Elizabeth Koehler

Phase I Study of Intravenous Vascular Endothelial Growth Factor Trap, Aflibercept, in Patients With Advanced Solid Tumors

PURPOSE Vascular endothelial growth factor (VEGF) Trap (aflibercept) is an angiogenesis inhibitor comprising portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of VEGF Trap administered intravenously (IV) every 2 weeks. PATIENTS AND METHODS Patients with refractory solid tumors or non-Hodgkins lymphoma with adequate organ function were eligible. Pharmacokinetic/pharmacodynamic markers included measurement of plasma VEGF bound to VEGF Trap and free VEGF Trap. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was incorporated to measure the biologic effects of the drug on tumor vascularity and permeability. RESULTS The study enrolled 47 patients at doses ranging from 0.3 to 7.0 mg/kg IV every 2 weeks. Dose-limiting toxicities were rectal ulceration and proteinuria at the 7.0 mg/kg dose. Other mechanism-specific toxicities included hypertension. On the basis of these observations and on pharmacokinetics, the recommended phase II dose of VEGF Trap as a single agent is 4 mg/kg every 2 weeks. Three RECIST (Response Evaluation Criteria in Solid Tumors) -defined partial responses were observed, one at the 3.0 mg/kg and two at the 7.0 mg/kg dose level. Maximum plasma concentration of free VEGF Trap increased proportionally with dose. Maximal VEGF-bound VEGF Trap complex levels were reached at doses > or = 2.0 mg/kg. Changes in volume transfer constant measured by DCE-MRI at baseline and at 24 hours after administration indicate a possible dose-related change in this pharmacodynamic marker. CONCLUSION IV VEGF Trap was well tolerated at the dose levels tested. Pharmacodynamic and pharmacokinetic markers were indicative of VEGF blockade.

Prehospital statin and aspirin use and the prevalence of severe sepsis and acute lung injury/acute respiratory distress syndrome.

Objectives: To determine whether prehospital statin use is associated with a lower risk of sepsis, acute lung injury/acute respiratory distress syndrome, and mortality in critically ill patients. We also investigated the effect of combined prehospital use of both statins and aspirin. Design: Cross-sectional analysis of a prospective cohort. Patients: A total of 575 critically ill patients admitted to the medical or surgical intensive care unit of an academic tertiary-care hospital. Interventions: None. Measurements and Main Results: Of 575 patients, 149 (26%) were on statin therapy before hospitalization. A multivariable analysis including age, gender, current tobacco use, prehospital aspirin use, race, and Acute Physiology and Chronic Health Evaluation II score revealed that patients on statin therapy before hospitalization were less likely to have or develop severe sepsis (odds ratio 0.62, 95% confidence interval 0.40–0.96) or acute lung injury/acute respiratory distress syndrome (odds ratio 0.60, 95% confidence interval 0.36–0.99) during the first four intensive care unit days. In-hospital mortalities for patients with and without prehospital statin use (odds ratio 1.06, 95% confidence interval 0.62–1.83) were similar. Patients who had prehospital use of both statins and aspirin had the lowest rates of severe sepsis, acute lung injury/acute respiratory distress syndrome, and mortality. Conclusions: Prehospital use of statins may be protective against sepsis and acute lung injury. This effect may be potentiated by prehospital aspirin use.

On the Assessment of Monte Carlo Error in Simulation-Based Statistical Analyses.

Statistical experiments, more commonly referred to as Monte Carlo or simulation studies, are used to study the behavior of statistical methods and measures under controlled situations. Whereas recent computing and methodological advances have permitted increased efficiency in the simulation process, known as variance reduction, such experiments remain limited by their finite nature and hence are subject to uncertainty; when a simulation is run more than once, different results are obtained. However, virtually no emphasis has been placed on reporting the uncertainty, referred to here as Monte Carlo error, associated with simulation results in the published literature, or on justifying the number of replications used. These deserve broader consideration. Here we present a series of simple and practical methods for estimating Monte Carlo error as well as determining the number of replications required to achieve a desired level of accuracy. The issues and methods are demonstrated with two simple examples, one evaluating operating characteristics of the maximum likelihood estimator for the parameters in logistic regression and the other in the context of using the bootstrap to obtain 95% confidence intervals. The results suggest that in many settings, Monte Carlo error may be more substantial than traditionally thought.

Body mass index and blood pressure changes over the course of treatment of pediatric acute lymphoblastic leukemia.

Obesity and hypertension are reported among survivors of pediatric acute lymphoblastic leukemia (ALL). However, little is known about the trajectory of body mass index (BMI) and blood pressure over the course of ALL therapy.

