First-line palliative systemic therapy alternated with oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy for unresectable colorectal peritoneal metastases: A single-arm phase II trial (CRC-PIPAC-II).

BACKGROUND: Palliative systemic therapy alternated with electrostatic precipitation oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (ePIPAC) has never been prospectively investigated in patients with unresectable colorectal peritoneal metastases (CPM). The CRC-PIPAC-II study aimed to assess safety, feasibility and efficacy of such bidirectional therapy. METHODS: This two-center, single-arm, phase II trial enrolled chemotherapy-naïve patients to undergo three treatment cycles, consisting of systemic therapy (CAPOX, FOLFOX, FOLFIRI, or FOLFOXIRI, all with bevacizumab) and oxaliplatin-based ePIPAC (92 mg/m2) with intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Primary outcome were major treatment-related adverse events. Secondary outcomes included minor events, tumor response, progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty patients completed 52 treatment cycles. Fifteen major events occurred in 7 patients (35 %): 5 events (33 %) related to systemic therapy; 5 (33 %) related to ePIPAC; and 5 (33 %) were biochemical events. No treatment-related deaths occurred. All patients experienced minor events, mostly abdominal pain, nausea and peripheral sensory neuropathy. After treatment, radiological, pathological, cytological, and biochemical response was observed in 0 %, 88 %, 38 %, and 31 % of patients respectively. Curative surgery was achieved in one patient. Median PFS was 10.0 months (95 % confidence interval [CI] 8.0-13.0) and median OS was 17.5 months (95 % CI 13.0-not reached). CONCLUSIONS: Combining palliative systemic therapy with oxaliplatin-based ePIPAC in patients with unresectable CPM was feasible and showed an acceptable safety profile. Treatment-induced response and survival are promising, yet further research is required to determine the additional value of ePIPAC to systemic therapy.

Using the BODY-Q to develop a prospective cohort of patients undergoing bariatric and body contouring surgery: A study protocol.

The BODY-Q is a patient-reported outcome measure designed to measure health-related quality of life, satisfaction with appearance and experience with healthcare in patients with obesity who undergo bariatric surgery and/or body contouring surgery after massive weight loss. The aim of this study is to collect long term PRO-data from patients living with obesity undergoing bariatric surgery, comparing patient undergoing or not undergoing body contouring surgery. This study will be a multicentre, prospective longitudinal cohort study with participation of three bariatric medical centres in the Netherlands. The BODY-Q will be used to measure the satisfaction with appearance and HRQL. Patients undergoing bariatric surgery, age >18 years and <65 years and who are able to read and understand Dutch can be included. All bariatric procedures are eligible for inclusion. Administration of the questionnaires will be done preoperatively for bariatric and body contouring surgery as well as at 3, 12, 24, 36, 48 and 60 months post-operatively. Patient-reported outcomes measurements are becoming more important with the shift to patient-centred healthcare. The collected longitudinal data can be helpful in determining the effectiveness and value of bariatric and body contouring surgery from the patient's perspective, and can contribute to patient tailored postoperative care.

Ciprofloxacin Pharmacokinetics After Oral and Intravenous Administration in (Morbidly) Obese and Non-obese Individuals: A Prospective Clinical Study.

