Comparing patient reported abdominal pain between patients treated with oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) and primary colorectal cancer surgery.

Oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) is an emerging palliative treatment for patients with unresectable colorectal peritoneal metastases. Previously, our study group reported that patients experienced abdominal pain for several weeks after PIPAC-OX. However, it is unknown how this compares to abdominal pain after regular colorectal cancer surgery. To provide some perspective, this study compared the presence of abdominal pain after PIPAC-OX to the presence of abdominal pain after primary tumor surgery. Patient reported abdominal pain scores (EORTC QLQ-CR-29), from two prospective, Dutch cohorts were used in this study. Scores ranged from 0 to 100, a higher score represents more abdominal pain. Abdominal pain at baseline and at four weeks after treatment were compared between the two groups. Twenty patients who underwent PIPAC-OX and 322 patients who underwent primary tumor surgery were included in the analysis. At baseline, there were no differences in abdominal pain between both groups (mean 20 vs. 18, respectively; p = 0.688). Four weeks after treatment, abdominal pain was significantly worse in the PIPAC group (39 vs 15, respectively; p < 0.001; Cohen's d = 0.99). The differential effect over time for abdominal pain differed significantly between both groups (mean difference: 19 vs - 3, respectively; p = 0.004; Cohen's d = 0.88). PIPAC-OX resulted in significantly worse postoperative abdominal pain than primary tumor surgery. These results can be used for patient counseling and stress the need for adequate analgesia during and after PIPAC-OX. Further research is required to prevent or reduce abdominal pain after PIPAC-OX.Trial registration CRC-PIPAC: Clinicaltrails.gov NCT03246321 (01-10-2017).

Prophylactic Mesh Placement During Formation of an End-colostomy: Long-term Randomized Controlled Trial on Effectiveness and Safety.

OBJECTIVE: The aim of this study was to determine if prophylactic mesh placement is an effective, safe, and cost-effective procedure to prevent parastomal hernia (PSH) formation in the long term. BACKGROUND: A PSH is the most frequent complication after stoma formation. Prophylactic placement of a mesh has been suggested to prevent PSH, but long-term evidence to support this approach is scarce. METHODS: In this multicentre superiority trial patients undergoing the formation of a permanent colostomy were randomly assigned to either retromuscular polypropylene mesh reinforcement or conventional colostomy formation. Primary endpoint was the incidence of a PSH after 5 years. Secondary endpoints were morbidity, mortality, quality of life, and cost-effectiveness. RESULTS: A total of 150 patients were randomly assigned to the mesh group (n = 72) or nonmesh group (n = 78). For the long-term follow-up, 113 patients were analyzed, and 37 patients were lost to follow-up. After a median follow-up of 60 months (interquartile range: 48.6-64.4), 49 patients developed a PSH, 20 (27.8%) in the mesh group and 29 (37.2%) in the nonmesh group ( P = 0.22; RD: -9.4%; 95% CI: -24, 5.5). The cost related to the meshing strategy was € 2.239 lower than the nonmesh strategy (95% CI: 491.18, 3985.49), and quality-adjusted life years did not differ significantly between groups ( P = 0.959; 95% CI: -0.066, 0.070). CONCLUSIONS: Prophylactic mesh placement during the formation of an end-colostomy is a safe procedure but does not reduce the incidence of PSH after 5 years of follow-up. It does, however, delay the onset of PSH without a significant difference in morbidity, mortality, or quality of life, and seems to be cost-effective.

Total bodyweight and sex both drive pharmacokinetic variability of fluconazole in obese adults.

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 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/m2) and non-obese healthy controls (n = 8, 18.5 ≤ BMI < 30.0 kg/m2). 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 Vd were found. Sex also significantly impacted Vd, 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.

The impact of body mass index (BMI) on satisfaction with work life: An international BODY-Q study.