Hypothyroidism as a Consequence of Intensity-Modulated Radiotherapy With Concurrent Taxane-Based Chemotherapy for Locally Advanced Head-and-Neck Cancer

PURPOSE To conduct a retrospective review of 168 consecutively treated locally advanced head-and-neck cancer (LAHNC) patients treated with intensity-modulated radiotherapy (IMRT)/chemotherapy, to determine the rate and risk factors for developing hypothyroidism. METHODS AND MATERIALS Intensity-modulated radiotherapy was delivered in 33 daily fractions to 69.3 Gy to gross disease and 56.1 Gy to clinically normal cervical nodes. Dose-volume histograms (DVHs) of IMRT plans were used to determine radiation dose to thyroid and were compared with DVHs using conventional three-dimensional radiotherapy (3D-RT) in 10 of these same patients randomly selected for replanning and with DVHs of 16 patients in whom the thyroid was intentionally avoided during IMRT. Weekly paclitaxel (30 mg/m(2)) and carboplatin area under the curve-1 were given concurrently with IMRT. RESULTS Sixty-one of 128 evaluable patients (47.7%) developed hypothyroidism after a median of 1.08 years after IMRT (range, 2.4 months to 3.9 years). Age and volume of irradiated thyroid were associated with hypothyroidism development after IMRT. Compared with 3D-RT, IMRT with no thyroid dose constraints resulted in significantly higher minimum, maximum, and median dose (p < 0.0001) and percentage thyroid volume receiving 10, 20, and 60 Gy (p < 0.05). Compared with 3D-RT, IMRT with thyroid dose constraints resulted in lower median dose and percentage thyroid volume receiving 30, 40, and 50 Gy (p < 0.005) but higher minimum and maximum dose (p < 0.005). CONCLUSIONS If not protected, IMRT for LAHNC can result in higher radiation to the thyroid than with conventional 3D-RT. Techniques to reduce dose and volume of radiation to thyroid tissue with IMRT are achievable and recommended.

A Phase I Trial of Bortezomib with Temozolomide in Patients with Advanced Melanoma: Toxicities, Antitumor Effects, and Modulation of Therapeutic Targets

Purpose: Preclinical studies show that bortezomib, a proteasome inhibitor, blocks NF-κB activation and, combined with temozolomide, enhances activity against human melanoma xenografts and modulates other critical tumor targets. We initiated a phase I trial of temozolomide plus bortezomib in advanced melanoma. Objectives included defining a maximum tolerated dose for the combination, characterizing biomarker changes reflecting inhibition of both proteasome and NF-κB activity in blood (if possible tumor), and characterizing antitumor activity. Experimental Design: Cohorts were enrolled onto escalating dose levels of temozolomide (50-75 mg/m2) daily, orally, for 6 of 9 weeks and bortezomib (0.75-1.5 mg/m2) by i.v. push on days 1, 4, 8, and 11 every 21 days. Peripheral blood mononuclear cells were assayed at specified time points for proteasome inhibition and NF-κB biomarker activity. Results: Bortezomib (1.3 mg/m2) and temozolomide (75 mg/m2) proved to be the maximum tolerated dose. Dose-limiting toxicities included neurotoxicity, fatigue, diarrhea, and rash. Nineteen melanoma patients were enrolled onto four dose levels. This melanoma population (17 M1c, 10 elevated lactate dehydrogenase, 12 performance status 1-2) showed only one partial response (8 months) and three with stable disease ≥4 months. A significant reduction in proteasome-specific activity was observed 1 hour after infusion at all bortezomib doses. Changes in NF-κB electrophoretic mobility shift assay and circulating chemokines in blood failed to correlate with the schedule/dose of bortezomib, inhibition of proteasome activity, or clinical outcome. Conclusions: We have defined phase II doses for this schedule of temozolomide with bortezomib. Although proteasome activity was inhibited for a limited time in peripheral blood mononuclear cells, we were unable to show consistent effects on NF-κB activation. Clin Cancer Res; 16(1); 348–57

Cardiovascular Medication Use and Risk for Colorectal Cancer

Objective: To evaluate the association between lipid-lowering agents, antihypertensive medications, and colorectal cancer risk. We hypothesized a reduction in colorectal cancer risk with 3-hydroxy-3-methylglutaryl coA reductase inhibitors (statins) and angiotensin-converting enzyme inhibitors. Methods: We conducted a case-control study at Group Health Cooperative, an integrated delivery system in Washington State. Incident colorectal cancer cases diagnosed between January 1, 2000, and December 31, 2003, were identified from the western Washington Surveillance, Epidemiology, and End Results cancer registry. Controls were matched by age, sex, and duration of enrollment. Data on medication use and potential confounders were obtained from health plan records. We estimated odds ratios and 95% confidence intervals (95% CI) using multivariate conditional logistic regression. Results: Risk for colorectal cancer was not associated with use of statins (odds ratio, 1.02; 95% CI, 0.65-1.59), other lipid-lowering agents (odds ratio, 1.31; 95% CI, 0.70-2.47), angiotensin-converting enzyme inhibitors (odds ratio, 0.98; 95% CI, 0.67-1.43), calcium channel blockers (odds ratio, 1.06; 95% CI, 0.72-1.55), or diuretics (odds ratio, 1.00; 95% CI, 0.70-1.44). Risk did not differ by duration of medication use, including long-term use. Conclusions: Risk for colorectal cancer was not reduced by use of statins or angiotensin-converting enzyme inhibitors. Other lipid-lowering and antihypertensive medications were also not associated with colorectal cancer risk. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3076–80)