BACKGROUND AND OBJECTIVE: Ciprofloxacin is a fluoroquinolone used for empirical and targeted therapy of a wide range of infections. Despite the increase in obesity prevalence, only very limited guidance is available on whether the ciprofloxacin dose needs to be adjusted when administered orally or intravenously in (morbidly) obese individuals. Our aim was to evaluate the influence of (morbid) obesity on ciprofloxacin pharmacokinetics after both oral and intravenous administration, to ultimately guide dosing in this population. METHODS: (Morbidly) obese individuals undergoing bariatric surgery received ciprofloxacin either orally (500 mg; n = 10) or intravenously (400 mg; n = 10), while non-obese participants received semi-simultaneous oral dosing of 500 mg followed by intravenous dosing of 400 mg 3 h later (n = 8). All participants underwent rich sampling (11-17 samples) for 12 h after administration. Non-linear mixed-effects modelling and simulations were performed to evaluate ciprofloxacin exposure in plasma. Prior data from the literature were subsequently included in the model to explore exposure in soft tissue in obese and non-obese patients. RESULTS: Overall, 28 participants with body weights ranging from 57 to 212 kg were recruited. No significant influence of body weight on bioavailability, clearance or volume of distribution was identified (all p > 0.01). Soft tissue concentrations were predicted to be lower in obese individuals despite similar plasma concentrations compared with non-obese individuals. CONCLUSION: Based on plasma pharmacokinetics, we found no evidence of the influence of obesity on ciprofloxacin pharmacokinetic parameters; therefore, ciprofloxacin dosages do not need to be increased routinely in obese individuals. In the treatment of infections in tissue where impaired ciprofloxacin penetration is anticipated, higher dosages may be required. TRIAL REGISTRATION: Registered in the Dutch Trial Registry (NTR6058).

Peritoneal metastases from colorectal cancer belong to Consensus Molecular Subtype 4 and are sensitised to oxaliplatin by inhibiting reducing capacity.

BACKGROUND: Peritoneal metastases (PM) in colorectal cancer (CRC) are associated with therapy resistance and poor survival. Oxaliplatin monotherapy is widely applied in the intraperitoneal treatment of PM, but fails to yield clinical benefit. We aimed to identify the mechanism(s) underlying PM resistance to oxaliplatin and to develop strategies overcoming such resistance. EXPERIMENTAL DESIGN: We generated a biobank consisting of 35 primary tumour regions and 59 paired PM from 12 patients. All samples were analysed by RNA sequencing. We also generated a series of PM-derived organoid (PMDO) cultures and used these to design and test strategies to overcome resistance to oxaliplatin. RESULTS: PM displayed various hallmarks of aggressive CRC biology. The vast majority of PM and paired primary tumours belonged to the Consensus Molecular Subtype 4 (CMS4). PMDO cultures were resistant to oxaliplatin and expressed high levels of glutamate-cysteine ligase (GCLC) causing detoxification of oxaliplatin through glutathione synthesis. Genetic or pharmacological targeting of GCLC sensitised PMDOs to a 1-h exposure to oxaliplatin, through increased platinum-DNA adduct formation. CONCLUSIONS: These results link oxaliplatin resistance of colorectal PM to their CMS4 status and high reducing capacity. Inhibiting the reducing capacity of PM may be an effective strategy to overcome PM resistance to oxaliplatin.

Single Anastomosis Duodenoileal Bypass or Roux-en-Y Gastric Bypass After Failed Sleeve Gastrectomy: Medium-Term Outcomes.

BACKGROUND: Although the sleeve gastrectomy (SG) has good short-term results, it comes with a significant number of patients requiring revisional surgery because of insufficient weight loss or functional complications. OBJECTIVE: To investigate the effectiveness of the single anastomosis duodenoileal bypass (SADI-S) versus the Roux-en-Y gastric bypass (RYGB) on health outcomes in (morbidly) obese patients who had previously undergone SG, with up to 5 years of follow-up. METHODS: Data from patients who underwent revisional SADI-S or RYGB after SG were retrospectively compared on indication of surgery, weight loss, quality of life, micronutrient deficiencies, and complications. RESULTS: From 2007 to 2017, 141 patients received revisional laparoscopic surgery after SG in three specialized Dutch bariatric hospitals (SADI-S n=63, RYGB n=78). Percentage total weight loss following revisional surgery at 1, 2, 3, 4, and 5 years was 22%, 24%, 22%, 18%, and 15% for SADI-S and 10%, 9%, 7%, 8%, and 2% for RYGB (P<.05 for 1-4 years). Patients who underwent RYGB surgery for functional complications experienced no persistent symptoms of GERD or dysphagia in 88% of cases. No statistical difference was found in longitudinal analysis of change in quality of life scores or cross-sectional analysis of complication rates and micronutrient deficiencies. CONCLUSION: Conversion of SG to SADI-S leads to significantly more total weight loss compared to RYGB surgery with no difference in quality of life scores, complication rates, or micronutrient deficiencies. When GERD in sleeve patients has to be resolved, RYGB provides adequate outcomes.

