Objective:This study evaluated the nationwide trends in care and accompanied postoperative outcomes for patients with distal esophageal and gastro-esophageal junction cancer. Summary of Background... Show moreObjective:This study evaluated the nationwide trends in care and accompanied postoperative outcomes for patients with distal esophageal and gastro-esophageal junction cancer. Summary of Background Data:The introduction of transthoracic esophagectomy, minimally invasive surgery, and neo-adjuvant chemo(radio)therapy changed care for patients with esophageal cancer. Methods:Patients after elective transthoracic and transhiatal esophagectomy for distal esophageal or gastroesophageal junction carcinoma in the Netherlands between 2007-2016 were included. The primary aim was to evaluate trends in both care and postoperative outcomes for the included patients. Additionally, postoperative outcomes after transthoracic and tran-shiatal esophagectomy were compared, stratified by time periods. Results:Among 4712 patients included, 74% had distal esophageal tumors and 87% had adenocarcinomas. Between 2007 and 2016, the proportion of transthoracic esophagectomy increased from 41% to 81%, and neo-adjuvant treatment and minimally invasive esophagectomy increased from 31% to 96%, and from 7% to 80%, respectively. Over this 10-year period, postoperative outcomes improved: postoperative morbidity decreased from 66.6% to 61.8% (P = 0.001), R0 resection rate increased from 90.0% to 96.5% (P <0.001), median lymph node harvest increased from 15 to 19 (P <0.001), and median survival increased from 35 to 41 months (P = 0.027). Conclusion:In this nationwide cohort, a transition towards more neo-adju-vant treatment, transthoracic esophagectomy and minimally invasive surgery was observed over a 10-year period, accompanied by decreased postoperative morbidity, improved surgical radicality and lymph node harvest, and improved survival. Show less
Introduction: Weight loss prior to bariatric-metabolic surgery (BMS) is recommended in most bariatric centers. However, there is limited high-quality evidence to support mandatory preoperative... Show moreIntroduction: Weight loss prior to bariatric-metabolic surgery (BMS) is recommended in most bariatric centers. However, there is limited high-quality evidence to support mandatory preoperative weight loss. In this study, we will evaluate whether weight gain prior to primary BMS is related to lower postoperative weight loss.Methods: A retrospective analysis of prospectively collected data was performed. Preoperative weight loss (weight loss from start of program to day of surgery), postoperative weight loss (weight loss from day of surgery to follow-up), and total weight loss (weight loss from start of program to follow-up) were calculated. Five groups were defined based on patients' preoperative weight change: preoperative weight loss of >5 kg (group I), 3-5 kg (group II), 1-3 kg (group III), preoperative stable weight (group IV), and preoperative weight gain >1 kg (group V). Linear mixed models were used to compare the postoperative weight loss between group V and the other four groups (I-IV).Results: A total of 1928 patients were included. Mean age was 44 years, 78.6% were female, and preoperative BMI was 43.7 kg/m2. Analysis showed significantly higher postoperative weight loss in group V, compared to all other groups at 12, 24, and 36 months follow-up. Up to three years follow-up, highest total weight loss was observed in group I.Conclusion: Weight gain before surgery should not be a reason to withhold a bariatric-metabolic operation. However, patients with higher preoperative weight loss have higher total weight loss. Therefore, preoperative weight loss should be encouraged prior to bariatric surgery. Show less
Objective: This study investigated the patterns, predictors, and survival of recurrent disease following esophageal cancer surgery. Background: Survival of recurrent esophageal cancer is usually... Show moreObjective: This study investigated the patterns, predictors, and survival of recurrent disease following esophageal cancer surgery. Background: Survival of recurrent esophageal cancer is usually poor, with limited prospects of remission. Methods: This nationwide cohort study included patients with distal esophageal and gastroesophageal junction adenocarcinoma and squamous cell carcinoma after curatively intended esophagectomy in 2007 to 2016 (follow-up until January 2020). Patients with distant metastases detected during surgery were excluded. Univariable and multivariable logistic regression were used to identify predictors of recurrent disease. Multivariable Cox regression was used to determine the association of recurrence site and treatment intent with postrecurrence survival. Results: Among 4626 patients, 45.1% developed recurrent disease a median of 11 months postoperative, of whom most had solely distant metastases (59.8%). Disease recurrences were most frequently hepatic (26.2%) or pulmonary (25.1%). Factors significantly associated with disease recurrence included young age (<= 65 y), male sex, adenocarcinoma, open surgery, transthoracic esophagectomy, nonradical resection, higher T-stage, and tumor positive lymph nodes. Overall, median postrecurrence survival was 4 months [95% confidence interval (95% CI): 3.6-4.4]. After curatively intended recurrence treatment, median survival was 20 months (95% CI: 16.4-23.7). Survival was more favorable after locoregional compared with distant recurrence (hazard ratio: 0.74, 95% CI: 0.65-0.84). Conclusions: This study provides important prognostic information assisting in the surveillance and counseling of patients after curatively intended esophageal cancer surgery. Nearly half the patients developed recurrent disease, with limited prospects of survival. The risk of recurrence was higher in patients with a higher tumor stage, nonradical resection and positive lymph node harvest. Show less
Background Fluconazole is commonly used to treat or prevent fungal infections. It is typically used orally but in critical situations, IV administration is needed. Obesity may influence the... Show moreBackground Fluconazole is commonly used to treat or prevent fungal infections. It is typically used orally but in critical situations, IV administration is needed. Obesity may influence the pharmacokinetics and therapeutic efficacy of a drug. In this study, we aim to assess the impact of obesity on fluconazole pharmacokinetics given orally or IV to guide dose adjustments for the obese population. Methods We performed a prospective pharmacokinetic study with intensive sampling in obese subjects undergoing bariatric surgery (n = 17, BMI >= 35 kg/m(2)) and non-obese healthy controls (n = 8, 18.5 <= BMI < 30.0 kg/m(2)). Participants received a semi-simultaneous oral dose of 400 mg fluconazole capsules, followed after 2 h by 400 mg IV. Population pharmacokinetic modelling and simulation were performed using NONMEM 7.3. Results A total of 421 fluconazole concentrations in 25 participants (total bodyweight 61.0-174 kg) until 48 h after dosing were obtained. An estimated bioavailability of 87.5% was found for both obese and non-obese subjects, with a 95% distribution interval of 43.9%-98.4%. With increasing total bodyweight, both higher CL and V-d were found. Sex also significantly impacted V-d, being 27% larger in male compared with female participants. Conclusions In our population of obese but otherwise healthy individuals, obesity clearly alters the pharmacokinetics of fluconazole, which puts severely obese adults, particularly if male, at risk of suboptimal exposure, for which adjusted doses are proposed. Show less
Bariatric or weight-loss surgery is a popular option for weight reduction. Depending on the surgical procedure, gastric changes like decreased transit time and volume and increased pH, decreased... Show moreBariatric or weight-loss surgery is a popular option for weight reduction. Depending on the surgical procedure, gastric changes like decreased transit time and volume and increased pH, decreased absorption surface in the small intestine, decreased exposure to bile acids and enterohepatic circulation, and decreased gastrointestinal transit time may be expected. In the years after bariatric surgery, patients will also substantially lose weight. As a result of these changes, the absorption, distribution, metabolism and/or elimination of drugs may be altered. The purpose of this article is to report the general influence of bariatric surgery on oral drug absorption, and to provide guidance for dosing of commonly used drugs in this special population. Upon oral drug administration, the time to maximum concentration is often earlier and this concentration may be higher with less consistent effects on trough concentrations and exposure. Additionally, prescription of liquid formulations to bariatric patients is supported by some reports, even though the high sugar load of these suspensions may be of concern. Studies on extended-release medications result in an unaltered exposure for a substantial number of drugs. Also, studies evaluating the influence of timing after surgery show dynamic absorption profiles. Although for this group specific advice can be proposed for many drugs, we conclude that there is insufficient evidence for general advice for oral drug therapy after bariatric surgery, implying that a risk assessment on a case-by-case basis is required for each drug. Show less
