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Equine coital exanthema (ECE) is an infectious, venereally transmitted muco-cutaneous disease affecting mares and stallions, caused by equid alphaherpesvirus 3 (EHV3). Diagnostic tools for rapid identification of EHV3 are of primary importance to diminish the risk of EHV3 dissemination at the time of breeding. In the last years, it has been shown that the performance of the insulated-isothermal polymerase chain reaction (iiPCR) is comparable to virus isolation, nested PCR and real-time PCR (qPCR) in detecting pathogens of various animal species. Analytical sensitivity and specificity of the iiPCR were compared with a qPCR, using a plasmid containing the target region of the EHV3 glycoprotein G gene and an Argentinian EHV3 isolate (E/9283/07 C3A). In order to evaluate the diagnostic performance of the iiPCR, nucleic acids of 85 perineal and genital swabs (PGS) of mares and stallions were extracted by tacoTM mini and tested by both techniques. EHV3 was detected in 46 and 45 of the 85 PGS by the iiPCR and qPCR, respectively. There was almost perfect agreement between the two diagnostic methods (98.82%; 95% CI: 95.03–100%; κ = 0.98). The iiPCR had a limit of detection of 95.00% at 6 genome equivalents per reaction and a detection endpoint for viral DNA comparable to that of the qPCR, and did not react with six non-targeted equine pathogens. The iiPCR represents a sensitive and specific method for the rapid on-site diagnosis of EHV3 infection. Its routinely implementation in breeding facilities, and artificial insemination and embryo transfer centers, will contribute to prevent the dissemination of this venereal, highly contagious disease in horses. Fil: Vissani, María Aldana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria; Argentina Fil: Tordoya, Maria Silvia. Instituto Nacional de Tecnología Agropecuaria; Argentina Fil: Tsai, Y.-L.. GeneReach; Estados Unidos Fil: Lee, P.-Y.A.. GeneReach; Estados Unidos Fil: Shen, Y.-H.. GeneReach; Estados Unidos Fil: Lee, F.-C.. GeneReach; Estados Unidos Fil: Wang, H.-T.T.. GeneReach; Estados Unidos Fil: Parreño, Gladys Viviana. Instituto Nacional de Tecnología Agropecuaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Barrandeguy, María Edith. Instituto Nacional de Tecnología Agropecuaria; Argentina. Universidad del Salvador. Escuela de Veterinaria; Argentina

The loss of beach sand from berm and dune due to high waves and surge is a universal phenomenon associated with sporadic storm activities. To protect the development in a coastal hazard zone, hard structures or coastal setback have been established in many countries around the world. In this paper, the requirement of a storm beach buffer, being a lesser extent landward comparing with the coastal setback to ensure the safety of infrastructures, is numerically assessed using the SBEACH model for three categories of wave conditions in terms of storm return period, median sand grain size, berm width, and design water level. Two of the key outputs from the numerical calculations, berm retreat and bar formation offshore, are then analysed, as well as beach profile change. After having performed a series of numerical studies on selected large wave tank (LWT) test results with monochromatic waves using SBEACH, we may conclude that: (1) Berm erosion increases and submerged bar develops further offshore as the storm return period increases for beach with a specific sand grain size, or as the sand grain reduces on a beach under the action of identical wave condition; (2) Higher storm waves yield a large bar to form quicker and subsequently cause wave breaking on the bar crest, which can reduce the wave energy and limit the extent of the eroding berm; (3) A larger buffer width is required for a beach comprising small sand grain, in order to effectively absorb storm wave energy; and (4) Empirical relationships can be tentatively proposed to estimate the storm beach buffer width, from the input of wave conditions and sediment grain size. These results would benefit a beach nourishment project for shore protection or design of a recreational beach.

Headland-bay beach (HBB) is one of the most prominent physiographic features on the oceanic margin of many countries in the world. Under the influence of a predominant swell, its curved periphery in natural environment may reach static equilibrium and remains stable without sediment supply from updrift and/or a riverain source within its own embayment. Coastal scientists and engineers have attempted to develop mathematical expressions to quantify this ideal bay shape since the 1940s. As the scenario with depleting sediment supply has become a common reality on many parts of the world coastline in more recent time, some coastal engineers have advocated a rational approach to mimicking the static bay shape found in nature in order to mitigate beach erosion as well as for coastal management. Nowadays, many useful applications have emerged since the publication of the parabolic bay shape equation (PBSE) developed for static equilibrium planform (SEP) in late 1980s. The advance in modern computer technologies and international collaboration has further facilitated the exchange of knowledge and applications of this static bay beach concept (SBBC). This paper reviews the progress on the research in HBB made by geographers and geologists since the 1940s, together with the involvement of coastal engineers working on shore protection and management from the 1960s. Aided by software MEPBAY developed in 2003 for the PBSE, several practical examples are demonstrated in this paper for the stability verification of natural and man-made bay beaches, shore protection, mitigating downdrift erosion of a harbour, design of recreational bay beach, as well as for environmental impact assessment. Limitations on and clarifications for engineering applications based on the SBBC are also discussed in this paper.