Obesity is a global health issue known to have a major influence on health-related quality of life (HR-QOL). HR-QOL is a concept evaluating physical and psychological health. Work life can impact HR-QOL in people with obesity. The aim of this study was to measure the association between body mass index (BMI) and satisfaction with work life. This study included participants from an international multicenter field-test study of BODY-Q scales. Recruitment took place at hospitals in Denmark, The Netherlands and USA between June 2019 and January 2020. The BODY-Q Work Life scale was used to measure work life satisfaction. The difference between BMI groups and work life satisfaction was examined using one-way analysis of variance. Multivariable linear regression analysis was used to examine the association between BMI and work life satisfaction, adjusted for significant confounders. Of 4123 participants, 2515 completed the BODY-Q Work Life scale. BMI groups showed significant difference in work life satisfaction (p < .0001). The Work Life scale mean score was 77.6 for the normal BMI group, 78.5 for the overweight group and 75.0, 68.9 and 63.8 for Class 1, 2 and 3 obesity, respectively. Furthermore, BMI was significantly associated with satisfaction with work life (adjusted regression coefficient -.962, p < .0001). Higher BMI was associated with lower work life satisfaction. This finding suggests that a reduction in BMI may have a positive influence on work life satisfaction in people with obesity.

The Diagnostic Accuracy of Abdominal Computed Tomography in Diagnosing Internal Herniation Following Roux-en-Y Gastric Bypass Surgery: A Systematic Review and Meta-analysis.

OBJECTIVE: To analyze the diagnostic accuracy of abdominal computed tomography (CT) in diagnosing internal herniation (IH) following Rouxen-Y gastric bypass (RYGB) surgery. SUMMARY OF BACKGROUND DATA: IH is one of the most important and challenging complications following RYGB. Therefore, early and adequate diagnosis of IH is necessary. Currently, exploratory surgery is considered the gold standard in diagnosing IH. Although CT scans are frequently being used, the true diagnostic accuracy in diagnosing IH remains unclear. METHODS: PubMed, Embase, and Cochrane databases were systematically searched for relevant articles describing the diagnostic accuracy of abdominal CT in diagnosing IH after RYGB. Data were extracted, recalculated, and pooled to report on the overall diagnostic accuracy of CT in diagnosing IH, and the diagnostic accuracy of specific radiological signs. RESULTS: A total of 20 studies describing 1637 patients were included. seventeen studies provided data regarding the overall diagnostic accuracy: pooled sensitivity of 82.0%, specificity of 84.8%, positive predictive value of 82.7%, and negative predictive value of 85.8% were calculated. Eleven studies reported on specific CT signs and their diagnostic accuracy. The radiological signs with the highest sensitivity were the signs of venous congestion, swirl, and mesenteric oedema (sensitivity of 78.7%, 77.8%, and 67.2%, respectively). CONCLUSIONS: This meta-analysis demonstrates that CT is a reliable imaging modality for the detection of IH. Therefore, abdominal CT imaging should be added to the diagnostic work-up for RYGB patients who present themselves with abdominal pain suggestive of IH to improve patient selection for explorative surgery.

Patient-reported outcomes during repetitive oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy for isolated unresectable colorectal peritoneal metastases in a multicenter, single-arm, phase 2 trial (CRC-PIPAC).

