Faculty Bibliography

Background: Observation of the kinetics of tissue enhancement after the injection of a bolus of tracer has been used for the analysis of perfusion and related variables. In general, a gradient of concentration in the exchanging vascular compartment between the arterial and venous ends is represented in models via focus on maintaining the detailed balance between the advective and diffusive exchange processes. Conventionally, this is by considering the exchange in an Eulerian framework, based on considering the exchange within each compartment as a separate unit (e.g., tissue homogeneity (TH) model [1]). Herein, we present a Lagrangian approach to the exchange modeling, such that the blood flowing between compartments is considered as the primary unit, and, thereby, allowing for coarser discretization and more efficient calculations (Figure 1a). Methods: Eight patients (age 63 + 12 years) underwent first-pass perfusion (FPP) rest and regadenoson stress cardiac MRI (CMR) (3T scanner, Tim Trio, Siemens), followed by invasive coronary angiography. Images were obtained at 4 slice locations (the aortic root for the arterial input function (AIF) and 3 short-axis slices of the left ventricle for the wall) using a TurboFLASH readout with centric k-space reordering [2]. A proton density-weighted image was acquired for normalization [3]. Myocardial blood flow (MBF) (mL/g/min) and perfusion reserve index (MPRI) were calculated in endocardial and epicardial areas (total 32 segments) using our method by an expert in the field of MRI blinded to coronary angiography results. Results: The results of a representative patient (66 year old man) with history of hypertension, hyperlipidemia, Diabetes Mellitus and known coronary artery disease with prior stents on maximal medical therapy are shown in Figure 1b-f. Coronary angiography was performed via the right femoral artery and demonstrated severe triple-vessel disease with left to right collaterals (Figure 1b). First-pass CMR perfusion imaging demonstrates a delay!

PURPOSE: Chemoradiation after surgery for locally advanced gastric cancer improves overall and relapse-free survival compared with observation. However, locoregional recurrences remain high. Accordingly, we instituted this pilot/feasibility study, including intraperitoneal 5-fluoro-2'-deoxyuridine (IP FUDR) as part of the treatment. METHODS: Gastric/gastroesophageal junction adenocarcinoma stage Ib-IV (M0) patients who underwent R(0) resection were eligible and had IP catheters inserted at time of surgery. IP FUDR (3 g/dose/day) was given during study days 1-3 and 15-17 before combined 5-fluorouracil, leucovorin, and external beam radiation (45 Gy). Endpoints included toxicity, completion rate, locoregional recurrence, and survival. RESULTS: Twenty-eight patients (22 men) were enrolled from 2002-2006 at two institutions; their median age was 59.5 years. After R(0) resection, a median 22 (range, 8-102) lymph nodes were examined, and 22 patients had positive nodes. AJCC stages were IB (n = 8), II (n = 10), IIIA (n = 5), IIIB (n = 1), and IV (n = 4). Full-dose IP FUDR and chemoradiation treatment was completed in 20 and 25 patients, respectively. At nearly 4-year median follow-up, 11 patients were disease-free, 5 were alive with disease, 7 were dead of disease, and 1 was dead from other cause; 4 have been lost to follow-up. Recurrences were local in one, intra-abdominal in six, distant in two, multiple sites in two, and unknown in one. The median relapse-free survival is 65.3 months, and the median overall survival has not yet been reached. CONCLUSIONS: IP FUDR before chemoradiation after R(0) gastric cancer resection is well tolerated without compromising completion of postoperative adjuvant treatment. Larger randomized trials studying IP FUDR as part of gastric cancer multidisciplinary treatment are needed to prove efficacy in reducing regional recurrence and improving survival

BACKGROUND: . Unique identifier: NCT00798122

BACKGROUND: A substantial minority of patients with acute coronary syndromes (ACS) do not have a diameter stenosis of any major epicardial coronary artery on angiography ('no obstruction at angiography') of >/= 50%. We examined the frequency of this finding and its relationship to race and sex. HYPOTHESIS: Among patients with myocardial infarction, younger age, female sex and non-white race are associated with the absence of obstructive coronary artery disease at angiography. METHODS: We reviewed the results of all angiograms performed from May 19, 2006 to September 29, 2006 at 1 private (n = 793) and 1 public (n = 578) urban academic medical center. Charts were reviewed for indication and results of angiography, and for demographics. RESULTS: The cohort included 518 patients with ACS. There was no obstruction at angiography in 106 patients (21%), including 48 (18%) of 258 patients with myocardial infarction. Women were more likely to have no obstruction at angiography than men, both in the overall cohort (55/170 women [32%] vs 51/348 men [15%], P < 0.001) and in the subset with MI (29/90 women [32%] vs 19/168 men [11%], P < 0.001). Black patients were more likely to have no obstruction at angiography relative to any other subgroup (24/66 [36%] vs 41/229 [18%] Whites, 31/150 [21%] Hispanics, and 5/58 [9%] Asians, P = 0.001). Among women, Black patients more frequently had no obstruction at angiography compared with other ethnic groups (16/27 [59%] vs 17/59 [29%] Whites, 17/60 [28%] Hispanics, and 3/19 [6%] Asians, P = 0.001). CONCLUSIONS: A high proportion of a multiethnic sample of patients with ACS were found to have no stenosis >/= 50% in diameter at coronary angiography. This was particularly common among women and Black patients.