BACKGROUND. S-1 is a promising oral fluoropyrimidine. The authors obtained extended Phase II safety and efficacy data in a multicenter setting for the S-1 plus cisplatin combination: The experimental arm of the global Phase III First-Line Advanced Gastric Cancer Study (FLAGS) is being compared with 5-fluorouracil/cisplatin. METHODS. Eligible patients had untreated, histologically confirmed advanced gastric cancer (AGC), a Karnofsky performance status (KPS) ≥70%, adequate organ function, and provided written consent. Patients received S-1 (25 mg/m2 twice daily on Days 1 through 21) plus cisplatin (75 mg/m2 on Day 1) every 28 days. The confirmed overall response rate (CORR) also was designated by an external review. The time to progression (TTP), median survival (MS), and safety were assessed. RESULTS. All 72 patients were assessed for safety and survival, and 64 patients were assessed for CORR. The median KPS was 90%. The median number of treatment cycles was 4. The CORR was 55% (95% confidence interval [95% CI], 42–67%). The median duration of response was >5 months. At 6 months, only an estimated 38% of patients had cancer progression. The estimated MS was 10.4 months (95% CI, 8.6–12.9 months). At least 1 serious adverse event occurred in 44% of patients. The frequent grade 3 or 4 toxicities (using the National Cancer Institute Common Toxicity Criteria), which occurred in >10% of patients, included fatigue/asthenia (24%), emesis (17%), nausea (15%), diarrhea (13%), and neutropenia (19%). Complicated neutropenia (1.4%) and grade 4 diarrhea (1.4%) were rare. CONCLUSIONS. The current extended data confirmed that S-1 combined with cisplatin had a highly desirable safety profile. The efficacy against AGC, according to an external review, was encouraging. FLAGS is expected to complete its accrual of 1050 patients by December 2007. Cancer 2007. © 2006 American Cancer Society.

Aims To develop a systematic generic method of enabling patients to report symptoms which they believe to be due to a particular prescribed drug. Methods A piloted body system-based questionnaire was distributed to patients registered with 79 medical practices in Grampian prescribed one of nine recently marketed ‘black triangle’ drugs. These comprised four antidepressants, three antiepileptics and two analgesics. This requested respondents to identify any symptoms experienced over the previous year which they thought could be due to the ‘black triangle’ drug they had used. A sample of medical records was examined to compare symptoms recorded with those reported by patients. A classification system was developed for the study to enable the assessment of symptoms reported for their potential relationship to patients' drug therapy. All symptoms reported were classified, taking into account information provided by patients on their concomitant drugs and diseases. A specialist pharmacist independently re-classified a sample of the symptoms to validate the process. Results A 36.3% response rate was obtained (837/2307) with 742 respondents (88.6%) reporting at least one symptom. The median per patient was 6.0 (range 0–71), with almost half (406, 48.5%) reporting fewer than five symptoms. Most symptoms (71.0%) were classified as being probably or possibly related to the drugs studied. Agreement between researcher and specialist on the classification of 75.3% of 716 symptoms was obtained (Kappa=0.563). Responses from patients prescribed antidepressant drugs were more likely to include symptoms potentially caused by these drugs (74.5% of all symptoms reported) than those from patients prescribed analgesics (67.4%) or antiepileptics (65.1%, χ2 = 23.858, d.f. = 2, P

Background: Angiotensin Converting Enzyme inhibitors reduce mortality in heart failure. One therapeutic mechanism is believed to be the reduction of circulating angiotensin II and aldosterone. However, the Renin–Angiotensin–Aldosterone axis (RAAS) is not uniformly suppressed during therapy for heart failure. This effect has been referred to as ‘angiotensin II reactivation’ and ‘aldosterone escape’ and their reactivation may herald clinical deterioration. In the CONSENSUS I trial, correlations were seen between mortality, and angiotensin II and aldosterone. Furthermore, mortality was lower in those with good angiotensin II suppression. Therefore, neurohormonal elevation despite adequate treatment may associate with a poorer prognosis. Aims: To follow chronic heart failure patients on ACE inhibitors for 18 months to assess whether or not angiotensin II and aldosterone reactivation are progressive with time, whether reactivation of both occurs simultaneously, and whether different ACE inhibitors have different neurohormonal profiles. Methods and results: We studied 22 patients (M/F 19:3, 72.5 ± 7 years) on stable ACE inhibitors. Five times, in 18 months, samples were taken for neurohormones and ACE activity. Mean levels of neurohormones were remarkably stable over time, although captopril takers had generally higher angiotensin II, but lower aldosterone and renin. Aldosterone ‘escape’ (> 80 pg/ml) occurred in 13/97 samples (13.5%), in 5/22 (23%) individuals. Angiotensin II was elevated ≥10 pg/ml in 8/102 samples (8%), in 6/22 (27%) individuals. Four subjects had isolated angiotensin II reactivation, and three had aldosterone escape alone. On regression analyses between neurohormones in captopril takers there were significant correlations between; renin and angiotensin II (r = 0.62; P < 0.02); angiotensin II and aldosterone (r = 0.6; P < 0.02); and renin and aldosterone (r = 0.92; P < 0.00001). Conclusion: In stable heart failure patients un-suppressed levels of angiotensin II and aldosterone occur despite therapy, but they are not necessarily progressive, nor simultaneous. Furthermore, contemporaneous serum ACE activity makes it unlikely the data presented reflects poor compliance. The results suggest that captopril takers may have different neurohormonal profiles, i.e. higher angiotensin II, and also better correlations between RAAS components, compared to longer acting preparations, although the numbers are small. Our data supports that of Swedberg et al. who showed reductions in both aldosterone and angiotensin II due to ACE inhibitor therapy, but no correlation between ACE activity and angiotensin II and only a limited correlation (r = 0.37) between angiotensin II and aldosterone. This suggests that the interaction between the components of the renin–angiotensin system is not simple and linear. The fact that each phenomenon appears to occur in isolation means that neurohormonal monitoring of individual could provide useful information to direct additional therapy. The RALES study has demonstrated reduced mortality from the addition of spironolactone to an ACE inhibitor emphasising the benefit of enhanced suppression of aldosterone in heart failure. Captopril may be less effective at suppressing the RAAS due to its short duration of action which would logically be associated with a more fluctuating pattern of ACE inhibition. In the presence of high levels of renin and angiotensin I even small differences in ACE activity will produce large variations in angiotensin II levels. Further studies should be directed at understanding the different mechanisms behind angiotensin II and aldosterone generation during ACE inhibition.