Implications for IV posaconazole dosing in the era of obesity.

BACKGROUND: The prevalence of obesity has shown a dramatic increase over recent decades. Obesity is associated with underdosing of antimicrobial drugs for prophylaxis and treatment. Posaconazole is a broad-spectrum triazole antifungal drug licensed for prophylaxis and treatment of invasive fungal infections. It is unclear how posaconazole should be dosed in obese patients. METHODS: We performed a prospective study investigating the pharmacokinetics of posaconazole in morbidly obese (n = 16) and normal-weight (n = 8) subjects, with a weight ranging between 61.4 and 190 kg, after a 300 or 400 mg IV dose. Population pharmacokinetic modelling was used to assess the effect of body size on posaconazole pharmacokinetics. ClinicalTrials.gov Identifier: NCT03246386. RESULTS: Total body weight best predicted changes in CL and V. Model-based simulations demonstrated that, for treatment of fungal infections, a daily IV dose of 300 mg will result in a PTA of ≥90% in individuals up to 140 kg, after which both twice daily loading and the daily maintenance dose should be increased to 400 mg. For prophylaxis, a 300 mg IV dose is adequate in patients up to 190 kg. CONCLUSIONS: Body size has a significant impact on posaconazole CL and V, resulting in a lower exposure in obese subjects compared with normal-weight subjects. For therapeutic use of posaconazole, a dose increase is required in patients above 140 kg. For prophylaxis, a 300 mg IV dose is adequate. For oral treatment, these recommendations can act as a starting point followed by therapeutic drug monitoring.

Fixed Dosing of Liposomal Amphotericin B in Morbidly Obese Individuals.

In this prospective study, we examined the pharmacokinetics of 1 and 2 mg/kg liposomal amphotericin B in 16 morbidly obese individuals (104-177 kg). Body size had no effect on clearance. We recommend a fixed dose in patients ≥100 kg (ie, 300 or 500 mg rather than the current dose of 3 and 5 mg/kg, respectively). Clinical Trials Registration NCT02320604.

Pharmacokinetics and probability of target attainment for micafungin in normal-weight and morbidly obese adults.

OBJECTIVES: The rising pandemic of obesity means an increasing number of obese patients who require antimicrobial therapy for serious infections. Micafungin is an echinocandin drug frequently used as therapy or prophylaxis for fungal infections, predominantly with Candida species. In order to maximize the efficacy of micafungin in obese patients, the dose that corresponds to optimal exposure for each obese individual needs to be identified. METHODS: We performed a prospective study in 16 obese and 8 normal-weight healthy subjects with a weight ranging from 61.5-184 kg (ClinicalTrials.gov Identifier: NCT03102658). A population pharmacokinetic model was developed and used to simulate several dosing regimens to evaluate the PTA for relevant MICs to define the optimal dose using the pharmacokinetic/pharmacodynamic target of an AUC/MIC ratio above 5000. RESULTS: Total body weight was found to be most predictive for CL and V. Simulations showed that a 100 mg dose results in a PTA of >90% in patients weighing ≤125 kg infected with a Candida species having an MIC of 0.016 mg/L. The maintenance dose should be increased to 200 mg in patients >125 kg infected with a Candida species with an MIC of 0.016 mg/L. For an MIC of 0.032 mg/L, a 300 mg maintenance dose is recommended above 125 kg weight. Furthermore, we demonstrate that patients can benefit from a loading dose (i.e. twice the maintenance dose). CONCLUSIONS: We present easy-to-use dose recommendations for obese patients, based on both weight and target MIC, that result in adequate exposure in patients with body weight up to 190 kg.

Failed Sleeve Gastrectomy: Single Anastomosis Duodenoileal Bypass or Roux-en-Y Gastric Bypass? A Multicenter Cohort Study.

