Towards Equal Access to Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy and Survival in Patients with Isolated Colorectal Peritoneal Metastases: A Nationwide Population-Based Study.

BACKGROUND: Before 2016, patients with isolated synchronous colorectal peritoneal metastases (PMCRC) diagnosed in expert centers had a higher odds of undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) and better overall survival (OS) than those diagnosed in referring centers. Nationwide efforts were initiated to increase awareness and improve referral networks. METHODS: This nationwide study aimed to evaluate whether the between-center differences in odds of undergoing CRS-HIPEC and OS have reduced since these national efforts were initiated. All patients with isolated synchronous PMCRC diagnosed between 2009 and 2021 were identified from the Netherlands Cancer Registry. Associations between hospital of diagnosis and the odds of undergoing CRS-HIPEC, as well as OS, were assessed using multilevel multivariable regression analyses for two periods (2009-2015 and 2016-2021). RESULTS: In total, 3948 patients were included. The percentage of patients undergoing CRS-HIPEC increased from 17.2% in 2009-2015 (25.4% in expert centers, 16.5% in referring centers), to 23.4% in 2016-2021 (30.2% in expert centers, 22.6% in referring centers). In 2009-2015, compared with diagnosis in a referring center, diagnosis in a HIPEC center showed a higher odds of undergoing CRS-HIPEC (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.02-2.67) and better survival (hazard ratio [HR] 0.80, 95% CI 0.66-0.96). In 2016-2021, there were no differences in the odds of undergoing CRS-HIPEC between patients diagnosed in HIPEC centers versus referring centers (OR 1.27, 95% CI 0.76-2.13) and survival (HR 1.00, 95% CI 0.76-1.32). CONCLUSION: Previously observed differences in odds of undergoing CRS-HIPEC were no longer present. Increased awareness and the harmonization of treatment for PMCRC may have contributed to equal access to care and a similar chance of survival at a national level.

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.

Omentectomy as Part of Radical Surgery for Gastric Cancer: 5-Year Follow-Up Results of a Multicenter Prospective Cohort Study.

INTRODUCTION: Curative therapy for gastric cancer usually consists of perioperative chemotherapy combined with a radical (R0) gastrectomy. In addition to a modified D2 lymphadenectomy, a complete omentectomy is recommended. However, there is little evidence for a survival benefit of omentectomy. This study presents the follow-up data of the OMEGA study. METHODS: This multicenter prospective cohort study included 100 consecutive patients with gastric cancer undergoing (sub)total gastrectomy with complete en bloc omentectomy and modified D2 lymphadenectomy. Primary outcome of the current study was 5-year overall survival. Patients with or without omental metastases were compared. Pathological factors associated with locoregional recurrence and/or metastases were tested with multivariable regression analysis. RESULTS: Of 100 included patients, five had metastases in the greater omentum. Five-year overall survival was 0.0% in patients with omental metastases and 44.2% in patients without omental metastases (p = 0.001). Median overall survival time for patients with or without omental metastases was 7 months and 53 months. A (y)pT3-4 stage tumor and vasoinvasive growth were associated with locoregional recurrence and/or metastases in patients without omental metastases. CONCLUSION: The presence of omental metastases in gastric cancer patients who underwent potentially curative surgery was associated with impaired overall survival. Omentectomy as part of radical gastrectomy for gastric cancer might not contribute to a survival benefit in case of undetected omental metastases.

Fibroblast activation protein identifies Consensus Molecular Subtype 4 in colorectal cancer and allows its detection by 68Ga-FAPI-PET imaging.