BACKGROUND: CRC-PIPAC prospectively assessed repetitive oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) as a palliative monotherapy (i.e., without concomitant systemic therapy in between subsequent procedures) for unresectable colorectal peritoneal metastases (CPM). The present study explored patient-reported outcomes (PROs) during trial treatment. METHODS: In this single-arm phase 2 trial in two tertiary centers, patients with isolated unresectable CPM received 6-weekly PIPAC-OX (92 mg/m2). PROs (calculated from EQ-5D-5L, and EORTC QLQ-C30 and QLQ-CR29) were compared between baseline and 1 and 4 weeks after the first three procedures using linear mixed modeling with determination of clinical relevance (Cohen's D ≥ 0.50) of statistically significant differences. RESULTS: Twenty patients underwent 59 procedures (median 3 [range 1-6]). Several PROs solely worsened 1 week after the first procedure (index value - 0.10, p < 0.001; physical functioning - 20, p < 0.001; role functioning - 27, p < 0.001; social functioning - 18, p < 0.001; C30 summary score - 16, p < 0.001; appetite loss + 15, p = 0.007; diarrhea + 15, p = 0.002; urinary frequency + 13, p = 0.004; flatulence + 13, p = 0.001). These PROs returned to baseline at subsequent time points. Other PROs worsened 1 week after the first procedure (fatigue + 23, p < 0.001; pain + 29, p < 0.001; abdominal pain + 32, p < 0.001), second procedure (fatigue + 20, p < 0.001; pain + 21, p < 0.001; abdominal pain + 20, p = 0.002), and third procedure (pain + 22, p < 0.001; abdominal pain + 22, p = 0.002). Except for appetite loss, all changes were clinically relevant. All analyzed PROs returned to baseline 4 weeks after the third procedure. CONCLUSIONS: Patients receiving repetitive PIPAC-OX monotherapy for unresectable CPM had clinically relevant but reversible worsening of several PROs, mainly 1 week after the first procedure. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03246321; Netherlands trial register: NL6426.

Development and Validation of New BODY-Q Scales Measuring Expectations, Eating Behavior, Distress, Symptoms, and Work Life in 4004 Adults From 4 Countries.

PURPOSE: The BODY-Q is a rigorously developed patient-reported outcome measure (PROM) for patients seeking treatment for obesity and body contouring surgery. A limitation of the uptake of the BODY-Q in weight management treatments is the absence of scales designed to measure eating-specific concerns. We aimed to develop and validate 5 new BODY-Q scales measuring weight loss expectations, eating behaviors, distress, symptoms, and work life. MATERIAL AND METHODS: In phase 1 (qualitative), patient and expert input was used to develop and refine the new BODY-Q scales. In phase 2 (quantitative), the scales were field-tested in bariatric and weight management clinics in the United States (US), The Netherlands, and Denmark between June 2019 and January 2020. Data were also collected in the US and Canada in September 2019 through a crowdworking platform. Rasch measurement theory (RMT) analysis was used for item reduction and to examine reliability and validity. RESULTS: The new BODY-Q scales were refined through qualitative input from 17 patients and 20 experts (phase 1) and field-tested in 4004 participants (phase 2). All items showed ordered thresholds and good fit to the Rasch model. The RMT analysis provided evidence of reliability, with PSI values ≥0.72, Cronbach alpha values ≥0.83, and test-retest values ≥0.79. Better scores on 4 scales (exception expectations scale) correlated with lower BMI, with the strongest correlation between the eating-related distress scale scores and BMI (r= -0.249, P < 0.001). CONCLUSION: The new BODY-Q scales can be used in research and clinical practice to assess weight loss treatments from the patient perspective.

Perioperative Systemic Therapy vs Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Alone for Resectable Colorectal Peritoneal Metastases: A Phase 2 Randomized Clinical Trial.