Aims We wished to see if renin release in man was inhibited by nitric oxide blockade, suggesting a role for nitric oxide in renin release. Evidence from animal studies has shown variable effects on renin release depending on the model and stimulus used. Methods Ten normal male volunteers, received either l-NMMA as a front loaded infusion (4 mg kg−1 bolus, with 4 mg kg−1 infusion), or placebo, followed by an intravenous bolus of 5 mg frusemide to stimulate renin. To investigate whether any alteration in renin release was due to the pressor effect of the l-NMMA, the experiment was repeated using an equipressor dose of phenylephrine (0.5 μg kg−1 min−1 ). Results l-NMMA caused the expected increase in mean arterial pressure (96±2.6 vs 89±3.3 mmHg P

Aims The aim of this study was to examine whether nitric oxide (NO) has an important role in maintaining basal vascular tone in normal man by examining the effects of nitric oxide inhibition using NG-monomethyl-l-arginine (l-NMMA) on systemic and pulmonary haemodynamics. Methods Ten normal male volunteers 26±1.6 years were studied on two separate occasions in a double-blind, placebo controlled crossover study. They were randomised to receive either a continuous infusion of l-NMMA (4 mg kg−1 h−1 ) with a front loaded bolus (4 mg kg−1 ) or volume matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Measurements were made prior to infusion (t0 ) and after 4, 8, and 12 min (t1, t2 and t3 ). Results Infusion of l-NMMA significantly increased mean arterial blood pressure (MAP), SVR and TPR and significantly reduced heart rate (HR), stroke volume (SV) and CO compared to placebo. These effects were observed at t1 and persisted during the entire infusion period. Conclusions These results are consistent with a role for basal nitric oxide generation in the maintenance of basal systemic and pulmonary vascular tone in normal man.

Resonant-switch topologies operating under the principle of zero-current switching and zero-voltage switching are introduced to minimize switching losses, stresses and noises. Employing the resonant-switch concept, the family of quasi-resonant converters (QRCs) and the family of multiresonant converters (MRCs) are derived from the conventional PWM converters. They are capable of operating in megahertz range, with a significant improvement in performance and power density. Characteristics of these QRCs and MRCs are reviewed and their relative merits and limitations are assessed.

Purpose S-1 plus cisplatin is considered highly active in Japanese gastric cancer patients. We conducted a phase II multi-institutional trial, in the West, in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma to evaluate activity and safety of this combination. Methods Patients received cisplatin intravenously at 75 mg/m2 on day 1 and S-1 orally at 25 mg/m2/dose bid (50 mg/m2/d) on days 1 to 21, repeated every 28 days. Patients with histologic proof of gastric or gastroesophageal junction adenocarcinoma with a Karnofsky performance status (KPS) of ≥ 70% and near-normal organ function were eligible. All patients provided a written informed consent. To observe a 45% confirmed overall response rate (ORR), 41 assessable patients were needed. Results All 47 patients were assessed for safety and survival, and 41 patients were assessed for ORR. The median age was 56 years and median KPS was 80%. The median number of chemotherapy cycles was four. The confirmed ORR was 51% (95% CI, 35% to 67%) and it was 49% by an independent review. At the 6-month interval, 71% of patients were alive, with a median survival time of 10.9 months. Frequent grade 3 or 4 toxicities included fatigue (26%), neutropenia (26%), vomiting (17%), diarrhea (15%), and nausea (15%); however, stomatitis (2%) and febrile neutropenia (2%) were uncommon. There was one (2%) treatment-related death. Conclusion S-1 plus cisplatin is active against gastric cancer and has a favorable toxicity profile. A global phase III study of S-1 plus cisplatin versus fluorouracil plus cisplatin currently is accruing patients.