Driving with an Arm Immobilized in a Splint: A Randomized Higher-Order Crossover Trial

BACKGROUND The aim of this study was to determine whether immobilization of an arm has detrimental effects on driving performance. METHODS Thirty-six healthy officers-in-training were assigned a sequence of fiberglass splints (left and right-sided above-the-elbow thumb spica and below-the-elbow splints) with use of a randomized higher-order crossover design. Runs were scored on a cone-marked driving course used for officer certification with predetermined passing requirements. Driving time, the number of cones hit per course section, and the cone-adjusted total time (a five-second penalty per hit cone) were recorded. A linear mixed-effect model with random environmental and learning effects for cone-adjusted time analysis was used. Participants rated perceived driving difficulty and safety with each splint, and ratings were compared with the Wilcoxon signed-rank test. RESULTS Thirty participants completed the entire set of runs. Analysis of total cone-adjusted time revealed a significant performance decrease with the left arm in an above-the-elbow thumb spica splint (average, 22.2 seconds; p < 0.001) and with the left arm in a below-the-elbow splint (average, 16.2; p = 0.007). Analysis of forward-only course sections revealed poorer performance trends with all splints, with the worst performance with the left arm in an above-the-elbow thumb spica splint. Driving with the left arm in an above-the-elbow thumb spica splint had the highest perceived difficulty (median, 8.0) and lowest perceived safety (median, 3.0). CONCLUSIONS Driving performance as measured with a standardized track and scoring system was significantly degraded with splint immobilization of the left arm. Further studies are required to determine the effect of arm immobilization on normal driving conditions.

Radiographic Outcomes of Volar Locked Plating for Distal Radius Fractures

PURPOSE To assess the ability of volar locked plating to achieve and maintain normal radiographic parameters for articular stepoff, volar tilt, radial inclination, ulnar variance, and radial height in distal radius fractures. METHODS We performed a retrospective review of 185 distal radius fractures that underwent volar locked plating with a single plate design over a 5-year period. We reviewed radiographs and recorded measurements for volar tilt, radial inclination, ulnar variance, radial height, and articular stepoff. We used logistic regression to determine the association between return to radiographic standard norms and fracture type. RESULTS At the first and final postoperative follow-up visits, we observed articular congruence less than 2 mm in 92% of fractures at both times. Normal volar tilt (11°) was restored in 46% at the first follow-up and 48% at the final one. Radial inclination (22°) was achieved in 44% at the first follow-up and 43% at the final one, and ulnar variance (01 ± 2 mm) was achieved in 53% at the first follow-up and 53% at the final one. In addition, radial height (14 ± 1mm) was restored in 14% at the first follow-up and 12% at the final one. More complex, intra-articular fractures (AO class B and C and Frykman types 3, 4, 7, and 8) were less likely to be restored to normal radiographic parameters. However, because of the small sample size for some fracture types, it was difficult to discover significant associations between fracture type and radiographic outcome. CONCLUSIONS Volar locked plating for distal radius fractures achieved articular stepoff less than 2 mm in most fractures but only restored and maintained normal radiographic measurements for volar tilt, radial inclination, and ulnar variance in 50% of fractures. The ability of volar locked plating to restore and maintain ulnar variance and volar tilt decreased with more complex intra-articular fracture types. TYPE OF STUDY/LEVEL OF EVIDENCE Therapeutic IV.

Assessing gonadal function after childhood ovarian surgery.

PURPOSE We aimed to assess the late effects of ovarian salvage or oophorectomy on gonadal function and fertility as measured by menstrual regularity. METHODS We performed a 10-year retrospective review of females aged 20 years or younger who required surgery to treat an ovarian disorder. A mail survey was distributed to these patients to evaluate the effects of ovarian surgery on menarche, menstrual regularity, and pregnancy. RESULTS A total of 180 females had surgery to treat an ovarian disorder. Eighty-six of these underwent unilateral oophorectomy (48%), whereas 94 (52%) had an ovary sparing procedure. Eighty-one patients (45%) returned completed surveys. Of the respondents, 44 had oophorectomy, and 37 had ovarian salvage. Ages of menarche were similar between surgical groups. Symptoms of menstrual irregularity differed most significantly according to painful menses (oophorectomy, 27.3%; salvage, 59.5%; P < .04). Interestingly, continuation of regular menses after surgery was higher in the oophorectomy group (oophorectomy, 70%; salvage, 15%; P = .013). CONCLUSIONS Unilateral oophorectomy does not appear to impair late gonadal function when compared with ovarian salvage. Surprisingly, oophorectomy appears to maintain more normal ovarian activity as estimated by menstrual regularity. Oophorectomy may be performed without apparent adverse effect on gonadal activity.