Importance: To date, no randomized clinical trials have investigated perioperative systemic therapy relative to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone for resectable colorectal peritoneal metastases (CPM). Objective: To assess the feasibility and safety of perioperative systemic therapy in patients with resectable CPM and the response of CPM to neoadjuvant treatment. Design, Setting, and Participants: An open-label, parallel-group phase 2 randomized clinical trial in all 9 Dutch tertiary centers for the surgical treatment of CPM enrolled participants between June 15, 2017, and January 9, 2019. Participants were patients with pathologically proven isolated resectable CPM who did not receive systemic therapy within 6 months before enrollment. Interventions: Randomization to perioperative systemic therapy or CRS-HIPEC alone. Perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (capecitabine and oxaliplatin), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin), or six 2-week neoadjuvant cycles of FOLFIRI (fluorouracil, leucovorin, and irinotecan) and either four 3-week adjuvant cycles of capecitabine or six 2-week adjuvant cycles of fluorouracil with leucovorin. Bevacizumab was added to the first 3 (CAPOX) or 4 (FOLFOX/FOLFIRI) neoadjuvant cycles. Main Outcomes and Measures: Proportions of macroscopic complete CRS-HIPEC and Clavien-Dindo grade 3 or higher postoperative morbidity. Key secondary outcomes were centrally assessed rates of objective radiologic and major pathologic response of CPM to neoadjuvant treatment. Analyses were done modified intention-to-treat in patients starting neoadjuvant treatment (experimental arm) or undergoing upfront surgery (control arm). Results: In 79 patients included in the analysis (43 [54%] men; mean [SD] age, 62 [10] years), experimental (n = 37) and control (n = 42) arms did not differ significantly regarding the proportions of macroscopic complete CRS-HIPEC (33 of 37 [89%] vs 36 of 42 [86%] patients; risk ratio, 1.04; 95% CI, 0.88-1.23; P = .74) and Clavien-Dindo grade 3 or higher postoperative morbidity (8 of 37 [22%] vs 14 of 42 [33%] patients; risk ratio, 0.65; 95% CI, 0.31-1.37; P = .25). No treatment-related deaths occurred. Objective radiologic and major pathologic response rates of CPM to neoadjuvant treatment were 28% (9 of 32 evaluable patients) and 38% (13 of 34 evaluable patients), respectively. Conclusions and Relevance: In this randomized phase 2 trial in patients diagnosed with resectable CPM, perioperative systemic therapy seemed feasible, safe, and able to induce response of CPM, justifying a phase 3 trial. Trial Registration: ClinicalTrials.gov Identifier: NCT02758951.

Oral drug dosing following bariatric surgery: General concepts and specific dosing advice.

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 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.

First-line palliative systemic therapy alternated with electrostatic pressurised intraperitoneal aerosol chemotherapy (oxaliplatin) for isolated unresectable colorectal peritoneal metastases: protocol of a multicentre, single-arm, phase II study (CRC-PIPAC-II).

INTRODUCTION: Despite its increasing use, first-line palliative systemic therapy alternated with electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX), hereinafter referred to as first-line bidirectional therapy, has never been prospectively investigated in patients with colorectal peritoneal metastases (CPM). As a first step to address this evidence gap, the present study aims to assess the safety, feasibility, antitumour activity, patient-reported outcomes, costs and systemic pharmacokinetics of first-line bidirectional therapy in patients with isolated unresectable CPM. METHODS AND ANALYSIS: In this single-arm, phase II study in two Dutch tertiary referral centres, 20 patients are enrolled. Key eligibility criteria are a good performance status, pathologically proven isolated unresectable CPM, no previous palliative systemic therapy for colorectal cancer, no (neo)adjuvant systemic therapy ≤6 months prior to enrolment and no previous pressurised intraperitoneal aerosol chemotherapy (PIPAC). Patients receive three cycles of bidirectional therapy. Each cycle consists of 6 weeks first-line palliative systemic therapy at the medical oncologists' decision (CAPOX-bevacizumab, FOLFOX-bevacizumab, FOLFIRI-bevacizumab or FOLFOXIRI-bevacizumab) followed by ePIPAC-OX (92 mg/m2) with an intraoperative bolus of intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Study treatment ends after the third ePIPAC-OX. The primary outcome is the number of patients with-and procedures leading to-grade ≥3 adverse events (Common Terminology Criteria for Adverse Events V.5.0) up to 4 weeks after the last procedure. Key secondary outcomes include the number of bidirectional cycles in each patient, treatment-related characteristics, grade ≤2 adverse events, tumour response (histopathological, cytological, radiological, biochemical, macroscopic and ascites), patient-reported outcomes, systemic pharmacokinetics of oxaliplatin, costs, progression-free survival and overall survival. ETHICS AND DISSEMINATION: This study is approved by the Dutch competent authority, a medical ethics committee and the institutional review boards of both study centres. Results will be submitted for publication in peer-reviewed medical journals and presented to patients and healthcare professionals. TRIAL REGISTRATION NUMBER: NL8303.