This Final Report compiles all the work carried out at the Center for Power Electronics Systems (CPES), corresponding to the "Standard-Cell, Open-Architecture Power Conversion Systems" project sponsored by the Office of Naval Research (ONR). This project was purposefully aimed to develop a standardized hierarchical design and analysis methodology for modular power electronics conversion systems using as basis the ISO/OSI seven-layer reference model. The foundational ideas of this engineering vision came from the Power Electronics Building Block (PEBB), seeking to expand the usage of this concept while exploiting the numerous advantages offered by it, namely modularity, scalability, reconfiguration and reduced design cycles. The means to the end chosen was the actual embracing of the hierarchical nature of PEBB-based converters by applying it to the modeling approach, control software, and energy processing characterization of power electronics systems. The resultant two-dimensional hierarchical reference model pursues the complete analysis and design of power electronics systems, covering not only the electromagnetic, thermal and mechanical interactions from semiconductors up to complete power systems, but also their associated controls, modeling and communications at every hierarchy level. In order to achieve these objectives several tasks were identified and undertaken in this project. Specifically, several studies were conducted in order to fully characterize the energy processing functions observed in shipboard power systems, individually addressing the PEBB, power converter and power system levels. The PEBB level -- using a CPES built 33 kW PEBB -- was subjected to a complete study describing it across all defined hierarchies, i.e., energy processing, controls and modeling. Further, the complete design and evaluation of its digital controller (Hardware Manager) is also presented, thus fully characterizing the controls hierarchy at this level.

Disaster management plans of emergency departments (EDs) in four major public hospitals were reviewed. A comparison was made between these plans, and they were analyzed to gain an understanding of the differing objectives and doctrines behind the practices. These were summarized into five major management concepts, which are considered to be critical to the success of a disaster plan: 1) staff mobilization systems (cascading vs batch mobilization); 2) staff deployment systems; 3) team organization (surgeons vs residents); 4) area management (the role of the area manager); 5) casualty volume management (accommodation vs expansion vs extension concepts). The concepts derived should serve as a useful guide to the development of an ED disaster plan and potentially influence how new ED facilities could be planned.

OBJECTIVE—Angiotensin II (AII) and aldosterone are not always fully suppressed during chronic angiotensin converting enzyme (ACE) inhibitor treatment. In congestive heart failure (CHF) such failure of hormonal suppression is associated with increased mortality. This study examined how common AII and aldosterone increases are observed during routine clinical practice. PATIENTS AND METHODS—91 patients with symptomatic (mean New York Heart Association class 2.7) CHF (mean (SD) left ventricular ejection fraction 29.9 (8)%, range 9-46%) were studied 4-6 hours after ACE inhibitor dosing. A representative range of ACE inhibitors (enalapril, lisinopril, captopril, perindopril, and fosinopril) was examined. RESULTS—Supine measurements showed a wide range of AII (10.5 (25.5) pg/ml), aldosterone (130.8 (136) pg/ml), and serum ACE (12.1 (13.3) EU/l; excludes captopril data) concentrations on diuretics. AII concentrations > 10 pg/ml were seen in 15% of patients, and aldosterone concentrations > 144 pg/ml were seen in 38% of patients. AII concentrations were significantly correlated (p

Background NICE guidance recommends risk stratification of patients presenting to chest pain clinics using the Pryor score. The Pryor score calculates a risk for a significant (>50%) coronary stenosis. This score influences which imaging modality to select to confirm or refute the presence of coronary artery disease (CAD) with patients with a risk score of 10–29% undergoing CT calcium scoring ±CT coronary angiography, 30–59% non-invasive functional testing and 60% or more invasive coronary angiography. Aim This study evaluates the accuracy of the Pryor risk score in predicting significant coronary artery disease in patients presenting to a rapid access chest pain clinic (RACPC) undergoing either CT evaluation or invasive angiography. Design Retrospective analysis of prospectively collected clinical data. Methods Data was collected by coronary CT report analysis, and coronary angiogram data base review of patients referred from the RACPC in our Trust from January 2011 to October 2012. Significant coronary disease was confirmed if the reporting consultant recorded a stensosis of 50% or more. Pryor scores were calculated at the time of initial attendance by the nurse specialist using a standardised Pryor risk calculator circulated by the Cardiovascular Network. Statistical analysis was carried out using the χ 2 test. Results In the study period 228 patients underwent CT assessment, one of whom had a non diagnostic study and was excluded. Of the 227, 168 underwent calcium scoring only, and 59 had subsequent CT coronary angiography reflecting the NICE recommendation of undertaking CT angiography in those patients with a calcium score in the range 1–400. Table 1 shows the distribution of patients with and without significant diseaase in the NICE recommended calcium scoring categories. The mean Pryor score for this patient group was 21.8% In the whole group, 17/227 (7.4%) had significant CAD compared to 210/227 (92.5%) who had no significant CAD (p The invasive angiography group was taken from the data base of a single consultant during the same time period. 81 patients were referred from the RACPC for this investigation with a mean Pryor score of 75%. Only 45 of these patients (55.5%) had significant CAD (p Discussion Our study shows that the Pryor risk score significantly overpredicts the prevalence of significant coronary artery disease in our patient population. The number of patients with significant CAD, undergoing calcium scoring and CT angiography was much lower than that expected and the same was also true of the higher risk invasive angiography group. A significant proportion of those referred for calcium scoring were found to have minor coronary disease. However, NICE may need to alter its guidance to improve clinical effectiveness.

