic metastasis.

[Percutaneous interventional treatment of vertebral artery stenosis with coronary stents: two case reports].

Two patients underwent percutaneous interventional treatment for vertebral artery stenosis using coronary stents. Vertebral angiography of Case 1 (78-year-old male) showed right ostial 100% obstruction and left ostial 99% stenosis. Balloon angioplasty and stent placement (Multilink 4.0 x 18 mm) were performed for the left vertebral artery. Vertebral angiography of Case 2 (64-year-old male) showed bilateral ostial severe stenoses (right 90%, left 99% + alpha). Balloon angioplasty and stent placement(Multilink 3.5 x 18 mm) were performed for the right vertebral artery. These two patients showed excellent angiographic results with no complication associated with stent placement. Vertebral artery angioplasty can be performed safely using coronary interventional equipment and techniques.

Effects of nitrous oxide on spike activity on electrocorticogram under sevoflurane anesthesia in epileptic patients.

We sought to investigate the effects of nitrous oxide on intraoperative electrocorticogram (ECoG) spike activities in 11 patients with intractable epilepsy. Grid electrodes were placed on the brain surface, and ECoG was recorded under the following conditions: 1.5 minimal alveolar anesthetic concentration (MAC) sevoflurane without nitrous oxide and 1.5 MAC sevoflurane with 50% nitrous oxide. The number of spikes for 5 minutes and the percentage of leads with spikes of total leads measured were assessed in each condition. The median numbers (25-75th) of spikes without and with nitrous oxide were 127 (87-368) and 61 (43-247), respectively. The numbers of spikes with nitrous oxide were significantly lower than those without nitrous oxide (P<0.05). The median percentages of leads with spikes without and with nitrous oxide were 68 (25-81) and 61 (28-70), respectively, and there were no significant differences in percentages of leads with spikes between the conditions. These results indicate that nitrous oxide attenuated the frequency of spikes on ECoG in epileptic patients, although it did not affect the extent of areas with spike activity.

The effects of sevoflurane and hyperventilation on electrocorticogram spike activity in patients with refractory epilepsy.

UNLABELLED: We investigated the effects of sevoflurane and hyperventilation on intraoperative electrocorticogram (ECoG) spike activity in 13 patients with intractable epilepsy. Grid electrodes were placed on the brain surface and ECoG was recorded under the following conditions: 1) 0.5 minimal alveolar anesthetic concentration (MAC) sevoflurane, 2) 1.5 MAC sevoflurane, and 3) 1.5 MAC sevoflurane with hyperventilation. The number of spikes per 5 min and the percentage of leads with spikes were assessed in each condition. In 4 patients with chronically implanted-subdural electrodes, the leads with seizure onset and with spikes during the interictal periods in the awake state were compared with those during sevoflurane anesthesia at 0.5 MAC and 1.5 MAC. The number of spikes and the percentage of leads with spikes were significantly more under 1.5 MAC sevoflurane anesthesia compared with those under 0.5 MAC sevoflurane (P < 0.05). The induction of hyperventilation significantly increased the number of spikes and percentage of leads with spikes (P < 0.05). With 0.5 MAC sevoflurane, the leads with spikes were similar to those at seizure onset in the awake state, whereas with 1.5 MAC sevoflurane, spikes were similar to those occurring during interictal periods in the awake state. These results indicate that sevoflurane and hyperventilation can affect the frequency and extent of ECoG spike activity in patients with intractable epilepsy. Careful attention should be paid to the concentration of sevoflurane used and ventilatory status when intraoperative EcoG is used to localize epileptic lesions. IMPLICATIONS: Electrocorticogram can be used to define the location and extent of epileptic foci during epilepsy surgery. However, electrocorticogram can be affected by anesthetic technique. The present study found that sevoflurane concentration and hyperventilation affected the frequency and the extent of electrocorticogram spike activity in epileptic patients.

Diffusion tensor imaging in cases with visual field defect after anterior temporal lobectomy.

BACKGROUND AND PURPOSE: Visual defect due to optic radiation injury is a complication of temporal lobectomy for temporal epilepsy. To investigate whether diffusion tensor imaging can delineate the changes in optic radiations after lobectomy, we evaluated parameters on tensor images for optic radiations and correlated them with visual defect. METHODS: We examined 14 cases after temporal lobectomy. Durations after surgeries ranged from 3 weeks to 9 years. The cases were classified into three groups on the basis of the severity of visual field defect (A-C, with group C the most severe). We evaluated signals on T2-weighted images and parameters of tensor images, including fractional anisotropy (FA) and apparent diffusion coefficient (ADC), for the optic radiation in both the operated and intact side. RESULTS: On T2-weighted images, high signals in optic radiations were seen in four cases, occurring more than 4 weeks after surgery. The mean operated-to-intact side FA ratio in the optic radiation decreased according to severity of visual defect (group A, 0.88; group B, 0.89; group C, 0.73). The mean operated-to-intact side ADC ratio showed no significant difference in the overall cases. The ratio for ADC, however, tended to increase according to visual defect in cases after 10 weeks postsurgery. CONCLUSION: Optic radiation showed a decreased FA value in cases after temporal lobectomy. In later stages, ADC values tended to increase and high signal intensities on T2-weighted images were observed. The FA value can be used for evaluating Wallerian degeneration of optic radiation even in the early stages after surgery.

