Reclassification of Appendiceal Mucinous Neoplasms and Associated Pseudomyxoma Peritonei According to the Peritoneal Surface Oncology Group International Consensus: Clinicopathological Reflections of a Two-Center Cohort Study.

BACKGROUND: International consensus on classifications of appendiceal mucinous neoplasms (AMNs) and associated pseudomyxoma peritonei (PMP) have been carefully made but clinicopathological associations supporting decision making remain scarce. OBJECTIVE: This study aimed to assess interdependence between AMNs and PMP and provide directions for clinical management. METHODS: This two-center retrospective cohort study reviewed patients with PMP treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy between 2005 and 2021. The primary objective was to reassess histopathologic grade of AMNs and PMP according to the Peritoneal Surface Oncology Group International classification and to establish its interdependence. Secondary outcomes were recurrence rate, PMP grade progression, ovarian involvement, and overall survival (OS). RESULTS: Of 105 patients included, 78 (74.3%) had low-grade AMNs as the primary tumor, 8 (7.6%) had high-grade AMNs, 7 (6.7%) had mucinous adenocarcinoma (MAC), 1 (0.9%) had MAC with signet ring cells (SRC), and 11 (10.5%) had unidentified tumors. Overall, 11 patients (10.5%) had no PMP, 21 (20.0%) had acellular mucin, 56 (53.3%) had low-grade PMP, 12 (11.4%) had high-grade PMP, and 5 (4.8%) had PMP-SRC. In 11 cases (13.3%), AMNs and matching PMP grade differed. Over a 16-year follow-up, recurrence occurred in 31.8%, with three cases showing histopathologically changed PMP. Ovarian involvement was observed in 43/65 females (66.2%). Median OS was 13.8 years, and 5-year OS rates were 100%, 74.4%, 44.4%, and 20% for acellular mucin, low-grade PMP, high-grade PMP and PMP-SRC, respectively (p < 0.001). CONCLUSIONS: AMN histology does not always reflects its associated PMP grade, while PMP grade strongly influences survival. Ovarian involvement and recurrent PMP showing unchanged histopathological features are common.

Patient-reported outcomes during first-line palliative systemic therapy alternated with pressurized intraperitoneal aerosol chemotherapy for unresectable colorectal peritoneal metastases: a single-arm phase II trial (CRC-PIPAC-II).

BACKGROUND: The CRC-PIPAC-II study prospectively assessed bidirectional therapy (BT) consisting of first-line palliative systemic therapy and electrostatic precipitation oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (ePIPAC-OX) in patients with unresectable colorectal peritoneal metastases (CPM). This study describes the exploration of patient-reported outcomes (PROs). METHODS: In this phase II trial, 20 patients with isolated CPM were treated with up to three cycles of BT, each cycle consisting of two to three courses of systemic therapy, followed by ePIPAC-OX (92 mg/m2). Patients were asked to complete the EuroQoL EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-CR29 questionnaires at baseline, during the first cycle of BT, and one and four weeks after each consecutive BT cycle. PRO scores were calculated and compared between baseline and each subsequent time point using linear-mixed modeling (LMM). PROs were categorized into symptom scales and function scales. Symptom scales ranged from 0 to 100, with 100 representing the maximum symptom load. Function scales ranged from 0 to 100, with 100 representing optimal functioning. RESULTS: Twenty patients underwent a total of 52 cycles of bidirectional therapy. Most PROs (29 of 37, 78%) were not significantly affected during trial treatment. In total, only eight PROs (22%) were significantly affected during trial treatment: Six PROs (index value, global health status, emotional functioning, C30, appetite, and insomnia) showed transient improvement at different time points. Two PROs transiently deteriorated: pain initially improved during the first BT cycle [- 16, p < 0.001] yet worsened temporarily one week after the first two BT cycles (+ 20, p < 0.001; + 17, p = 0.004; respectively). Abdominal pain worsened temporarily one week after the first BT cycle (+ 16, p = 0.004), before improving again four weeks after treatment ended (- 10, p = 0.004). All significant effects on Pros were clinically significant and all deteriorations in PROs were of temporary nature. DISCUSSION: Patients undergoing BT for unresectable CPM had significant, but reversible alterations in several PROs. Most affected PROs concerned improvements and only two PROs showed deteriorations. Both deteriorated PROs returned to baseline after trial treatment and were of a temporary nature. These outcomes help to design future studies on the role of ePIPAC in the palliative setting.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Second and third look laparoscopy in pT4 colon cancer patients for early detection of peritoneal metastases; the COLOPEC 2 randomized multicentre trial.