There is recent interest in the possibility that angiotensin converting enzyme inhibitors (ACE inhibitors) may reduce the damage inflicted on the arterial wall by common cardiovascular risk factors such as hypertension, hyperlipidaemia and ageing. The efficacy of these drugs in blood pressure reduction is accepted, but whether there is an excess benefit on arterial structure and function, conferred by use of ACE inhibitors over more traditional antihypertensives, is still under debate. There is also evidence in animal models to suggest that ACE inhibition is effective in reduction of arterial damage due to experimental hyperlipidaemia. ACE inhibitors not only reduce the conversion of angiotensin I and angiotensin II, which can interact with the sympathetic nervous system, but also prevent the degradation of bradykinin. This means that ACE inhibitors have several potential mechanisms through which they could suppress intimai hypertrophy and prevent endothelial dysfunction, which is believed to precede arteriosclerosis in man. Although much further work is needed to clarify the mechanism underlying the beneficial effects on the arterial wall of this group of drugs, they do appear to have significant potential in the effort to reduce cardiovascular mortality and morbidity, especially in high risk groups.

Reengineering is an industrial method for rethinking and redesigning basic business processes in order to improve performance and lower cost. Just as many of the corporate clients of managed behavioral healthcare companies go through reengineering initiatives, behavioral healthcare needs to streamline its production processes, in order to deliver services that are high quality but affordable. Traditional, cumbersome, bureaucratic and labor-intensive work processes must be reexamined. This article reviews basic principles of reengineering in the context of the evolving managed behavioral healthcare industry, defines ten core processes for managed behavioral healthcare companies and then illustrates how reengineering methods can be applied to two intermediate processes: "manage access" and "manage network."

3091 Background: INCB028060 is a potent and selective inhibitor of c-MET receptor tyrosine kinase (RTK). This first-in-human study aims to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and potential efficacy of INCB028060. Methods: In a standard 3+3 escalation, patients (pts) age =18 years with advanced solid tumors are treated with INCB028060 orally once (QD) or twice daily on a continuous 28-day schedule. C-MET inhibition is evaluated by adding c-MET overexpressing SNU-5 human gastric cancer cells to pts whole blood and then analyzing for inhibition of phospho-c-MET by ELISA. Results: At this time 17 pts have been treated across dose levels of 10, 20, 50, and 70 mg/once daily. Median age is 63 years, median ECOG PS is 0, and the most common tumor types are colorectal (4), NSCLC (3), and prostate/HCC/cholangiocarcinoma (2 each). One pt with breast cancer and diffuse liver metastases treated at 50 mg QD developed grade 3 AST elevation on C1D22, having had grade ...

e14117 Background: Achieving complete pathological response (CPR) with neoadjuvant chemoradiation may predict a higher likelihood of long-term survival in patients with operable rectal cancer. Howe...

Managed mental health has evolved from company-run employee assistance programs and a few specialty utilization review firms to a mind-boggling array of specialists. New developments portend a more comprehensive, measurable and aggressively interventionist industry in the making.

15180 Background: For metastatic pancreatic cancer, no combination chemotherapy has been shown to improve survival significantly in comparison to single agent gemcitabine. A novel combination with oxaliplatin 60 mg/m2, irinotecan 90 mg/m2, cetuximab 250 mg/m2 (OIC) given every two weeks appears to produce a high rate of radiographic response. Since our reporting (ASCO 2007 GI Conference), we continue to see a high rate of clinical and radiographic responses (50% by Recist Criteria). We therefore decided to look carefully on the survival data of OIC versus control (mainly gemcitabine single agent or in combination with other agents). Methods: We retrospective reviewed patients seen from 10/2002 to 10/2006 with diagnosis of metastatic pancreatic cancer. The survival duration was calculated from the date of diagnosis to the date of death. We included only patients whose dates of death could be confirmed with death certificates. Results: A total of 37 patients were identified. 11 of those were in the OIC arm and 26 were treated with other regimens (17 with gemcitabine-based regimens, 9 with either capecitabine or 5-FU-based regimens) that function as control. The range of survival duration was 4 - 28 months for OIC arm and 1 - 28 months for the control. Median survival was 10 months for the OIC arm versus 5 months for the control. Conclusions: OIC regimen produces a high rate of tumor response and may have a survival advantage with this retrospective analysis. We believe it is a regimen deserves further evaluation. No significant financial relationships to disclose.

3592 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. This phase I study assesses the safety, tolerability and pharmacokinetics (PK) of SU in combination with capecitabine (C). Methods: Pts with advanced solid tumors not amenable to curative therapy, previously treated with =2 prior chemotherapy regimens, and ECOG PS =1 were eligible. Prior antiangiogenic therapy was not permitted. Three SU schedules were evaluated: 4 wks on treatment followed by 2 wks off in 6-wk cycles (4/2 schedule); 2 wks on followed by 1 wk off in 3-wk cycles (2/1 schedule), and continuous dosing (CD schedule). In all cases C was administered orally bid on days 1–14. SU and C doses were alternately escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) of SU for all schedules using a standard 3 + 3 design. PK and antitumor efficacy were also assessed. Results: A total of 50 pts have been enrolled; 28 pts have been treated on the 4/2 schedule: SU 50 mg + C 1,000 mg/m2, and SU 37.5 mg + C 1,250 mg/m2 were not tolerated. Dose limiting toxicities (DLTs) included: grade 3 myalgia (n=1), grade 3 fatigue (n=2), and grade 3 hand- foot syndrome (n=2). The MTD for the 4/2 schedule was SU 37.5 mg/day + C 1,000 mg/m2. No DLTs nor dose reductions were observed among 9 pts treated at the MTD. Preliminary PK data do not indicate drug-drug interactions between SU and C. 3 pts (1 each with breast cancer, neuroendocrine carcinoma, and thyroid carcinoma) achieved confirmed partial responses. On the 2/1 schedule patients are being accrued to SU 37.5 or 50 mg + C 1,000 mg/m2 and doses of SU 37.5 mg + C 1,000 mg/m2 or SU 25 mg + C 1,250 mg/m2 are being explored on the CD schedule. Conclusions: The combination of SU 37.5 mg/day (4/2 schedule) with C 1,000 mg/m2 in pts with advanced solid tumors appears tolerable. SU may be administered in combination with C with no apparent drug-drug interaction. Subsequent cohorts will define the MTD of SU administered on the 2/1 and CD schedules. Further studies of this combination in breast cancer are warranted. No significant financial relationships to disclose.