BACKGROUND: In colorectal cancer (CRC), the consensus molecular subtype 4 (CMS4) is associated with therapy resistance and poor prognosis. Clinical diagnosis of CMS4 is hampered by locoregional and temporal variables influencing CMS classification. Diagnostic tools that comprehensively detect CMS4 are therefore urgently needed. METHODS: To identify targets for molecular CMS4 imaging, RNA sequencing data of 3232 primary CRC patients were explored. Heterogeneity of marker expression in relation to CMS4 status was assessed by analysing 3-5 tumour regions and 91.103 single-tumour cells (7 and 29 tumours, respectively). Candidate marker expression was validated in CMS4 peritoneal metastases (PM; n = 59). Molecular imaging was performed using the 68Ga-DOTA-FAPI-46 PET tracer. RESULTS: Fibroblast activation protein (FAP) mRNA identified CMS4 with very high sensitivity and specificity (AUROC > 0.91), and was associated with significantly shorter relapse-free survival (P = 0.0038). Heterogeneous expression of FAP among and within tumour lesions correlated with CMS4 heterogeneity (AUROC = 1.00). FAP expression was homogeneously high in PM, a near-homogeneous CMS4 entity. FAPI-PET identified focal and diffuse PM that were missed using conventional imaging. Extra-peritoneal metastases displayed extensive heterogeneity of tracer uptake. CONCLUSION: FAP expression identifies CMS4 CRC. FAPI-PET may have value in the comprehensive detection of CMS4 tumours in CRC. This is especially relevant in patients with PM, for whom effective imaging tools are currently lacking.

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.

Functional Dyspepsia and Irritable Bowel Syndrome are Highly Prevalent in Patients With Gallstones and Are Negatively Associated With Outcomes After Cholecystectomy: A Prospective, Multicenter, Observational Study (PERFECT - Trial).

OBJECTIVE: To determine the prevalence of FD and IBS in patients eligible for cholecystectomy and to investigate the association between presence of FD/ IBS and resolution of biliary colic and a pain-free state. SUMMARY BACKGROUND DATA: More than 30% of patients with symptomatic cholecystolithiasis reports persisting pain postcholecystectomy. Coexistence of FD/IBS may contribute to this unsatisfactory outcome. METHODS: We conducted a multicenter, prospective, observational study (PERFECT-trial). Patients ≥18 years with abdominal pain and gallstones were included at 5 surgical outpatient clinics between 01/2018 and 04/2019. Follow-up was 6 months. Primary outcomes were prevalence of FD/IBS, and the difference between resolution of biliary colic and pain-free state in patients with and without FD/IBS. FD/IBS was defined by the Rome IV criteria, biliary colic by the Rome III criteria, and pain-free by an Izbicki Pain Score ≤10 and visual analogue scale ≤4. RESULTS: We included 401 patients with abdominal pain and gallstones (assumed eligible for cholecystectomy), mean age 52 years, 76% females. Of these, 34.9% fulfilled criteria for FD/IBS. 64.1% fulfilled criteria for biliary colic and 74.9% underwent cholecystectomy, with similar operation rates in patients with and without FD/IBS. Postcholecystectomy, 6.1% of patients fulfilled criteria for biliary colic, with no significant difference between those with and without FD/IBS at baseline (4.9% vs 8.6%, P = 0.22). Of all patients, 56.8% was pain-free after cholecystectomy, 40.7% of FD/IBS-group vs 64.4% of no FD/IBS-group, P < 0.001. CONCLUSIONS: One third of patients eligible for cholecystectomy fulfil criteria for FD/IBS. Biliary colic is reported by only a few patients postcholecys-tectomy, whereas nonbiliary abdominal pain persists in >40%, particularly in those with FD/IBS precholecystectomy. Clinicians should take these symptom-dependent outcomes into account in their shared decision-making process. TRIAL REGISTRATION: The Netherlands Trial Register NTR-7307. Registered on 18 June 2018.

Outcomes of Combined Peritoneal and Local Treatment for Patients with Peritoneal and Limited Liver Metastases of Colorectal Origin: A Systematic Review and Meta-Analysis.