Incidence and treatment of intussusception following Roux-en-Y gastric bypass: a systematic review and meta-analysis.

Intussusception is a rare yet potentially life-threatening complication following Roux-en-Y gastric bypass (RYGB). Multiple case reports have described this complication, and recently, several retrospective studies have been published describing the surgical treatment of intussusception. The aim of this study was to determine the incidence of intussusception following RYGB and provide insight into outcomes of subsequent operative treatment. A systematic search was performed using the PubMed and Cochrane databases. Article selection was performed using the preferred reporting items for systematic reviews and meta-analyses criteria, and selecting articles describing the incidence of intussusception following RYGB. Data was pooled only when 3 or more comparable studies reported on the same outcome. The incidence of intussusception and outcomes of subsequent treatment were analyzed. Furthermore, all published case reports describing intussusception following RYGB were analyzed. A total of 74 studies published between 1991 and 2020 were included, describing 191 patients who underwent RYGB and developed intussusception. We retrieved 68 case reports, including 84 patients, and 6 retrospective studies describing outcomes of surgical treatment in 107 patients, which were used to pool data. There was a predominance of females among the included patients (85%-98%), and patients had significant weight loss following RYGB. The pooled incidence of intussusception following RYGB was .64%. Resection of the affected segment was performed in 34% of the patients. A pooled recurrence rate of 22% was found during follow-up. Resection and reconstruction of the jejunojejunostomy appears to be associated with the lowest risk of recurrence and acceptable complication rates. The pooled incidence of intussusception following RYGB is 0.64%. Typically, patients are female with significant weight loss after RYGB. Symptoms include abdominal pain, nausea, and vomiting. Diagnosis is based on clinical findings and computed tomography scans, warranting early surgical exploration due to the high risk for ischemia. Resection of the jejunojejunostomy appears to be associated with the lowest recurrence rates and acceptable complication rates.

Pressurized Intraperitoneal Aerosol Chemotherapy (Oxaliplatin) for Unresectable Colorectal Peritoneal Metastases: A Multicenter, Single-Arm, Phase II Trial (CRC-PIPAC).

BACKGROUND: Despite its increasing use, pressurized intraperitoneal aerosol chemotherapy with oxaliplatin (PIPAC-OX) has never been prospectively investigated as a palliative monotherapy for colorectal peritoneal metastases in clinical trials. This trial aimed to assess the safety (primary aim) and antitumor activity (key secondary aim) of PIPAC-OX monotherapy in patients with unresectable colorectal peritoneal metastases. METHODS: In this two-center, single-arm, phase II trial, patients with isolated unresectable colorectal peritoneal metastases in any line of palliative treatment underwent 6-weekly PIPAC-OX (92 mg/m2). Key outcomes were major treatment-related adverse events (primary outcome), minor treatment-related adverse events, hospital stay, tumor response (radiological, biochemical, pathological, ascites), progression-free survival, and overall survival. RESULTS: Twenty enrolled patients underwent 59 (median 3, range 1-6) PIPAC-OX procedures. Major treatment-related adverse events occurred in 3 of 20 (15%) patients after 5 of 59 (8%) procedures (abdominal pain, intraperitoneal hemorrhage, iatrogenic pneumothorax, transient liver toxicity), including one possibly treatment-related death (sepsis of unknown origin). Minor treatment-related adverse events occurred in all patients after 57 of 59 (97%) procedures, the most common being abdominal pain (all patients after 88% of procedures) and nausea (65% of patients after 39% of procedures). Median hospital stay was 1 day (range 0-3). Response rates were 0% (radiological), 50% (biochemical), 56% (pathological), and 56% (ascites). Median progression-free and overall survival were 3.5 months (interquartile range [IQR] 2.5-5.7) and 8.0 months (IQR 6.3-12.6), respectively. CONCLUSIONS: In patients with unresectable colorectal peritoneal metastases undergoing PIPAC-OX monotherapy, some major adverse events occurred and minor adverse events were common. The clinical relevance of observed biochemical, pathological, and ascites responses remains to be determined, especially since radiological response was absent.