10056 Background: The combination of G and D has shown efficacy against refractory STS (Hensley, JCO 2002). STS have a high content of VEGF, which is associated with poor prognosis. This phase I/II study assesses the safety, tolerability, efficacy, and pharmacodynamics (PD) of B in combination with G+D, given on a two-weekly schedule to minimize adverse events (AEs). We are reporting the phase I results. Methods: Untreated pts with advanced or recurrent STS and ECOG PS =2 were eligible. Some pts were treated in a neoadjuvant setting, when surgically appropriate. Planned doses were G 1,000, 1,250, and 1,500 mg/m2, D 50 mg/m2, and B 5 mg/kg iv, every 2 wks. G doses were escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) of G with fixed doses of D and B. MTD was assessed on the first 2 cycles (1 cycle = 2 wks). Treatment was continued until progression or unacceptable toxicity. For neoadjuvant therapy, B was given only for 4 cycles, followed by 4 cycles without B in anticipation of surgery and pts came off study at that point. PD and antitumor efficacy were also assessed. Results: Nine pts have been treated on the phase I escalation arm, including 3 in the neoadjuvant setting. There were no dose limiting toxicities. After 4 cycles with G at 1,500 mg/m2, there was 1 asymptomatic grade 4 bowel perforation at the site of the tumor in a pt with initially inoperable leiomyosarcoma (LMS). After emergency surgery, the pt is free of disease. Observed grade 1 and 2 AEs include alopecia, diarrhea, fatigue (5 each), rigors (4), nausea, dyspnea, headaches (3 each), chest pain, epistaxis, stomatitis, anemia (2 each), rash, hypertension, neuropathy, leukopenia (1 each). There were 1 CR (angiosarcoma), 2 PR, (myxoid sarcoma, undifferentiated sarcoma), 4 NC (2 LMS, liposarcoma, PNST), and 2 PD (myxoid sarcoma, PNST). Necrosis was observed, including in NC disease. Three pts are free of disease after surgery. Conclusions: The combination of G, D, and B given every 2 weeks is safe and has demonstrated some activity in pts with advanced or recurrent STS. The phase II arm is ongoing at G 1,500 mg/m2 with 4 pts already enrolled. Mature data including PD will be reported at the meeting. No significant financial relationships to disclose.

4083 Background: We obtained additional phase II safety and efficacy data in a multi-center setting on an active regimen of S-1 plus cisplatin; the experimental arm of the global phase III First-Line Advanced Gastric cancer Study (FLAGS). Methods: Eligible patients had untreated advanced gastric cancer (AGC), histologic proof, KPS ≥70%, adequate organ function, and gave written consent. Patients received S-1 (25mg/m2 p.o. bid on days 1–21) plus cisplatin (75mg/m2 i.v. on day 1) every 28 days. All reported confirmed overall response rate (C-ORR), response durations, and time-to-progression (TTP) are externally reviewed. Results: All 72 patients were assessed for safety and 64 for efficacy. The median age was 56 years and median KPS was 90%. Median no. of cycles was 4. C-ORR was 50% (95% CI, 37%-63%). Median duration of response is >6 months. At 6 months, only 35% of patients have had cancer progression. Median survival (n=72) is 10.5 months (95% CI, 9.3 to NR). At least one SAE occurred in 43% of patients. The frequent grade 3 or 4 adverse events (occurring in >10% of patients) included: fatigue/asthenia (26%), vomiting (21%), nausea (18%), diarrhea (17%), neutropenia (18%), anorexia (11%), and dehydration (11%). Febrile neutropenia (1.4%) and grade 4 diarrhea (1.4%) were rare. Conclusions: These extended data confirm that S-1 plus cisplatin has a very desirable safety profile and impressive efficacy data in AGC. FLAGS will complete accrual of >700 patients by March of 2007. (Supported by Taiho Pharma-USA). [Table: see text]