BACKGROUND: Almost half of all colorectal cancer (CRC) patients will experience metastases at some point, and in the majority of cases, multiple organs will be involved. If the peritoneum is involved in addition to the liver, the current guideline-driven treatment options are limited. The reported overall survival ranges from 6 to 13 months for the current standard of care (systemic treatment). This study aimed to evaluate morbidity and clinical long-term outcomes from a combined local treatment of hepatic metastases with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) used to treat peritoneal metastases. METHODS: A systematic search was performed in PubMed, Embase.com, Web of Science, and Cochrane. Studies evaluating the clinicopathologic data of patients who had both peritoneal and hepatic metastases treated with CRS-HIPEC were included provided sufficient data on the primary outcomes (overall and disease-free survival) were presented. The quality of included studies was assessed using the Methodological Index for Non-Randomized Studies (MINORS). RESULTS: Patients treated for peritoneal and liver metastases (PMLM group) had a pooled mean survival of 26.4 months (95% confidence interval [CI] 22.4-30.4 months), with a 3-year survival rate of 34% (95% CI 26.7-42.0%) and a 5-year survival rate of 25% (95% CI 17.3-33.8%). Surgical complications occurred more frequently for these patients than for those with peritoneal metastasis only (40% vs 22%; p = 0.0014), but the mortality and reoperation rates did not differ significantly. CONCLUSION: This systematic review showed that CRS and HIPEC combined with local treatment of limited liver metastasis for selected patients is feasible, although with increased morbidity and an association with a long-term survival rate of 25%, which is unlikely to be achievable with systemic treatment only.

Antibiotic prophylaxis for acute cholecystectomy: PEANUTS II multicentre randomized non-inferiority clinical trial.

BACKGROUND: Guidelines recommending antibiotic prophylaxis at emergency cholecystectomy for cholecystitis were based on low-quality evidence. The aim of this trial was to demonstrate that omitting antibiotics is not inferior to their prophylactic use. METHODS: This multicentre, randomized, open-label, non-inferiority clinical trial randomly assigned adults with mild-to-moderate acute calculous cholecystitis (immediate cholecystectomy indicated) to 2 g cefazolin administered before incision or no antibiotic prophylaxis. The primary endpoint was a composite of all postoperative infectious complications in the first 30 days after surgery. Secondary endpoints included all individual components of the primary endpoint, other morbidity, and duration of hospital stay. RESULTS: Sixteen of 226 patients (7.1 per cent) in the single-dose prophylaxis group and 29 of 231 (12.6 per cent) in the no-prophylaxis group developed postoperative infectious complications (absolute difference 5.5 (95 per cent c.i. -0.4 to 11.3) per cent). With a non-inferiority margin of 10 per cent, non-inferiority of no prophylaxis was not proven. The number of surgical-site infections was significantly higher in the no-prophylaxis group (5.3 versus 12.1 per cent; P = 0.010). No differences were observed in the number of other complications, or duration of hospital stay. CONCLUSION: Omitting antibiotic prophylaxis is not recommended.

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.

Unusual site of pseudomyxoma peritonei recurrence after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a case report of intraluminal disease manifestation in the small bowel.

BACKGROUND: Pseudomyxoma peritonei (PMP) is an uncommon clinical condition characterized by the presence of mucinous ascites, mainly induced by perforated appendiceal mucinous neoplasms (AMN). The peritoneal surface of the small bowel is usually spared from disease manifestation due to peristaltic movements. Mucinous tumours can disseminate as PMP on the entire peritoneum, but are rarely intraluminal. For the first time in literature, we report a case of intraluminal PMP involving the ileum. CASE PRESENTATION: A 75-year-old male was treated for perforated AMN and disseminated PMP with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. During follow-up, the patient developed intraperitoneal recurrence together with intraluminal depositions in the ileum, both disease manifestations with identical KRAS and SMAD4 mutations. Hereafter, the patient was treated with palliative care. CONCLUSION: This case illustrates the variation in the biological and clinical behaviour of this rare disease. Clinicians should be aware of unusual tumour distribution patterns of PMP, including the presence of mucinous tumour within the small bowel.

