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4606 Background: Preclinical studies have indicated that TP is one of the most useful markers of tumor response to capecitabine; with elevated TP expression resulting in higher intratumor levels of 5-FU. TP level in the tumor may be associated directly with survival and may be up-regulated by XRT. Methods: Twenty patients (pts) who had newly diagnosed locally advanced pancreatic cancer, age ≥ 19 years, ECOG PS 0–2, and adequate organ function received 50.4 Gy XRT with capecitabine 1,600 mg/m2 M-F x 6 wks determined from our phase I study (JCO, Dec 2005). Following capecitabine-XRT, stable and responding pts received capecitabine 2,000mg/m2 x 14 days every 3 wks till progression. Restaging was performed every 9 wks. Tumor specimens were procured with EUS-FNA prior and week 2 after starting capecitabine-XRT to evaluate TP mRNA levels by RT-PCR. Results: TP levels were elevated post-XRT when compared to pre-XRT TP (p= 0.01). Each of the 20 pts had at least one observation of TP. Mean TP level of each pt was obtained by averaging the pre-XRT and post-XRT TP levels. If one value was missing, then the other value was used for the mean TP level. Mean TP level was significantly associated with survival using the Cox proportional hazards model (p= 0.0072). Pts were separated into two groups - those with high baseline TP level and those with lower TP level with a cut off value of 213.85 using median of mean TP level. It was observed that group with higher TP levels had better survival as compared to the group with lower TP levels. However, the survival curves of these two groups crossed over after 18 months. Conclusions: Our study suggests that the higher the TP level in tumor post-XRT, the better the survival. This is most probably due to a higher accumulation of 5-FU in tumor due to up-regulation of TP. Possible explanation for the two groups crossing over after 18 months may include heterogeneity in TP due to a difference in pharmacogenomics or idiosyncratic drug toxicity profile of capecitabine. Further studies of long-term effects of treatment with a larger number of pts are needed to study exact effects of capecitabine and XRT, and to evaluate the differential role of TP with survival. [Table: see text]

BACKGROUNDIncreased susceptibility to 5‐fluorouracil (5‐FU)/capecitabine can lead to rapidly occurring toxicity caused by impaired clearance, dihydropyrimidine dehydrogenase deficiency, and other genetic variations in the enzymes that metabolize 5‐FU. Life‐threatening 5‐FU overdoses occur because of infusion pump errors, dosage miscalculations, and accidental or suicidal ingestion of capecitabine. Uridine triacetate (Vistogard) was approved in 2015 for adult and pediatric patients who exhibit early‐onset severe or life‐threatening 5‐FU/capecitabine toxicities or present with an overdose. Uridine triacetate delivers high concentrations of uridine, which competes with toxic 5‐FU metabolites.METHODSIn 2 open‐label clinical studies, patients who presented with a 5‐FU/capecitabine overdose or an early onset of severe toxicities were treated. Patients received uridine triacetate as soon as possible (most within the first 96 hours after 5‐FU/capecitabine). Outcomes included survival, resumption of chemotherapy, and safety. Their survival was compared with the survival of a historical cohort of overdose patients who received only supportive care.RESULTSA total of 137 of 142 overdose patients (96%) treated with uridine triacetate survived and had a rapid reversal of severe acute cardiotoxicity and neurotoxicity; in addition, mucositis and leukopenia were prevented, or the patients recovered from them. In the historical cohort, 21 of 25 patients (84%) died. Among the 141 uridine triacetate–treated overdose patients with a diagnosis of cancer (the noncancer patients included 6 intentional or accidental pediatric overdoses), 53 resumed chemotherapy in < 30 days (median time after 5‐FU, 19.6 days), and this indicated a rapid recovery from toxicity. Adverse reactions in patients receiving uridine triacetate included vomiting (8.1%), nausea (4.6%), and diarrhea (3.5%).CONCLUSIONSIn these studies, uridine triacetate was a safe and effective lifesaving antidote for capecitabine and 5‐FU overexposure, and it facilitated the rapid resumption of chemotherapy. Cancer 2017;123:345–356. © 2016 American Cancer Society.