13099 Background: Flavopiridol is a cyclin-dependent kinase (CDK) inhibitor. The major toxicities are secretory diarrhea and neutropenia for the 72- and 1-hour infusion schedules, respectively, fatigue, and thrombosis. Gemcitabine or irinotecan (SN-38) followed by flavopiridol at concentrations that correlate with CDK inhibition, produce sequence-dependent cytotoxic synergy with increase in apoptosis by 10–15-fold in all the cell lines tested. Both gemcitabine and irinotecan have broad activity in a number of solid tumors and may be synergistic with flavopiridol. Methods: Eligibility criteria included: patients (pts) with any advanced solid tumors; >18 years old; PS ≤ 2; life expectancy > 3 months; and normal kidney, liver, and marrow functions. Treatment consisted in gemcitabine 800 mg/m2 and irinotecan 80 mg/m2 on day 1 and flavopiridol, starting dose of 30 mg/m2 on day 2 with increment of 15 mg/m2 per dose level, repeated on days 8 and 9 for the first 6 patients, then on days 15 and 16 for the other patients (protocol was amended for inability to redose after one week). Results: Fifteen pts (12 women and 3 men) were enrolled. Characteristics were: Median age, 49 (33–77) years; Median PS 1; ethnicities, 6 whites, 3 native americans, 3 hispanics, and 3 others; Median number of prior chemotherapies, 2 (0–9). Six pts were treated on the first schedule at the first dose level, which caused 1 neutropenic sepsis and death, 1 grade 3 diarrhea, and 5 neutropenia preventing retreatment. On the q 2 week schedule, we have reached the second dose level. Side effects at flavopiridol 30 mg/m2 were all grade 1: nausea (3/3), fatigue (2/3), anorexia (1/3), and neuropathy (1/3). At 45 mg/m2 one heavily pretreated pt had DLT of diarrhea and fatigue. The other 5 pts had grade 2 fatigue (2/5), nausea (2/5), diarrhea (1/5), anorexia (1/5). Additional grade 1 side effects include thrombocytopenia, pitting edema, and pain. Response were seen a small cell tumor of the ovary, and a leiomyosarcoma of the uterus. Conclusions: The every two week dosing is well tolerated and the MTD has not yet been reached. Main side effects are consistent with known toxicity profile for irinotecan and gemcitabine. Mild pitting edema and sensory neuropathy have been noted in 2 patients each. No significant financial relationships to disclose.

14135 Background: Gemcitabine-based chemotherapy is considered standard approach for patients with metastatic pancreatic cancer but the results remain unsatisfactory with survival averaging about 6 to 10 months. Cell line study indicates more than 90% of pancreatic cancer cells express EGFR receptor. We therefore explore the use of non-gemcitabine-containing regimen and add an EGFR inhibitor. Method: We initiated a regimen with irinotecan 120 mg/m2, oxaliplatin 85 mg/m2, and cetuximab 400 mg/m2 first dose followed by 250 mg/m2 for all subsequent doses delivered every 14 days for patients with metastatic pancreatic cancer. Results: From 1/2005 to 12/2005, a total of 5 patients were treated. Two males and three females, age 59 to 78. Three presented with metastatic disease. One had Whipple’s procedure then had disease recur 2 months post-surgery. One had locally advanced disease and progressed 10 months after concurrent chemoradiation. Grade III/IV neutropenia, anemia developed in 1/5 patients. Grade III/IV diarrhea and nausea/vomiting developed in 3/5 patients. Grade III/IV fatigue, anorexia developed in 4/5 patients. The non-hematologic toxicity was the main reason for dose reduction. 4 had CT scan for response evaluation. The fifth patient completed first cycle of treatment on 1/3/2006 and had CA19–9 dropped from 15,900 to 9,398 u/ml (40% decline). By CT scan, partial response rate is 75% as shown in the table. So far, two patients have died, 5 and 10 months since initiating treatment, one from recurrent hepatic abscess and one from fungus infection. Conclusions: This combination delivered every other week appears promising for patients with metastatic pancreatic cancer. The planned phase II trial will adopt a lower dose approach with irinotecan 90 mg/m2, oxaliplatin 60 mg/m2, and cetuximab 250 mg/m2. [Table: see text] No significant financial relationships to disclose.

14126 Background: Patients with metastatic biliary cancers continue to face a very grim prognosis with no effective chemotherapy. Median survival is around 6–9 months. Irinotecan and capecitabine have modest activity against cholangiocarcinoma. Cyclooxygenase-2 (COX-2) enzyme expression is reported in many human cholangiocarcinoma cell line studies and is linked to tumor cell resistance to chemotherapy-induced apoptosis. We hypothesized that adding a COX-2 inhibitor would improve the therapeutic benefits in patients with biliary tumors. Methods: From 9/2003 to 2/2005, a total of 12 patients were treated with a combination regimen, delivered at a cycle interval of 21 days, that consisted of 120 mg/m2 irinotecan given intravenously over 60 minutes on day 1, 1500 mg/m2/day capecitabine taken orally in divided doses on days 1–14 and 400 mg/day celecoxib taken orally in divided doses on days 1–21. Results: A total of 117 treatments were administered to the 12 patients (9 females and 3 males; median age, 56 years; 10 cholangiocarcinoma and 2 gallbladder cancer). Based on the tumor marker CA19–9, 7 of the patients had a partial response (7/12, 58%). Of the seven patients for which sequential CT evaluation was available, the partial response rate was 43% (3/7) and two additional patients had stable disease. The median progression-free survival was 13 months and the median overall survival was 17 months. We encountered grade II neutropenia and anemia (2/12 each, 17%) and grade I diarrhea and hand-foot syndrome (33% and 7%, respectively). Conclusions: These data suggest that the combination of irinotecan, capecitabine and celecoxib is an effective palliative regimen for patients with metastatic biliary cancers. Further development of this regimen is severely hindered by the potential cardiovascular risk associated with long-term use of COX-2 inhibitor. No significant financial relationships to disclose.