BODY-Q patient-reported outcomes measure (PROM) to assess sleeve gastrectomy vs. Roux-en-Y gastric bypass: eating behavior, eating-related distress, and eating-related symptoms.

BACKGROUND: Post-operative changes in eating behavior, eating-related distress and eating-related symptoms play an important role in the lives of bariatric surgery patients. However, there are no studies that assess these outcomes using a specifically designed patient-reported outcome measure (PROM) for patients undergoing bariatric surgery. We use our newly developed and validated scales as part of the well-established BODY-Q PROMs to compare laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass patients (LRYGB). METHODS: We analyzed data from an international multi-center prospective cohort study of patients over 18 who underwent bariatric surgery. We used multivariable linear regression models to assess the difference between LRYGB and LSG for the new BODY-Q scales, which include eating behavior, eating-related distress and eating-related symptoms. All analyses were corrected for significant confounding variables. RESULTS: Out of 1420 patients, 920 underwent LRYGB and 500 underwent LSG. The LRYGB group had a higher percentage total weight loss (p < 0.001). There was no significant difference in eating behavior (e.g., stop eating before feeling full, avoiding unhealthy snacks, etc.) or eating-related distress (e.g., feeling ashamed or out of control after eating). Patients who underwent LSG scored significantly better on the post-prandial eating-related symptoms scale (e.g., vomiting, reflux; p < 0.001). Symptoms more prevalent in the LRYGB patients were related to dumping syndrome whereas symptoms more prevalent in LSG patients were related to reflux. CONCLUSION: Patients who underwent LRYGB had a significantly better weight loss after surgery, but they scored worse on post-prandial symptoms in comparison to LSG patients. This information may be relevant for patients in the pre-operative counseling setting, as it may influence their decision for surgical procedure selection.

Protocol of a multicentre, prospective cohort study that evaluates cost-effectiveness of two perioperative care strategies for potential obstructive sleep apnoea in morbidly obese patients undergoing bariatric surgery.

INTRODUCTION: Despite the high prevalence of obstructive sleep apnoea (OSA) in obese patients undergoing bariatric surgery, OSA is undiagnosed in the majority of patients and thus untreated. While untreated OSA is associated with an increased risk of preoperative and postoperative complications, no evidence-based guidelines on perioperative care for these patients are available. The aim of the POPCORN study (Post-Operative Pulse oximetry without OSA sCreening vs perioperative continuous positive airway pressure (CPAP) treatment following OSA scReeNing by polygraphy (PG)) is to evaluate which perioperative strategy is the most cost-effective for obese patients undergoing bariatric surgery without a history of OSA. METHODS AND ANALYSIS: In this multicentre observational cohort study, data from 1380 patients who will undergo bariatric surgery will be collected. Patients will receive either postoperative care with pulse oximetry monitoring and supplemental oxygen during the first postoperative night, or care that includes preoperative PG and CPAP treatment in case of moderate or severe OSA. Local protocols for perioperative care in each participating hospital will determine into which cohort a patient is placed. The primary outcome is cost-effectiveness, which will be calculated by comparing all healthcare costs with the quality-adjusted life-years (QALYs, calculated using EQ-5D questionnaires). Secondary outcomes are mortality, complications within 30 days after surgery, readmissions, reoperations, length of stay, weight loss, generic quality of life (QOL), OSA-specific QOL, OSA symptoms and CPAP adherence. Patients will receive questionnaires before surgery and 1, 3, 6 and 12 months after surgery to report QALYs and other patient-reported outcomes. ETHICS AND DISSEMINATION: Approval from the Medical Research Ethics Committees United was granted in accordance with the Dutch law for Medical Research Involving Human Subjects Act (WMO) (reference number W17.050). Results will be submitted for publication in peer-reviewed journals and presented at (inter)national conferences. TRIAL REGISTRATION NUMBER: NTR6991.