BACKGROUND: Sleeve gastrectomy (SG) has become the most performed bariatric procedure to induce weight loss worldwide. Unfortunately, a significant portion of patients show insufficient weight loss or weight regain after a few years. OBJECTIVE: To investigate the effectiveness of the single anastomosis duodenoileal (SADI) bypass versus the Roux-en-Y gastric bypass (RYGB) on health outcomes in morbid obese patients who had undergone SG previously, with up to 2 years of follow-up. METHODS: From 2007 to 2017, 140 patients received revisional laparoscopic surgery after SG in four specialized Dutch bariatric hospitals. Data was analyzed retrospectively and included comparisons for indication of surgery, vitamin/mineral deficiencies, and complications; divided into short-, medium-term. To compare weight loss, linear regression and linear mixed models were used. RESULTS: Conversion of a SG to SADI was performed in 66 patients and to RYGB in 74 patients. For patients in which additional weight loss was the main indication for surgery, SADI achieved 8.7%, 12.4%, and 19.4% more total body weight loss at 6, 12, and 24 months compared to RYGB (all p < .001). When a RYGB was indicated in case of gastroesophageal reflux or dysphagia, it greatly reduced complaints almost directly after surgery. Furthermore, a similar amount of complications and nutritional deficiencies was observed for both groups. There was no intra- or post-operative mortality. CONCLUSION: Conversion into a SADI resulted in significantly more weight loss while complications rates and nutritional deficiencies were similar and may therefore be considered the recommended operation for patients in which only additional weight loss is required.

Population pharmacodynamic model for low molecular weight heparin nadroparin in morbidly obese and non-obese patients using anti-Xa levels as endpoint.

PURPOSE: In absence of specific dosing guidelines, the optimal dose of low molecular weight heparins for thrombosis prophylaxis in morbidly obese patients (BMI>40 kg/m(2)) remains unknown. In order to guide dosing in this patient group, a pharmacodynamics model is developed for nadroparin in morbidly obese and non-obese patients using anti-Xa levels as an endpoint, thereby characterizing the influence of excessive body weight on different pharmacodynamic model parameters. METHODS: Twenty-eight morbidly obese and seven non-obese patients receiving 5700 IU and 2850 IU subcutaneous (s.c.) nadroparin for surgery, respectively, were included with a mean total body weight (TBW) of 135 kg (range 72-252 kg). Up to 11 anti-Xa levels were collected from the start until 24 h after nadroparin administration. Population pharmacodynamic modelling with covariate analysis was performed using NONMEM. RESULTS: In a two-compartment pharmacodynamic model with baseline endogenous anti-Xa levels, the effect of nadroparin was found to be delayed and could be best described using a transit compartment. TBW was the most predictive covariate for clearance (CL=23.0 mL/min × (TBW/70)), while lean body weight (LBW) proved the most predictive covariate for central volume of distribution (V1=7.0 L × (LBW/60)). CONCLUSIONS: A pharmacodynamic model was developed characterizing anti-Xa levels after s.c. administration of nadroparin in patients weighing between 72 and 252 kg with TBW and LBW as the major determinants for clearance and volume of distribution, respectively.

Midazolam pharmacokinetics in morbidly obese patients following semi-simultaneous oral and intravenous administration: a comparison with healthy volunteers.