BACKGROUND: Approximately 20-30% of patients with pT4 colon cancer develop metachronous peritoneal metastases (PM). Due to restricted accuracy of imaging modalities and absence of early symptoms, PM are often detected at a stage in which only a quarter of patients are eligible for curative intent treatment. Preliminary findings of the COLOPEC trial (NCT02231086) revealed that PM were already detected during surgical re-exploration within two months after primary resection in 9% of patients with pT4 colon cancer. Therefore, second look diagnostic laparoscopy (DLS) to detect PM at a subclinical stage may be considered an essential component of early follow-up in these patients, although this needs confirmation in a larger patient cohort. Furthermore, a third look DLS after a negative second look DLS might be beneficial for detection of PM occurring at a later stage. METHODS: The aim of this study is to determine the yield of second look DLS and added value of third look DLS after negative second look DLS in detecting occult PM in pT4N0-2 M0 colon cancer patients after completion of primary treatment. Patients will undergo an abdominal CT at 6 months postoperative, followed by a second look DLS within 1 month if no PM or other metastases not amenable for local treatment are detected. Patients without PM will subsequently be randomized between routine follow-up including 18 months abdominal CT, or an experimental arm with a third look DLS provided that PM or incurable metastases are absent at the 18 months abdominal CT. Primary endpoint is the proportion of PM detected after a negative second look DLS and will be determined at 20 months postoperative. DISCUSSION: Second look DLS is supposed to result in 10% occult PM, and third look DLS after negative second look DLS is expected to detect an additional 10% of PM compared to routine follow-up alone in patients with pT4 colon cancer. Detection of PM at an early stage will likely increase the proportion of patients eligible for curative intent treatment and subsequently improve survival, given the uniformly reported direct association between the extent of peritoneal disease and survival. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03413254 , January 2018.

Perioperative systemic therapy and cytoreductive surgery with HIPEC versus upfront cytoreductive surgery with HIPEC alone for isolated resectable colorectal peritoneal metastases: protocol of a multicentre, open-label, parallel-group, phase II-III, randomised, superiority study (CAIRO6)

BACKGROUND: Upfront cytoreductive surgery with HIPEC (CRS-HIPEC) is the standard treatment for isolated resectable colorectal peritoneal metastases (PM) in the Netherlands. This study investigates whether addition of perioperative systemic therapy to CRS-HIPEC improves oncological outcomes. METHODS: This open-label, parallel-group, phase II-III, randomised, superiority study is performed in nine Dutch tertiary referral centres. Eligible patients are adults who have a good performance status, histologically or cytologically proven resectable PM of a colorectal adenocarcinoma, no systemic colorectal metastases, no systemic therapy for colorectal cancer within six months prior to enrolment, and no previous CRS-HIPEC. Eligible patients are randomised (1:1) to perioperative systemic therapy and CRS-HIPEC (experimental arm) or upfront CRS-HIPEC alone (control arm) by using central randomisation software with minimisation stratified by a peritoneal cancer index of 0-10 or 11-20, metachronous or synchronous PM, previous systemic therapy for colorectal cancer, and HIPEC with oxaliplatin or mitomycin C. At the treating physician's discretion, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles. The first 80 patients are enrolled in a phase II study to explore the feasibility of accrual and the feasibility, safety, and tolerance of perioperative systemic therapy. If predefined criteria of feasibility and safety are met, the study continues as a phase III study with 3-year overall survival as primary endpoint. A total of 358 patients is needed to detect the hypothesised 15% increase in 3-year overall survival (control arm 50%; experimental arm 65%). Secondary endpoints are surgical characteristics, major postoperative morbidity, progression-free survival, disease-free survival, health-related quality of life, costs, major systemic therapy related toxicity, and objective radiological and histopathological response rates. DISCUSSION: This is the first randomised study that prospectively compares oncological outcomes of perioperative systemic therapy and CRS-HIPEC with upfront CRS-HIPEC alone for isolated resectable colorectal PM. TRIAL REGISTRATION: Clinicaltrials.gov/ NCT02758951 , NTR/ NTR6301 , ISRCTN/ ISRCTN15977568 , EudraCT/ 2016-001865-99 .

