Population pharmacokinetic analysis of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in adult patients with solid tumors.

PURPOSE: To identify sources of exposure variability for the tumor growth inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) using a population pharmacokinetic analysis. METHODS: A total 67 solid tumor patients at 2 centers were given 1 h infusions of 17-DMAG either as a single dose, daily for 3 days, or daily for 5 days. Blood samples were extensively collected and 17-DMAG plasma concentrations were measured by liquid chromatography/mass spectrometry. Population pharmacokinetic analysis of the 17-DMAG plasma concentration with time was performed using nonlinear mixed effect modeling to evaluate the effects of covariates, inter-individual variability, and between-occasion variability on model parameters using a stepwise forward addition then backward elimination modeling approach. The inter-individual exposure variability and the effects of between-occasion variability on exposure were assessed by simulating the 95 % prediction interval of the AUC per dose, AUC(0-24 h), using the final model and a model with no between-occasion variability, respectively, subject to the five day 17-DMAG infusion protocol with administrations of the median observed dose. RESULTS: A 3-compartment model with first order elimination (ADVAN11, TRANS4) and a proportional residual error, exponentiated inter-individual variability and between occasion variability on Q2 and V1 best described the 17-DMAG concentration data. No covariates were statistically significant. The simulated 95% prediction interval of the AUC(0-24 h) for the median dose of 36 mg/m(2) was 1,059-9,007 mg/L h and the simulated 95 % prediction interval of the AUC(0-24 h) considering the impact of between-occasion variability alone was 2,910-4,077 mg/L h. CONCLUSIONS: Population pharmacokinetic analysis of 17-DMAG found no significant covariate effects and considerable inter-individual variability; this implies a wide range of exposures in the population and which may affect treatment outcome. Patients treated with 17-DMAG may require therapeutic drug monitoring which could help achieve more uniform exposure leading to safer and more effective therapy.

Thirty-day mortality after bariatric surgery: independently adjudicated causes of death in the longitudinal assessment of bariatric surgery.

BACKGROUND: Mortality following bariatric surgery is a rare event in contemporary series, making it difficult for any single center to draw meaningful conclusions as to cause of death. Nevertheless, much of the published mortality data come from single-center case series and reviews of administrative databases. These sources tend to produce lower mortality estimates than those obtained from controlled clinical trials. Furthermore, information about the causes of death and how they were determined is not always available. The aim of the present report is to describe in detail all deaths occurring within 30 days of surgery in the Longitudinal Assessment of Bariatric Surgery (LABS). METHODS: LABS is a ten-center observational cohort study of bariatric surgical outcomes. Data were collected prospectively for bariatric surgeries performed between March 2005 and April 2009. All deaths occurring within 30-days of surgery were identified, and cause of death assigned by an independent Adjudication Subcommittee, blinded to operating surgeon and site. RESULTS: Six thousand one hundred eighteen patients underwent primary bariatric surgery. Eighteen deaths (0.3%) occurred within 30-days of surgery. The most common cause of death was sepsis (33% of deaths), followed by cardiac causes (28%), and pulmonary embolism (17%). For one patient cause of death could not be determined despite examination of all available information. CONCLUSIONS: This study confirms the low 30-day mortality rate following bariatric surgery. The recognized complications of anastomotic leak, cardiac events, and pulmonary emboli accounted for the majority of 30-day deaths.

Comparison of 30-day outcomes after non-LapBand primary and revisional bariatric surgical procedures from the Longitudinal Assessment of Bariatric Surgery study.

BACKGROUND: The goals were to compare the morbidity and mortality between primary and revisional bariatric surgery and to identify the clinical predictors of adverse outcomes among patients undergoing revisional surgery in the Longitudinal Assessment of Bariatric Surgery consortium. The study was multi-institutional at university hospitals in the United States. METHODS: Data from the LABS-1 (safety) cohort were analyzed, excluding primary gastric banding patients. A total of 3802 LABS-1 patients were included: 3577 who underwent primary surgery and 225 who underwent revisional surgery. The demographic, clinical, operative, and 30-day outcome data were compared between the 2 groups. A nonlinear mixed effects logit model was used to identify independent risk factors for adverse outcomes (death, deep vein thrombosis, pulmonary embolism, reintubation, reoperation, or discharge after 30 days). RESULTS: Compared with those undergoing revisional surgery, the primary surgery patients were younger (median age 44 versus 49 years, P <.0001) and more likely to be male (20.5% versus 12.7%, P = .006) and heavier (median body mass index 47.3 versus 41.2 kg/m(2), P <.0001) and to have more co-morbidities (P <.0001), including hypertension (56.0% versus 46.0%, P = .0044), diabetes (35.7% versus 20.0%, P <.0001), and sleep apnea (50.3% versus 27.2%, P <.0001). The operative time for the revisional procedures was longer (median 181 versus 135 min, P <.0001) and associated with greater blood loss (median 100 versus <50 mL, P <.0001). Adverse outcomes were more likely after revisional surgery (15.1% versus 5.3%, P <.0001, odds ratio 2.4, 95% confidence interval 1.6-3.6). After adjusting for patient characteristics previously shown to be associated with adverse outcomes, this difference remained statistically significant (odds ratio 2.3, 95% confidence interval 1.5-3.8). The 30-day mortality rate was similar in the 2 groups (.4%). CONCLUSION: Revisional surgery was performed without substantial mortality but with a greater incidence of adverse outcomes than was primary bariatric surgery.

The mini-fellowship concept: a six-week focused training program for minimally invasive bariatric surgery.

OBJECTIVE: To devise a six-week hands-on training program customized to meet the needs of practicing general surgeons. The aim of this program is to provide the required training experience that will bestow the knowledge and skill necessary to implement a successful practice in laparoscopic bariatric surgery. METHODS: Ten board-certified/board-eligible practicing general surgeons with no prior hands-on or formal training in laparoscopic bariatric surgery. We report on the participants training experience and the impact that the program had on their subsequent laparoscopic bariatric clinical activity. RESULTS: Ten surgeons completed training programs from 9/01 to 3/03. None of the trainees had prior experience in laparoscopic bariatric surgery. Program operative experience averaged 42 cases (range 29-66). Trainees were integrated into all preoperative and postoperative hospital and outpatient care on the service, including workshops and seminars. Seven graduates are in practice performing laparoscopic bariatric surgery and three are implementing new bariatric programs. The active surgeons report performing an average of 101 laparoscopic bariatric procedures (range 18-264) over a mean practice period of 10 months (range 4-16) CONCLUSION: A six-week focused mini-fellowship with hands-on operative and clinical participation enables practicing surgeons to acquire the skill and experience necessary to successfully implement a laparoscopic bariatric surgical practice.