Correction to: Tobramycin Clearance Is Best Described by Renal Function Estimates in Obese and Nonobese Individuals: Results of a Prospective Rich Sampling Pharmacokinetic Study.

There was a mistake in the units of CL and Q, and in the parentheses of the formula for CL in the final model in Table 2. The corrected Table appears below.

Measuring quality of life in bariatric surgery: a multicentre study.

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 (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 (ß 2.758; p-value 0.008) and general health perception (ß 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.

Population pharmacokinetics of vancomycin in obesity: Finding the optimal dose for (morbidly) obese individuals.

AIMS: For vancomycin treatment in obese patients, there is no consensus on the optimal dose that will lead to the pharmacodynamic target (area under the curve 400-700 mg h L-1 ). This prospective study quantifies vancomycin pharmacokinetics in morbidly obese and nonobese individuals, in order to guide vancomycin dosing in the obese. METHODS: Morbidly obese individuals (n = 20) undergoing bariatric surgery and nonobese 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; nonobese: 1000 mg) with plasma concentrations measured over 48 h (11-13 samples per individual). Modelling, internal validation, external validation using previously published data and simulations (n = 10.000 individuals, TBW 60-230 kg) were performed using NONMEM. RESULTS: In a 3-compartment model, peripheral volume of distribution and clearance increased with TBW (both p < 0.001), which was confirmed in the external validation. A dose of 35 mg kg-1 day-1 (maximum 5500 mg/day) resulted in a > 90% target attainment (area under the curve > 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. CONCLUSION: 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 day-1 (maximized at 5500 mg/day). When given over 2 daily doses, trough concentrations of 5.7-14.6 mg L-1 correspond to the target exposure in obese individuals.

Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial.

BACKGROUND: Nearly a quarter of patients with locally advanced (T4 stage) or perforated colon cancer are at risk of developing peritoneal metastases, often without curative treatment options. We aimed to determine the efficacy of adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with locally advanced colon cancer. METHODS: This multicentre, open-label trial was done in nine hospitals that specialised in HIPEC in the Netherlands. Patients with clinical or pathological T4N0-2M0-stage tumours or perforated colon cancer were randomly assigned (1:1), with a web-based randomisation application, before resection of the primary tumour, to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy (experimental group) or to adjuvant systemic chemotherapy alone (control group). Patients were stratified by tumour characteristic (T4 or perforation), age (<65 years or ≥65 years), and surgical approach of the primary tumour resection (laparoscopic or open). Key eligibility criteria included age between 18 and 75 years, adequate clinical condition for HIPEC, and intention to start adjuvant systemic chemotherapy. Patients with metastatic disease were ineligible. Adjuvant HIPEC consisted of fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) delivered intravenously followed by intraperitoneal delivery of oxaliplatin (460 mg/m2) for 30 min at 42°C, delivered simultaneously or within 5-8 weeks after primary tumour resection. In all patients without evidence of recurrent disease at 18 months, a diagnostic laparoscopy was done. The primary endpoint was peritoneal metastasis free-survival at 18 months, measured in the intention-to-treat population, with the Kaplan-Meier method. Adverse events were assessed in all patients who received assigned treatment. This study is registered with ClinicalTrials.gov, number NCT02231086. FINDINGS: Between April 1, 2015, and Feb 20, 2017, 204 patients were randomly assigned to treatment (102 in each group). In the HIPEC group, two patients withdrew consent after randomisation. In this group, 19 (19%) of 100 patients were diagnosed with peritoneal metastases: nine (47%) during surgical exploration preceding intentional adjuvant HIPEC, eight (42%) during routine follow-up, and two (11%) during diagnostic laparoscopy at 18-months. In the control group, 23 (23%) of 102 patients were diagnosed with peritoneal metastases, of whom seven (30%) were diagnosed by laparoscopy at 18-months and 16 during regular follow-up (therefore making them ineligible for diagnostic laparoscopy). In the intention-to-treat analysis (n=202), there was no difference in peritoneal-free survival at 18-months (80·9% [95% CI 73·3-88·5] for the experimental group vs 76·2% [68·0-84·4] for the control group, log-rank one-sided p=0·28). 12 (14%) of 87 patients who received adjuvant HIPEC developed postoperative complications and one (1%) encapsulating peritoneal sclerosis. INTERPRETATION: In patients with T4 or perforated colon cancer, treatment with adjuvant HIPEC with oxaliplatin did not improve peritoneal metastasis-free survival at 18 months. Routine use of adjuvant HIPEC is not advocated on the basis of this trial. FUNDING: Organization for Health Research and Development and the Dutch Cancer Society.