Tobramycin Clearance Is Best Described by Renal Function Estimates in Obese and Non-obese Individuals: Results of a Prospective Rich Sampling Pharmacokinetic Study.

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 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.

Prophylactic Mesh Placement During Formation of an End-colostomy Reduces the Rate of Parastomal Hernia: Short-term Results of the Dutch PREVENT-trial.

OBJECTIVE: The aim of this study was to investigate the incidence of parastomal hernias (PSHs) after end-colostomy formation using a polypropylene mesh in a randomized controlled trial versus conventional colostomy formation. BACKGROUND: A PSH is the most frequent complication after stoma formation. Symptoms may range from mild abdominal pain to life-threatening obstruction and strangulation. The treatment of a PSH is notoriously difficult and recurrences up to 20% have been reported despite the use of mesh. This has moved surgical focus toward prevention. METHODS: Augmentation of the abdominal wall with a retro-muscular lightweight polypropylene mesh was compared with the traditional formation of a colostomy. In total, 150 patients (1:1 ratio) were included. The incidence of a PSH, morbidity, mortality, quality of life, and cost-effectiveness was measured after 1 year of follow-up. RESULTS: There was no difference between groups regarding demographics and predisposing factors for PSH. Three out of 67 patients (4.5%) in the mesh group and 16 out of 66 patients (24.2%) in the nonmesh group developed a PSH (P = 0.0011). No statistically significant difference was found in infections, concomitant hernias, SF-36 questionnaire, Von Korff pain score, and cost-effectiveness between both study groups. CONCLUSION: Prophylactic augmentation of the abdominal wall with a retromuscular lightweight polypropylene mesh at the ostomy site significantly reduces the incidence of PSH without a significant difference in morbidity, mortality, quality of life, or cost-effectiveness.

Treatment-Related Mortality After Cytoreductive Surgery and HIPEC in Patients with Colorectal Peritoneal Carcinomatosis is Underestimated by Conventional Parameters.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) as treatment for patients with colorectal peritoneal carcinomatosis (PC) is regarded as an extensive procedure. The risk of postoperative mortality after major abdominal surgery might be substantially higher than described by the 30-day mortality. This study aims to identify causes of 1-year mortality, thereby assessing a more accurate treatment-related mortality rate after CRS + HIPEC. METHODS: All subsequent patients with colorectal PC treated with CRS + HIPEC with complete macroscopic cytoreduction in two tertiary hospitals between April 2005 and April 2013 were included in this study. Causes of 1-year mortality were carefully analyzed and patient data were compared between patients who died or did not die within 12 months after CRS + HIPEC. RESULTS: Of the 245 included patients, 34 (13.9 %) died within 12 months after CRS + HIPEC. The overall treatment-related mortality rate was 4.9 % (n = 12), and the 30-day and in-hospital mortality rates were 1.6 % (n = 4) and 2.4 % (n = 6), respectively. Furthermore, 18 patients (7.3 %) died due to early recurrent disease. Three patients (1.2 %) died of cardiovascular events, unrelated to CRS + HIPEC. The 1-year mortality group had more extensive peritoneal disease (p = 0.02) and the operative time in this group was longer (p < 0.001). CONCLUSIONS: Overall treatment-related mortality was considerably higher than described by the 30-day and in-hospital mortality rate. However, even though complete macroscopic cytoreduction was achieved in every patient, the main cause of 1-year mortality was early recurrent disease. Both findings are valuable in preoperative patient selection, as well as in preoperative counseling of patients undergoing a CRS + HIPEC procedure.