Retinotopy with coordinates of lateral occipital cortex in humans.

OBJECT: The lateral occipital cortex in humans is known as the "extrastriate visual cortex." It is, however, an unexplored field of research, and the anatomical nomenclature for its surface has still not been standardized. This study was designed to investigate whether the lateral occipital cortex in humans has retinotopic representation. METHODS: Four right-handed patients with a diagnosis of intractable epilepsy from space-occupying lesions in the occipital lobe or epilepsy originating in the occipital lobe received permanently implanted subdural electrodes. Electrical cortical stimulation was applied directly applied to the brain through metal electrodes by using a biphasic stimulator. The location of each electrode was measured on a lateral skull x-ray study. Each patient considered a whiteboard with vertical and horizontal median lines. The patient was asked to look at the midpoint on the whiteboard. If a visual hallucination or illusion occurred, the patient recorded its outline, shape, color, location, and motion on white paper one tenth the size of, and with vertical and horizontal median lines similar to those on, the whiteboard. Polar angles and eccentricities of the midpoints of the phosphenes from the coordinate origin were measured on the paper. On stimulation of the lateral occipital lobe, 44 phosphenes occurred. All phosphenes were circular or dotted, with a diameter of approximately 1 cm, except one that was like a curtain in the peripheral end of the upper and lower visual fields on stimulation of the parietooccipital region. All phosphenes appeared in the visual field contralateral to the cerebral hemisphere stimulated. On stimulation of the lateral occipital lobe, 22 phosphenes moved centrifugally or toward a horizontal line. From three-dimensional scatterplots and contour maps of the polar angles and eccentricities in relation to the x-ray coordinates of the electrodes, one can infer that the lateral occipital cortex in humans has retinotopic representation. CONCLUSIONS: The authors found that phosphenes induced by electrical cortical stimulation of the lateral occipital cortex represent retinotopy. From these results one can assert that visual field representation with retinotopic relation exists in the extrastriate visual cortex.

[Infantile partial seizures due to temporal lesions--analysis of 4 cases].

We studied 4 cases of complex partial seizures due to temporal lesions presenting with benign partial epilepsy in infancy. None of them had neurologic abnormalities. All cases had complex partial seizures, and two had lateralizing signs. All cases had temporal lesions. One of them was detected only by fluid-attenuated inversion recovery (FLAIR) imaging. Histopathologically they were astrocytomas (grade 2 and 3), glio neuronal hamartoma and focal cortical dysplasia. The present cases suggest that patient with infantile complex partial seizures should be carefully followed up, even after the disappearance of seizures, by serial MRI examination including FLAIR imaging and by clinical observation.

Gene therapy for pancreatic cancer using an adenovirus vector encoding soluble flt-1 vascular endothelial growth factor receptor.

INTRODUCTION: Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis. The soluble form of flt-1 VEGF receptor inhibits VEGF activity in a dominant-negative manner. AIM: This study demonstrated the regional tumor suppression effect of adenovirus-mediated soluble flt-1 in human pancreatic cancer cells. METHODOLOGY: The VEGF expression level was examined in nine cell lines. Panc-1 and PK-8 were used as lower- and higher-VEGF-producing cell lines, respectively. The in vitro proliferation of cancer cells infected with adenovirus vectors encoding soluble flt-1 (Adsflt) and control vectors (AdLacZ) was not different. To assess the in vivo tumor growth suppression, cancer cells were inoculated subcutaneously in SCID mice. Adsflt, AdLacZ, or vehicle was injected directly into the tumors. The early process of tumor angiogenesis in a dorsal skinfold chamber was monitored by intravital microscopy. RESULTS: In both Panc-1 cells and PK-8 cells, the tumor growth of the Adsflt-treated group was significantly suppressed. The microvessel density, revealed by CD31 immunostaining, was also significantly lower in the Adsflt-treated group. Apoptosis index was higher in the Adsflt group. Immunofluorescence staining revealed the expression of VEGF not only in cancer cells but also in tumor stromal cells. Wild-type cells and AdLacZ-infected cells prompted strong tumor angiogenesis, whereas Adsflt-infected cells failed to exert such an effect. CONCLUSION: These results indicate that antiangiogenic gene therapy using soluble flt-1 might be an effective approach for pancreatic cancer treatment.