Faculty Bibliography

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)

AIMS: To determine sensitivity and specificity of urine bile acid sulfate (UBAS) and non-sulfated urine bile acid (UBA) assays for detection of intrahepatic cholestasis of pregnancy (ICP). METHODS: Urine was collected prospectively from healthy and pruritic patients evaluated for ICP. Results were expressed as a ratio to urinary creatinine. RESULTS: Of 20 patients evaluated for ICP, 14 had confirmed ICP by serum testing and six had pruritus only. UBAS results were higher with ICP (P<0.001) and increased with gestational age in healthy controls. Adjusted for gestational age, the multiples of the median (MoM) were still higher (2.64+/-1.11, 1.05+/-0.54, P<0.001). The sensitivity was 100% and specificity 83% at 1.5 MoM in pruritic patients. UBA results were higher with ICP (23.0+/-9.8, 12.8+/-7.4, P<0.001), with sensitivity of 100% and specificity of 50% at 10.2 micromol/g cretinine. CONCLUSION: Urinary bile acids can detect or exclude ICP with serum abnormalities. Urine bile acid sulfates have higher specificity than non-sulfated urine bile acids at equivalent sensitivities, but co-detection of progestin sulfates is suspected

Longitudinal health-related quality of life data arise naturally from studies of progressive and neurodegenerative diseases. In such studies, patients' mental and physical conditions are measured over their follow-up periods and the resulting data are often complicated by subject-specific measurement times and possible terminal events associated with outcome variables. Motivated by the 'Predictor's Cohort' study on patients with advanced Alzheimer disease, we propose in this paper a semiparametric modeling approach to longitudinal health-related quality of life data. It builds upon and extends some recent developments for longitudinal data with irregular observation times. The new approach handles possibly dependent terminal events. It allows one to examine time-dependent covariate effects on the evolution of outcome variable and to assess nonparametrically change of outcome measurement that is due to factors not incorporated in the covariates. The usual large-sample properties for parameter estimation are established. In particular, it is shown that relevant parameter estimators are asymptotically normal and the asymptotic variances can be estimated consistently by the simple plug-in method. A general procedure for testing a specific parametric form in the nonparametric component is also developed. Simulation studies show that the proposed approach performs well for practical settings. The method is applied to the motivating example

Interval mapping using normal mixture models has been an important tool for analyzing quantitative traits in experimental organisms. When the primary phenotype is time-to-event, it is natural to use survival models such as Cox's proportional hazards model instead of normal mixtures to model the phenotype distribution. An extra challenge for modeling time-to-event data is that the underlying population may consist of susceptible and nonsusceptible subjects. In this article, we propose a semiparametric proportional hazards mixture cure model which allows missing covariates. We discuss applications to quantitative trait loci (QTL) mapping when the primary trait is time-to-event from a population of mixed susceptibility. This model can be used to characterize QTL effects on both susceptibility and time-to-event distribution, and to estimate QTL location. The model can naturally incorporate covariate effects of other risk factors. Maximum likelihood estimates for the parameters in the model as well as their corresponding variance estimates can be obtained numerically using an EM-type algorithm. The proposed methods are assessed by simulations under practical settings and illustrated using a real data set containing survival times of mice after infection with Listeria monocytogenes. An extension to multiple intervals is also discussed

Objective: Vaginal deliveries have been associated with pelvic organ prolapse and incontinence. The objective was to show whether markers of ischemia/reperfusion injury are dependent upon the mode of delivery and length of labor. Method: Complete venipuncture sets were obtained on 62 subjects. All samples collected were analyzed for serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). Lipid peroxidation was analyzed, using thiobarbituric acid reactive substances (TBARS), on a subset of 37 patients. Results: There was a significant increase in CPK from admission to 1 h postpartum and postpartum day 1 in vaginal delivery versus cesarean delivery. Longer second stages were associated with significant increases in CPK. There were no significant changes in either LDH or TBARS from admission to any other time point regardless of mode of delivery. Conclusion: Vaginal delivery and longer second stages were associated with a much greater increase in one of these injury markers

When censored time-to-event data are used to map quantitative trait loci (QTL), the existence of nonsusceptible subjects entails extra challenges. If the heterogeneous susceptibility is ignored or inappropriately handled, we may either fail to detect the responsible genetic factors or find spuriously significant locations. In this article, an interval mapping method based on parametric mixture cure models is proposed, which takes into consideration of nonsusceptible subjects. The proposed model can be used to detect the QTL that are responsible for differential susceptibility and/or time-to-event trait distribution. In particular, we propose a likelihood-based testing procedure with genome-wide significance levels calculated using a resampling method. The performance of the proposed method and the importance of considering the heterogeneous susceptibility are demonstrated by simulation studies and an application to survival data from an experiment on mice infected with Listeria monocytogenes