Cytoreductive surgery and HIPEC offers similar outcomes in patients with rectal peritoneal metastases compared to colon cancer patients: a matched case control study.

BACKGROUND & OBJECTIVES: The effect of cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with rectal peritoneal metastases (PM) is unclear. This case-control study aims to assess the results of cytoreduction and HIPEC in patients with rectal PM compared to colon PM patients. METHODS: Colorectal PM patients treated with complete macroscopic cytoreduction and HIPEC were included. Two colon cancer patients were case-matched for each rectal cancer patient, based on prognostic factors (T stage, N stage, histology type, and extent of PM). Short- and long-term outcomes were compared between both groups. RESULTS: From 317 patients treated with complete macroscopic cytoreduction and HIPEC, 29 patients (9.1%) had rectal PM. Fifty-eight colon cases were selected as control patients. Baseline characteristics were similar between groups. Major morbidity was 27.6% and 34.5% in the rectal and colon group, respectively (P = 0.516). Median disease-free survival was 13.5 months in the rectal group and 13.6 months in the colon group (P = 0.621). Two- and five-year overall survival rates were 54%/32% in rectal cancer patients, and 61%/24% in colon cancer patients (P = 0.987). CONCLUSIONS: Cytoreduction and HIPEC in selected patients with rectal PM is feasible and provides similar outcomes as in colon cancer patients. Rectal PM should not be regarded a contra-indication for cytoreduction and HIPEC in selected patients. J. Surg. Oncol. 2016;113:548-553. © 2016 Wiley Periodicals, Inc.

Skeletal Muscle Depletion is Associated with Severe Postoperative Complications in Patients Undergoing Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis of Colorectal Cancer.

BACKGROUND: In patients undergoing colorectal cancer surgery, skeletal muscle depletion (sarcopenia) is associated with impaired postoperative recovery and decreased survival. This study aimed to determine whether skeletal muscle depletion can predict postoperative complications for patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for peritoneal carcinomatosis of colorectal cancer. METHODS: All consecutive patients with an available preoperative computed tomography (CT) scan who underwent CRS-HIPEC for peritoneal carcinomatosis of colorectal cancer in two centers were analyzed. Skeletal muscle mass was determined using the L3 muscle index on the preoperative CT scan. The cutoff values defined by Prado et al. were used to classify the patients as sarcopenic or nonsarcopenic. RESULTS: Of the study's 206 patients, 90 (43.7 %) were classified as sarcopenic. The sarcopenic patients underwent significantly more reoperations than the nonsarcopenic patients (25.6 vs. 12.1 %; p = 0.012). The mean L3 muscle index was significantly lower for the patients who experienced severe postoperative complications than for the patients without severe postoperative complications (85.6 vs. 110.2 cm(2)/m(2); p = 0.008). In a multivariable logistic regression model, L3 muscle index was the only parameter independently associated with the risk of severe postoperative complications (odds ratio 0.93; 95 % confidence interval 0.87-0.99; p = 0.018). CONCLUSION: Skeletal muscle mass depletion, assessed using CT-based muscle mass measurements, is associated with an increased risk of severe postoperative complications in patients undergoing CRS-HIPEC for colorectal peritoneal carcinomatosis and could therefore be used in preoperative risk assessment.