BACKGROUND: While in vitro and animal studies have shown reduced cytochrome P450 (CYP) 3A activity due to obesity, clinical studies in (morbidly) obese patients are scarce. As CYP3A activity may influence both clearance and oral bioavailability in a distinct manner, in this study the pharmacokinetics of the CYP3A substrate midazolam were evaluated after semi-simultaneous oral and intravenous administration in morbidly obese patients, and compared with healthy volunteers. METHODS: Twenty morbidly obese patients [mean body weight 144 kg (range 112-186 kg) and mean body mass index 47 kg/m(2) (range 40-68 kg/m(2))] participated in the study. All patients received a midazolam 7.5 mg oral and 5 mg intravenous dose (separated by 159 ± 67 min) and per patient 22 samples over 11 h were collected. Data from 12 healthy volunteers were available for a population pharmacokinetic analysis using NONMEM(®). RESULTS: In the three-compartment model in which oral absorption was characterized by a transit absorption model, population mean clearance (relative standard error %) was similar [0.36 (4 %) L/min], while oral bioavailability was 60 % (13 %) in morbidly obese patients versus 28 % (7 %) in healthy volunteers (P < 0.001). Central and peripheral volumes of distribution increased substantially with body weight (both P < 0.001) and absorption rate (transit rate constant) was lower in morbidly obese patients [0.057 (5 %) vs. 0.130 (14 %) min(-1), P < 0.001]. CONCLUSIONS: In morbidly obese patients, systemic clearance of midazolam is unchanged, while oral bioavailability is increased. Given the large increase in volumes of distribution, dose adaptations for intravenous midazolam should be considered. Further research should elucidate the exact physiological changes at intestinal and hepatic level contributing to these findings.

Anti-Xa Levels 4 h After Subcutaneous Administration of 5,700 IU Nadroparin Strongly Correlate with Lean Body Weight in Morbidly Obese Patients.

BACKGROUND: Morbidly obese patients (BMI > 40 kg/m(2)) are at increased risk for venous thromboembolism, especially after surgery. Despite limited evidence, morbidly obese patients are often administered a double dose of nadroparin for thromboprophylaxis compared to non-obese patients. The aim of this study was to evaluate the influence of different body size descriptors on anti-Xa levels after a double dose of nadroparin (5,700 IU) in morbidly obese patients. METHODS: In 27 morbidly obese patients with a mean total body weight of 148 kg (range 107-260 kg), anti-Xa levels were determined peri-operatively until 24 h after administration of a subcutaneous dose of 5,700 IU of nadroparin. RESULTS: Anti-Xa level 4 h after administration (A(4h), mean 0.22 ± 0.07 IU/ml) negatively correlated strongly with lean body weight (r = -0.66 (p < 0.001)) and moderately with total body weight (r = -0.56 (p = 0.003)) and did not correlate with body mass index (r = -0.26 (p = 0.187)). The area under the anti-Xa level-time curve from 0 to 24 h (AUA(0-24h), mean 2.80 ± 0.97 h IU/ml) correlated with lean body weight (r = -0.63 (p = 0.007)), but did not correlate with total body weight (r = -0.44 (p = 0.075)) or body mass index (r = -0.10 (p = 0.709)). CONCLUCIONS: Following a subcutaneous dose of nadroparin 5,700 IU, A(4h) and AUA(0-24h) were found to negatively correlate strongly with lean body weight. From these results, individualized dosing of nadroparin based on lean body weight should be considered in morbidly obese patients.

Preoperative very low-calorie diet and operative outcome after laparoscopic gastric bypass: a randomized multicenter study.

HYPOTHESIS: A 14-day very low-calorie diet (VLCD) regimen before a laparoscopic gastric bypass procedure will improve perioperative and postoperative outcomes. DESIGN: Multicenter, randomized, single-blind study. SETTING: Five high-volume bariatric centers in Sweden, the Netherlands, Lithuania, Spain, and Belgium. PATIENTS: Two hundred ninety-eight morbidly obese patients undergoing laparoscopic gastric bypass from March 1, 2009, through December 5, 2010. INTERVENTION: Patients were randomly allocated to a 2-week preoperative VLCD regimen or no preoperative dietary restriction (control group). MAIN OUTCOME MEASURES: Operating time, surgeon's perceived difficulty of the operation, liver lacerations, intraoperative bleeding and complications, 30-day weight loss, and morbidity. RESULTS: Mean (SD) preoperative weight change was -4.9 (3.6) kg in the VLCD group vs -0.4 (3.2) kg in the control group (P < .001). Although the surgeon's perceived difficulty of the procedure was lower in the VLCD group (median [interquartile range], 26 [15-42] vs 35 [18-50] mm on a visual analog scale; P = .04), no differences were found regarding mean (SD) operating time (81 [21] vs 80 [23] min; P = .53), estimated blood loss (P = .62), or intraoperative complications (P = .88). At the 30-day follow-up, the number of complications was greater in the control compared with the VLCD group (18 vs 8; P = .04). CONCLUSIONS: Although weight reduction with a 14-day VLCD regimen before laparoscopic gastric bypass performed in high-volume centers seems to reduce the perceived difficulty of the procedure, only minor effects on operating time, intraoperative complications, and short-term weight loss could be expected. However, the finding of reduced postoperative complication rates suggests that such a regimen should be recommended before bariatric surgery.