Previous studies have reported that left ventricular (LV) thrombus is a complication in 10-56% of ST-segment elevation acute anterior wall myocardial infarctions (AWMI). Data suggest that changes in acute myocardial infarction management such as early anticoagulation, thrombolysis, and most recently, primary percutaneous coronary intervention (PCI), may decrease thrombus occurrence. Early time to reperfusion has been shown to decrease mortality and improve LV function recovery. To determine if door-to-balloon time (DTBT) affects the incidence of LV thrombus, we retrospectively analyzed data on 43 consecutive patients who underwent successful PCI of a primary acute ST-segment elevation AWMI. Transthoracic echocardiography was performed for detecting LV thrombus and measuring LV ejection fraction (EF) within 5 days on all patients (average time: 2.17 days post event). Nineteen patients underwent PCI within 2 h of arrival to the Emergency Department (Group A, average 88 min) and 24 patients underwent PCI with DTBT of more than 2 h (Group B, average 193 min). Clinically significant LV thrombus was detected in 35% of all patients. The incidence of LV thrombus formation in Group A was not significantly different from that in Group B (42.1% vs. 29.0%, respectively; P = 0.52). The risk of LV thrombus was independent of in-hospital anticoagulation and medical management, peak enzyme levels, and LVEF but did relate to age (odds ratio = 1.96, 95% CI 1.03-3.73, P = 0.04 per decade). No embolic events in hospital were observed (average hospital stay 9.2 days). We conclude that the incidence of LV thrombus remains high despite PCI. Also, we find that DTBT in patients presenting with an ST-segment elevation AWMI does not affect the incidence of LV thrombus formation. Increased age, however, does appear to increase the risk of LV thrombus development.

Aberrant expression of vascular endothelial growth factor (VEGF) is associated with human prostate cancer (PCa) metastasis and poor clinical outcome. We found that both phosphorylation of cyclic AMP-responsive element-binding protein (CREB) and VEGF levels were significantly elevated in patient bone metastatic PCa specimens. A PCa ARCaP progression model demonstrating epithelial-to-mesenchymal transition exhibited increased CREB phosphorylation and VEGF expression as ARCaP cells became progressively more mesenchymal and bone-metastatic. Activation of CREB induced, whereas inhibition of CREB blocked, VEGF expression in ARCaP cells. CREB may regulate VEGF transcription via a hypoxia-inducible factor-dependent mechanism in normoxic conditions. Activation of CREB signaling is involved in the coordinated regulation of VEGF and may pre-dispose to PCa bone metastasis

Background: ChemoRT after surgery for locally advanced gastric cancer improves overall and relapse-free survival (OS and RFS) compared to observation (NEJM 2000,345:72530). However, loco-regional recurrences (>50%) remain high and we hypothesized that adding IP FUDR would further improve outcome. Methods: Patients (pts) ECOG performance status (PS) 02, gastric/gastroesphogeal(GEJ) adenocarcinoma stage Ib-IV (M0) undergoing R0 resection were eligible, and had insertion of IP catheters at surgery. IP FUDR(3gm/dose/day) was given on protocol days 1, 2, 3 and 15, 16, 17 prior to 5-FU/LV and external beam RT (45Gy) as in cited study. Simon 2-stage optimum design was used to demonstrate safety. Endpoints also included were loco-regional recurrence and survival. Results: 28 pts with gastric/GEJ adenocarcinoma (25/3) were enrolled from 2002 to 2006 at 2 institutions: median age 59.5 years (range 3981), M /F (21/7). R0 gastric resection was performed with dissection of median 22 (range 8102) lymph nodes(LN's). 22/28 pts were lymph node positive. Full dose IP FUDR was completed in 20/28 pts. 4 pts required dose reduction (1 for grade(gr) 2 hepatic enzyme elevation, 2 gr 2 neutropenia, 1 gr 4 neutropenia), 3 discontinued therapy (1 gr 3 abdominal pain, 1 GI abscess, and 1 bleeding arterial pseudoaneurysm). One pt received no IP treatment due to catheter failure. 24/28 pts completed chemoRT and had toxicity comparable to that previously reported in the Intergroup 0116 trial. At 26 month median follow up (range 2.843.4), of the 26 pts evaluable for response, 16 pts are NED, 6 alive with disease, 3 dead of disease, and 1 dead from other cause. 5 recurrences were intra-abdominal, 1 local, 2 distant, and 1 at multiple sites. At present analysis, the median RFS is 32.5 months. Conclusions: IP FUDR prior to chemoRT after R0 gastric cancer resection is well tolerated. A randomized study to test its role in reducing regional recurrence and improving outcome is warranted. (FDA Orphan Products grant# FD-R-215004)