Systemic Pharmacokinetics of Oxaliplatin After Intraperitoneal Administration by Electrostatic Pressurized Intraperitoneal Aerosol Chemotherapy (ePIPAC) in Patients with Unresectable Colorectal Peritoneal Metastases in the CRC-PIPAC Trial.

BACKGROUND: Electrostatic pressurized intraperitoneal aerosol chemotherapy (ePIPAC) is a palliative treatment for unresectable peritoneal metastases from various primary cancers. However, little is known about the systemic pharmacokinetics of oxaliplatin after ePIPAC. METHODS: Twenty patients with unresectable colorectal peritoneal metastases were treated with repetitive ePIPAC monotherapy with oxaliplatin (92 mg/m2) and a simultaneous intravenous bolus of leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Samples were collected during each ePIPAC: whole blood at t = 0, t = 5, t = 10, t = 20, t = 30, t = 60, t = 120, t = 240, t = 360 and t = 1080 min for plasma and plasma ultrafiltrate concentrations; urine at t = 0, t = 1, t = 3, t = 5 and t = 7 days. Samples were analyzed using atomic absorption spectrometry. Pharmacokinetics were analyzed using nonlinear mixed-effects modeling. RESULTS: Four patients received one ePIPAC, three patients received two ePIPAC, and thirteen patients received ≥ 3 ePIPAC. The population pharmacokinetic models adequately described the pharmacokinetics of oxaliplatin after ePIPAC. The plasma ultrafiltrate Cmax of oxaliplatin reached 1.36-1.90 µg/mL after 30 min with an AUC0-24 h of 9.6-11.7 µg/mL * h. The plasma Cmax reached 2.67-3.28 µg/mL after 90 min with an AUC0-24 h of 49.0-59.5 µg/mL * h. The absorption rate constant (Ka) was 1.13/h. Urine concentrations of oxaliplatin rapidly decreased to less than 3.60 µg/mL in 90% of the samples at day 7. DISCUSSION: Systemic exposure to oxaliplatin after ePIPAC seemed comparable to that after systemic chemotherapy, as described in other literature. Since this is an indirect comparison, future research should focus on the direct comparison between the systemic exposure to oxaliplatin after ePIPAC and after systemic chemotherapy. TRIAL REGISTRATION: NCT03246321, Pre-results; ISRCTN89947480, Pre-results; NTR6603, Pre-results; EudraCT: 2017-000927-29, Pre-results.

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.

Tumor characteristics and clinical outcome of peritoneal metastasis of gastric origin treated with a hyperthermic intraperitoneal chemotherapy procedure in the PERISCOPE I trial.

INTRODUCTION: The PERISCOPE I (Treatment of PERItoneal dissemination in Stomach Cancer patients with cytOreductive surgery and hyPErthermic intraperitoneal chemotherapy) study was conducted to investigate the safety and feasibility of hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer patients with limited peritoneal dissemination. In this study, tumor characteristics and clinical outcome of the patients treated in the PERISCOPE I trial were investigated. METHODS: Patients who had undergone the full study protocol were selected; that is, preoperative systemic chemotherapy, followed by a surgical procedure consisting of a (sub)total gastrectomy, cytoreductive surgery, and HIPEC with oxaliplatin (460 mg/m2 ) and docetaxel (in escalating doses). RESULTS: Twenty-five PERISCOPE I patients underwent the full study protocol. Most patients had an ypT3-4 tumor (96%) and the diffuse-type histology was predominant (64%). Seven patients (28%) had a microscopically irradical (R1) resection. In all patients, a complete cytoreduction was achieved. Median follow-up was 37 (95% confidence interval [CI]: 34-39) months. Disease recurrence was detected in 17 patients (68%). Median disease-free and overall survival were 12 and 15 months, respectively. CONCLUSION: In this series of gastric cancer patients with limited peritoneal dissemination who underwent HIPEC surgery, unfavorable tumor characteristics were common. Survival might be encouraging but disease recurrence was frequent. The efficacy of an HIPEC procedure in improving prognosis is currently being investigated in the PERISCOPE II trial.