3744 Background: Concurrent neoadjuvant chemoradiation in operable rectal cancer seeks to: decrease tumor burden; increase chance for sphincter-sparing surgery; and demonstrate tumor response to se...

4265 Background: There is no known effective chemotherapy regimen for patients with unresectable/metastatic cholangiocarcinoma. We are here to report a single institution, retrospective chart revie...

4024 Background: A Phase I study of S-1 (tegafur, oxonic acid, and CDHP) plus cisplatin performed in Western patients defined the MTD (S-1 50mg/m2/d taken orally on d 1–21 and cisplatin 75 mg/m2 gi...

2114 Purpose: 5-Fluorouracil (5-FU) has been shown to modulate DNA repair activity. This study tests (1) what is the maximum tolerated dose of capecitabine (C) given for 10 days prior to cisplatin (P) and irinotecan (I); (2) the changes in DNA repair induced by C. Patients and Methods: Patients (pt) with incurable cancers were eligible if they had normal hematologic, renal and liver functions, and had not failed 5-FU analogs or topoisomerase I inhibitors. The first cycle was P+I day 1 and I day 8 and 15, 50 mg/m2 each, to serve as control. C was started at the second cycle at a dose of 500 mg/m2/day x 10 days for the first cohort prior to P+I, which was administered on day 11, 18, and 25. Increments were by 250 mg/m2/cohort. A 3+3 design was used. Blood was drawn for DNA repair studies before the first 3 cycles and before cisplatin for the first 2 cycles. DNA repair analyses will be performed by measuring the residual cisplatin concentrations in DNAs collected from these patients. Patients stayed on study...

3161 Background:Since the approval of thalidomide by the FDA in 1998, there has been wide off-label use in oncology based on its purported cytokine modulating and anti-angiogenesis properties. We c...

4239 Background: With highly active anti-retroviral therapy, HIV-positive patients are living longer. Increased incidence of anal squamous cell carcinoma (ASCC) has been noted in these patients. Op...

Endothelial function is defective in hypercholesterolaemia, and animal models have suggested that angiotensin-converting enzyme inhibitors may prevent arterial damage. We studied the effect of 6 months treatment with lisinopril on endothelial function in a group of patients with hypercholesterolaemia. Forty patients were studied. Forearm blood flow responses to acetylcholine and sodium nitroprusside were assessed by venous occlusion plethysmography. Subjects were then randomized in a double-blind fashion to receive either lisinopril, 20 mg/day (n = 20), or placebo (n = 20) for 6 months. Plethysmography was then repeated. Baseline variables between groups were comparable. In the lisinopril group blood pressure fell significantly [systolic: 145±4 to 128±4 mmHg (P< 0.001); diastolic: 84±2 to 74±2 mmHg (P< 0.001)]. An improvement was found in the vasodilatory response (expressed as a ratio of the infused/control arm) to acetylcholine, e.g. 3.33±0.3 (pre) versus 4.45±0.48 (post) at 30 μg/ml (P< 0.03), and also to nitroprusside, e.g. 3.0±0.2 (pre) versus 3.86±0.3 (post) at 3.2 μg/ml (P< 0.01). In the placebo group vasodilatation did not change significantly in response to acetylcholine, and nitroprusside responses were unchanged. The data presented suggest that 6 months of lisinopril therapy have a beneficial effect on arterial function in subjects with hyperlipidaemia. Further work should now investigate whether angiotensin-converting enzyme inhibitors are beneficial in reducing mortality and morbidity in hypercholesterolaemia.

Moist tracking characteristics were determined for different classes of organic insulators, varying the electrolytes and electrolyte concentrations, conductor material, spacings, and temperature. The nature and concentration of an electrolyte and the conductor material were found to have a major influence upon an insulator's moist tracking behavior; the effect of conductor spacing was less pronounced, whereas temperature, up to 160°C, had a minimal effect only. Tracking was invariably associated with combustion. In agreement with prediction, aromatic polymers were observed to track at relatively low voltages, whereas compositions which decomposed by eatilization required high voltages to effect tracking. The response of a given insulator to changes in electrolyte, conductor material, and spacing appeared to depend solely on the chemical nature of the major constituent or constituents; the latter includes fillers.

Ethanol extract of Panax ginseng C. A. Meyer, which has been used for centuries as a tonic in Asian countries, exhibited a selective induction of epoxide hydratase and cytosolic glutathione transferase activity without the concurrent induction of aryl hydrocarbon hydroxylase activity. Thus, Panax ginseng appears to have the potential to alter the metabolic patterns of benzo(a)pyrene and its reactive metabolites.

State space techniques are employed to derive accurate models for buck, boost, and buck/boost converter power stages operating with and without zero-inductor-current dwell time. A generalized procedure is developed which treats the continuous-inductor-current mode without the dwell time as a special case of the discontinuous-current mode, when the dwell time vanishes. An abrupt change of system behavior including a reduction of the system order when the dwell time appears is shown both analytically experimentally.