Population pharmacokinetics and pharmacodynamics of propofol in morbidly obese patients.

BACKGROUND AND OBJECTIVES: In view of the increasing prevalence of morbidly obese patients, the influence of excessive total bodyweight (TBW) on the pharmacokinetics and pharmacodynamics of propofol was characterized in this study using bispectral index (BIS) values as a pharmacodynamic endpoint. METHODS: A population pharmacokinetic and pharmacodynamic model was developed with the nonlinear mixed-effects modelling software NONMEM VI, on the basis of 491 blood samples from 20 morbidly obese patients (TBW range 98-167 kg) and 725 blood samples from 44 lean patients (TBW range 55-98 kg) from previously published studies. In addition, 2246 BIS values from the 20 morbidly obese patients were available for pharmacodynamic analysis. RESULTS: In a three-compartment pharmacokinetic model, TBW proved to be the most predictive covariate for clearance from the central compartment (CL) in the 20 morbidly obese patients (CL 2.33 L/min × [TBW/70]^[0.72]). Similar results were obtained when the morbidly obese patients and the 44 lean patients were analysed together (CL 2.22 L/min × [TBW/70]^[0.67]). No covariates were identified for other pharmacokinetic parameters. The depth of anaesthesia in the morbidly obese patients was adequately described by a two-compartment biophase-distribution model with a sigmoid maximum possible effect (E(max)) pharmacodynamic model (concentration at half-maximum effect [EC(50)] 2.12 mg/L) without covariates. CONCLUSION: We developed a pharmacokinetic and pharmacodynamic model of propofol in morbidly obese patients, in which TBW proved to be the major determinant of clearance, using an allometric function with an exponent of 0.72. For the other pharmacokinetic and pharmacodynamic parameters, no covariates could be identified. Trial registration number (clinicaltrials.gov): NCT00395681.

[Endoscopic posterior adrenalectomy; results of 100 procedures in University Medical Center Utrecht]. / Posterieure endoscopische adrenalectomie: Resultaten van 100 procedures in het Universitair Medisch Centrum Utrecht.

OBJECTIVE: To describe the results of 100 endoscopic posterior retroperitoneal adrenalectomies performed in the University Medical Center Utrecht, the Netherlands. DESIGN: Descriptive, retrospective. METHOD: In the period August 1997-March 2008 100 endoscopic posterior retroperitoneal adrenalectomies were performed in the University Medical Center Utrecht. Data were collected retrospectively on patients, operations, complications and course following the procedure. RESULTS: In this period 88 unilateral and 6 bilateral EPRA procedures were performed in 94 patients. The most common indications for unilateral EPRA were pheochromocytoma (33), Cushing's syndrome (16) and Conn's syndrome (20). Preoperative diagnosis involved clinical examination, hormonal analysis and radiological imaging. Mean operative time was 110 min and showed a clear learning curve. The mean intraoperative blood loss was 30 ml. The median size of the lesions was 2.8 cm (range: 0.4-7.5). Conversion to open surgery was necessary in 2 patients. No major intraoperative complications occurred. Postoperative complications occurred in 7 patients, of which 2 were severe and 5 were mild. Surgical reintervention was required in 1 patient. Median postoperative stay was 3 days. CONCLUSION: In experienced hands endoscopic posterior retroperitoneal adrenalectomy appears to be a safe and effective treatment for adrenal gland lesions.