Restrictive strategy versus usual care for cholecystectomy in patients with gallstones and abdominal pain (SECURE): a multicentre, randomised, parallel-arm, non-inferiority trial.

BACKGROUND: International guidelines advise laparoscopic cholecystectomy to treat symptomatic, uncomplicated gallstones. Usual care regarding cholecystectomy is associated with practice variation and persistent post-cholecystectomy pain in 10-41% of patients. We aimed to compare the non-inferiority of a restrictive strategy with stepwise selection with usual care to assess (in)efficient use of cholecystectomy. METHODS: We did a multicentre, randomised, parallel-arm, non-inferiority study in 24 academic and non-academic hospitals in the Netherlands. We enrolled patients aged 18-95 years with abdominal pain and ultrasound-proven gallstones or sludge. Patients were randomly assigned (1:1) to either usual care in which selection for cholecystectomy was left to the discretion of the surgeon, or a restrictive strategy with stepwise selection for cholecystectomy. For the restrictive strategy, cholecystectomy was advised for patients who fulfilled all five pre-specified criteria of the triage instrument: 1) severe pain attacks, 2) pain lasting 15-30 min or longer, 3) pain located in epigastrium or right upper quadrant, 4) pain radiating to the back, and 5) a positive pain response to simple analgesics. Randomisation was done with an online program, implemented into a web-based application using blocks of variable sizes, and stratified for centre (academic versus non-academic and a high vs low number of patients), sex, and body-mass index. Physicians and patients were masked for study-arm allocation until after completion of the triage instrument. The primary, non-inferiority, patient-reported endpoint was the proportion of patients who were pain-free at 12 months' follow-up, analysed by intention to treat and per protocol. A 5% non-inferiority margin was chosen, based on the estimated clinically relevant difference. Safety analyses were also done in the intention-to treat population. This trial is registered at the Netherlands National Trial Register, number NTR4022. FINDINGS: Between Feb 5, 2014, and April 25, 2017, we included 1067 patients for analysis: 537 assigned to usual care and 530 to the restrictive strategy. At 12 months' follow-up 298 patients (56%; 95% CI, 52·0-60·4) were pain-free in the restrictive strategy group, compared with 321 patients (60%, 55·6-63·8) in usual care. Non-inferiority was not shown (difference 3·6%; one-sided 95% lower CI -8·6%; pnon-inferiority=0·316). According to a secondary endpoint analysis, the restrictive strategy resulted in significantly fewer cholecystectomies than usual care (358 [68%] of 529 vs 404 [75%] of 536; p=0·01). There were no between-group differences in trial-related gallstone complications (40 patients [8%] of 529 in usual care vs 38 [7%] of 536 in restrictive strategy; p=0·16) and surgical complications (74 [21%] of 358 vs 88 [22%] of 404, p=0·77), or in non-trial-related serious adverse events (27 [5%] of 529 vs 29 [5%] of 526). INTERPRETATION: Suboptimal pain reduction in patients with gallstones and abdominal pain was noted with both usual care and following a restrictive strategy for selection for cholecystectomy. However, the restrictive strategy was associated with fewer cholecystectomies. The findings should encourage physicians involved in the care of patients with gallstones to rethink cholecystectomy, and to be more careful in advising a surgical approach in patients with gallstones and abdominal symptoms. FUNDING: The Netherlands Organization for Health Research and Development, and CZ healthcare insurance.

Minimally Invasive Versus Open Distal Pancreatectomy (LEOPARD): A Multicenter Patient-blinded Randomized Controlled Trial.