Repetitive electrostatic pressurised intraperitoneal aerosol chemotherapy (ePIPAC) with oxaliplatin as a palliative monotherapy for isolated unresectable colorectal peritoneal metastases: protocol of a Dutch, multicentre, open-label, single-arm, phase II study (CRC-PIPAC).

INTRODUCTION: Repetitive electrostatic pressurised intraperitoneal aerosol chemotherapy with oxaliplatin (ePIPAC-OX) is offered as a palliative treatment option for patients with isolated unresectable colorectal peritoneal metastases (PM) in several centres worldwide. However, little is known about its feasibility, safety, tolerability, efficacy, costs and pharmacokinetics in this setting. This study aims to explore these parameters in patients with isolated unresectable colorectal PM who receive repetitive ePIPAC-OX as a palliative monotherapy. METHODS AND ANALYSIS: This multicentre, open-label, single-arm, phase II study is performed in two Dutch tertiary referral hospitals for the surgical treatment of colorectal PM. Eligible patients are adults who have histologically or cytologically proven isolated unresectable PM of a colorectal or appendiceal carcinoma, a good performance status, adequate organ functions and no symptoms of gastrointestinal obstruction. Instead of standard palliative treatment, enrolled patients receive laparoscopy-controlled ePIPAC-OX (92 mg/m2 body surface area (BSA)) with intravenous leucovorin (20 mg/m2 BSA) and bolus 5-fluorouracil (400 mg/m2 BSA) every 6 weeks. Four weeks after each procedure, patients undergo clinical, radiological and biochemical evaluation. ePIPAC-OX is repeated until disease progression, after which standard palliative treatment is (re)considered. The primary outcome is the number of patients with major toxicity (grade ≥3 according to the Common Terminology Criteria for Adverse Events v4.0) up to 4 weeks after the last ePIPAC-OX. Secondary outcomes are the environmental safety of ePIPAC-OX, procedure-related characteristics, minor toxicity, postoperative complications, hospital stay, readmissions, quality of life, costs, pharmacokinetics of oxaliplatin, progression-free survival, overall survival, and the radiological, histopathological, cytological, biochemical and macroscopic tumour response. ETHICS AND DISSEMINATION: This study is approved by an ethics committee, the Dutch competent authority and the institutional review boards of both study centres. Results are intended for publication in peer-reviewed medical journals and for presentation to patients, healthcare professionals and other stakeholders. TRIAL REGISTRATION NUMBER: NCT03246321, Pre-results; ISRCTN89947480, Pre-results; NTR6603, Pre-results; EudraCT: 2017-000927-29, Pre-results.