Background Current studies mainly focus on total weight loss and comorbidity reduction. Only a few studies compare Quality of Life (QoL) after sleeve gastrectomy (SG) and Roux-en-Y gastric bypass ... Show moreBackground Current studies mainly focus on total weight loss and comorbidity reduction. Only a few studies compare Quality of Life (QoL) after sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). This study was conducted to examine the extent of improvement in QoL on different domains after primary bariatric surgery and compare these results to Dutch reference values. Methods The study included prospectively collected data from patients who underwent primary bariatric surgery in five Dutch hospitals. The RAND-36 questionnaire was used to measure the patient's QoL; preoperatively and twelve months postoperatively. Postoperative scores were compared to Dutch reference values, standardized for age, using t-test. A difference of more than 5% was considered a minimal important difference. A multivariate linear regression analysis was used to compare SG and RYGB on the extent of improvement, adjusted for case-mix factors. Results In total, 4864 patients completed both the pre- and postoperative questionnaire. Compared with Dutch reference values, patients postoperatively reported clinically relevant better physical functioning (RYGB + 6.8%), physical role limitations (SG + 5.6%; RYGB + 6.2%) and health change (SG + 77.1%; RYGB + 80.0%), but worse general health perception (SG - 22.8%; RYGB - 17.0%). Improvement in QoL was similar between SG and RYGB, except for physical functioning (beta 2.758; p-value 0.008) and general health perception (beta 2.607; p-value < 0.001) for which RYGB patients improved more. Conclusions SG and RYGB patients achieved a better postoperative score in physical functioning, physical role limitations and health change compared to Dutch reference values, and a worse score in general health perception. Show less
AIMS:For vancomycin treatment in obese patients, there is no consensus on the optimal dose that will lead to the pharmacodynamic target (AUC 400-700 mg*h L-1 ). This prospective study quantifies... Show moreAIMS:For vancomycin treatment in obese patients, there is no consensus on the optimal dose that will lead to the pharmacodynamic target (AUC 400-700 mg*h L-1 ). This prospective study quantifies vancomycin pharmacokinetics in morbidly obese and non-obese individuals, in order to guide vancomycin dosing in the obese.METHODS:Morbidly obese individuals (n=20) undergoing bariatric surgery and non-obese healthy volunteers (n=8) (total body weight (TBW) 60.0-234.6 kg) received a single vancomycin dose (obese: 12.5 mg kg-1 , maximum 2500 mg; non-obese: 1000 mg) with plasma concentrations measured over 48 hours (11-13 samples per individual). Modelling, internal validation, external validation using previously published data and simulations (n=9950 individuals, TBW 60-230 kg) were performed using NONMEM.RESULTS:In a three-compartment model, peripheral volume and clearance increased with TBW (both p<0.001), which was confirmed in the external validation. A dose of 35 mg kg-1 per day (maximum 5500 mg/day) resulted in a >90% target attainment (AUC>400 mg*h L-1 ) in individuals up to 200 kg, with corresponding trough concentrations of 5.7-14.6 mg L-1 (twice daily dosing). For continuous infusion, a loading dose of 1500 mg is required for steady state on day 1.CONCLUSIONS:In this prospective, rich sampling pharmacokinetic study, vancomycin clearance was well predicted using TBW. We recommend that in obese individuals without renal impairment, vancomycin should be dosed as 35 mg kg-1 per day (maximized at 5500 mg/day). When given over two daily doses, trough concentrations between 5.7-14.6 mg L-1 correspond to the target exposure in obese individuals. Show less
Purpose: Tobramycin is an aminoglycoside antibiotic of which the 24 h exposure correlates with efficacy. Recently, we found that clearance of the aminoglycoside gentamicin correlates with total... Show morePurpose: Tobramycin is an aminoglycoside antibiotic of which the 24 h exposure correlates with efficacy. Recently, we found that clearance of the aminoglycoside gentamicin correlates with total body weight (TBW). In this study, we investigate the full pharmacokinetic profile of tobramycin in obese and non-obese individuals with normal renal function.Methods: Morbidly obese individuals (n = 20) undergoing bariatric surgery and non-obese healthy volunteers (n = 8), with TBW ranging 57-194 kg, received an IV dose of tobramycin with plasma concentrations measured over 24 h (n = 10 per individual). Statistical analysis, modelling and simulations were performed using NONMEM.Results: In a two-compartment model, TBW was the best predictor for central volume of distribution (p < 0.001). For clearance, MDRD (de-indexed for body surface area) was identified as best covariate (p < 0.001), and was superior over TBW ((p < 0.05). Other renal function estimates (24 h urine GFR and de-indexed CKD-EPI) led to similar results as MDRD (all p < 0.001)).Conclusions: In obese and non-obese individuals with normal renal function, renal function estimates such as MDRD were identified as best predictors for tobramycin clearance, which may imply that other processes are involved in clearance of tobramycin versus gentamicin. To ensure similar exposure across body weights, we propose a MDRD-based dosing nomogram for obese patients. Show less