OBJECTIVE: This trial followed a structured nationwide training program in minimally invasive distal pancreatectomy (MIDP), according to the IDEAL framework for surgical innovation, and aimed to compare time to functional recovery after minimally invasive and open distal pancreatectomy (ODP). BACKGROUND: MIDP is increasingly used and may enhance postoperative recovery as compared with ODP, but randomized studies are lacking. METHODS: A multicenter patient-blinded randomized controlled superiority trial was performed in 14 centers between April 2015 and March 2017. Adult patients with left-sided pancreatic tumors confined to the pancreas without vascular involvement were randomly assigned (1:1) to undergo MIDP or ODP. Patients were blinded for type of surgery using a large abdominal dressing. The primary endpoint was time to functional recovery. Analysis was by intention to treat. This trial was registered with the Netherlands Trial Register (NTR5689). RESULTS: Time to functional recovery was 4 days [interquartile range (IQR) 3-6) in 51 patients after MIDP versus 6 days (IQR 5-8) in 57 patients after ODP (P < 0.001). The conversion rate of MIDP was 8%. Operative blood loss was less after MIDP (150 vs 400 mL; P < 0.001), whereas operative time was longer (217 vs 179 minutes; P = 0.005). The Clavien-Dindo grade ≥III complication rate was 25% versus 38% (P = 0.21). Delayed gastric emptying grade B/C was seen less often after MIDP (6% vs 20%; P = 0.04). Postoperative pancreatic fistulas grade B/C were seen in 39% after MIDP versus 23% after ODP (P = 0.07), without difference in percutaneous catheter drainage (22% vs 20%; P = 0.77). Quality of life (day 3-30) was better after MIDP as compared with ODP, and overall costs were non-significantly less after MIDP. No 90-day mortality was seen after MIDP versus 2% (n = 1) after ODP. CONCLUSIONS: In patients with left-sided pancreatic tumors confined to the pancreas, MIDP reduces time to functional recovery compared with ODP. Although the overall rate of complications was not reduced, MIDP was associated with less delayed gastric emptying and better quality of life without increasing costs.

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 .

Intestinal Mucosal and Serosal Microcirculation at the Planned Anastomosis during Abdominal Surgery.

INTRODUCTION: Intestinal blood flow is often named as a key factor in the pathophysiology of anastomotic leakage. The distribution between mucosal and serosal microperfusion during surgery remains to be elucidated. OBJECTIVE: The aim of this study was to assess if the mucosal microcirculation of the intestine is more vulnerable to a surgical hit than the serosal microcirculation during surgery. METHODS: In an observational cohort study (n = 9 patients), the microcirculation of the bowel serosa and mucosa was visualized with incident dark-field imaging during surgery. At the planned anastomosis, the following microcirculatory parameters were determined: microvascular flow index (MFI), percentage of perfused vessels (PPV), perfused vessel density (PVD), and total vessel density (TVD). Data are presented as median (interquartile range [IQR]). RESULTS: Perfusion parameters and vessel density were significantly higher for the mucosa than the serosal microcirculation at the planned site for anastomosis or stoma. Mucosal MFI was 3.00 (IQR 3.00-3.00) compared to a serosal MFI of 2.75 (IQR 2.21-2.94), p = 0.03. The PPV was 99% (IQR 98-100) versus 92% (IQR 66-94), p = 0.01. The TVD was 16.77 mm/mm2 (IQR 13.04-18.01) versus 10.42 mm/mm2 (IQR 9.36-11.81), p = 0.01, and the PVD was 15.44 mm/mm2 (IQR 13.04-17.78) versus 9.02 mm/mm2 (IQR 6.43-9.43), p = 0.01. CONCLUSIONS: The mucosal microcirculation was preserved, while lower perfusion of the serosa was found at the planned anastomosis or stoma during surgery. Further research is needed to link our observations to the clinically relevant endpoint of anastomotic leakage.