Background: In the initial PARTNER trial (Placement of Aortic Transcatheter Valves) of transcatheter aortic valve replacement for high-risk (HR) and inoperable patients, mortality at 1 year was 24% in HR and 31% in inoperable patients. A recent report of the 30-day outcomes with the low-profile SAPIEN 3 transcatheter aortic valve replacement system demonstrated very low rates of adverse events, but little is known about the longer-term outcomes with this device. Methods: Between October 2013 and September 2014, 583 HR (65%) or inoperable (35%) patients were treated via the transfemoral (84%) or transapical/transaortic (16%) access route at 29 US sites. Major clinical events at 1 year were adjudicated by an independent clinical events committee, and echocardiographic results were analyzed by a core laboratory. Results: Baseline characteristics included age of 83 years, 42% female, and median Society of Thoracic Surgeons score of 8.4%. At the 1-year follow-up, survival (all-cause) was 85.6% for all patients, 87.3% in the HR subgroup, and 82.3% in the inoperable subgroup. Survival free of all-cause and cardiovascular mortality in the transfemoral patients from the HR cohort was 87.7% and 93.3%, respectively. There was no severe paravalvular leak. Moderate paravalvular leak (2.7%) was associated with an increase in mortality at 1 year, whereas mild paravalvular leak had no significant association with mortality. Symptomatic improvement as assessed by the percentage of patients in New York Heart Association class III and IV (90.1% to 7.7% at 1 year; P <0.0001) and by Kansas City Cardiomyopathy Questionnaire overall summary score (improved from 46.9 to 72.4; P <0.0001) was marked. Multivariable predictors of 1-year mortality included alternative access, Society of Thoracic Surgeons score, and disabling stroke. Conclusions: In this large, adjudicated registry of SAPIEN 3 HR and inoperable patients, the very low rates of important complications resulted in a strikingly low mortality rate at 1 year. Between 30 and 365 days, the incidence of moderate paravalvular aortic regurgitation did not increase, and no association between mild paravalvular leak and 1-year mortality was observed, although a small increase in disabling stroke occurred. These results, which likely reflect device iteration and procedural evolution, support the use of transcatheter aortic valve replacement as the preferred therapy in HR and inoperable patients with aortic stenosis. Clinical Trial Registration : URL: http://www.clinicaltrials.gov . Unique identifier: NCT01314313.

BackgroundTranscatheter aortic valve replacement (TAVR) with the balloon‐expandable Sapien transcatheter heart valve improves survival compared to standard therapy in patients with severe aortic stenosis (AS) and is noninferior to surgical aortic valve replacement (AVR) in patients at high operative risk. Nonetheless, a significant proportion of patients may require pre‐emptive or emergent support with cardiopulmonary bypass (CPB) and/or intra‐aortic balloon pump (IABP) during TAVR due to pre‐existing comorbid conditions or as a result of procedural complications. Objectives: We hypothesized that patients who required CPB or IABP would have increased periprocedural complications and reduced long‐term survival. In addition, we sought to determine whether preprocedural variables could predict the need for CPB and IABP. Methods: The study population included 2,525 patients in the PARTNER Trial (Cohort A and B) and the continuing access registry (CAR). Patients that received CPB or IABP were compared to patients that did not receive either, and then further divided into those that received support pre‐TAVR and those that were placed on support emergently. Results: One‐hundred sixty‐three patients (6.5%) were placed on CPB and/or IABP. The use of CPB or IABP was associated with higher 1 year mortality (49.1% vs. 21.6%, P < 0.001). In multivariable analysis, utilization of CPB or IABP was an independent predictor of 30 day (HR 6.95) and 1‐year (HR 2.56) mortality. Although mortality was highest in emergent cases, mortality was also greater in planned CPB and IABP cases compared with non‐CPB/IABP cases (53.3% and 40.3% vs. 21.6%, P < 0.001). Conclusions: These findings indicate that CPB and IABP use in TAVR portends a poor prognosis and its utilization, particularly in the setting of pre‐emptive use, needs reconsideration. © 2015 Wiley Periodicals, Inc.

Background —Although prompt treatment is a cornerstone of the management of acute myocardial infarction (AMI), prior studies have shown that one fourth of AMI patients arrive at the hospital >6 hours after symptom onset. It would be valuable to identify individuals at highest risk for late arrival, but predisposing factors have yet to be fully characterized. Methods and Results —Data from the Cooperative Cardiovascular Project, involving Medicare beneficiaries aged >65 years hospitalized between January 1994 and February 1996 with confirmed AMI, were used to identify patients who presented “late” (≥6 hours after symptom onset). Patient characteristics were tested for associations with late presentation by use of backward stepwise logistic regression. Among 102 339 subjects, 29.4% arrived late. Significant predictors of late arrival (odds ratio, 95% CI) included diabetes (1.11, 1.07 to 1.14) and a history of angina (1.32, 1.28 to 1.35), whereas prior MI (0.82, 0.79 to 0.85), prior angioplasty (0.80, 0.75 to 0.85), prior bypass surgery (0.93, 0.89 to 0.98), and cardiac arrest (0.52, 0.46 to 0.58) predicted early presentation. Additionally, initial evaluation at an outpatient clinic (2.63, 2.51 to 2.75) and daytime presentation (1.67, 1.59 to 1.72) predicted late arrival. Finally, female sex, black race, and poverty, which were evaluated with an 8-level race–sex–socioeconomic status interaction term, were also risk factors for delay. Conclusions —Delayed hospital presentation is a common problem among Medicare beneficiaries with AMI. Factors associated with delay include not only clinical and logistical issues but also race, sex, and socioeconomic characteristics. Education efforts designed to hasten AMI treatment should be directed at individuals with risk factors for late arrival.