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Colorectal cancer is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways 1 . Here, to understand the functional and prognostic impact of cancer-causing somatic mutations, we analysed the whole genomes and transcriptomes of 1,063 primary colorectal cancers in a population-based cohort with long-term follow-up. From the 96 mutated driver genes, 9 were not previously implicated in colorectal cancer and 24 had not been linked to any cancer. Two distinct patterns of pathway co-mutations were observed, timing analyses identified nine early and three late driver gene mutations, and several signatures of colorectal-cancer-specific mutational processes were identified. Mutations in WNT, EGFR and TGFβ pathway genes, the mitochondrial CYB gene and 3 regulatory elements along with 21 copy-number variations and the COSMIC SBS44 signature correlated with survival. Gene expression classification yielded five prognostic subtypes with distinct molecular features, in part explained by underlying genomic alterations. Microsatellite-instable tumours divided into two classes with different levels of hypoxia and infiltration of immune and stromal cells. To our knowledge, this study constitutes the largest integrated genome and transcriptome analysis of colorectal cancer, and interlinks mutations, gene expression and patient outcomes. The identification of prognostic mutations and expression subtypes can guide future efforts to individualize colorectal cancer therapy., (© 2024. The Author(s).)

Background: The greater omentum is routinely resected during cytoreductive surgery (CRS), but few studies have analyzed the rationale behind this. This study aimed to assess the prevalence of omental metastases (OM) and the correlation between macroscopically suspected and microscopically confirmed OM, in patients with pseudomyxoma peritonei (PMP) or colorectal peritoneal metastases (PM)., Method: All patients without previous omentectomy, treated with initial CRS and hyperthermic intraperitoneal chemotherapy for PMP or colorectal PM, at Uppsala University Hospital in 2013-2021, were included. Macroscopic OM in surgical reports was compared with histopathological analyses., Results: In all, 276 patients were included. In those with PMP, 112 (98%) underwent omentectomy and 67 (59%) had macroscopic suspicion of OM. In 5 (4%) patients, the surgeon was uncertain. Histopathology confirmed OM in 81 (72%). In patients with macroscopic suspicion, 96% had confirmed OM (positive predictive value, PPV). In patients with no suspicion, 24% had occult OM (negative predictive value, NPV = 76%). In patients with colorectal PM, 156 (96%) underwent omentectomy and 97 (60%) had macroscopic suspicion. For 5 (3%) patients, the surgeon was uncertain. OM was microscopically confirmed in 90 (58%). PPV was 85% and NPV was 89%. The presence of OM was a univariate risk factor for death in PMP (HR 3.62, 95%CI 1.08-12.1) and colorectal PM (HR 1.67, 95%CI 1.07-2.60), but not in multivariate analyses., Conclusion: OM was common and there was a high risk of missing occult OM in both PMP and colorectal PM. These results support the practice of routine omentectomy during CRS.

Background: Peritoneal cancer index (PCI) >20 is often seen as a contraindication for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastases (PM) from colorectal cancer. The aim of this study was to compare the overall survival in colorectal PM patients with PCI >20 and PCI ≤20 treated with CRS and HIPEC to those having open-close/debulking procedure only., Methods: All patients with colorectal PM and intention to treat with CRS and HIPEC in Uppsala Sweden 2004-2017 were included. Patients scheduled for CRS and HIPEC were divided into three groups, PCI >20, PCI ≤20, and those not operated with CRS and HIPEC stated as open-close including those treated with palliative debulking., Results: Of 201 operations, 112 (56%) resulted in CRS and HIPEC with PCI ≤20, 45 (22%) in CRS and HIPEC with PCI >20 and 44 (22%) resulted in open-close/debulking. Median survival for CRS and HIPEC and PCI >20 was 20 months (95%CI 14-27 months) with 7% surviving longer than 5 years (n = 3). For CRS and HIPEC and PCI ≤20 the median survival was 33 months (95%CI 30-39 months) with 23% (n = 26) surviving >5years. The median survival for open-close was 9 months (95%CI 4-10 months), no one survived >5years., Conclusion: Patients with PM from colorectal cancer and PCI >20 that were treated with CRS and HIPEC experience a one year longer and doubled overall survival compared with open-close/debulking patients. In addition to PCI, more factors should be taken into account when a decision about proceeding with CRS or not is taken., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: KRAS and BRAF mutations are prognostic and predictive tools in metastatic colorectal cancer, but little is known about their prognostic value in patients scheduled for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Therefore, we analyzed the prognostic impact of KRAS and BRAF mutations in patients with peritoneal metastases scheduled for CRS and HIPEC., Patients and Methods: In a consecutive series of 399 patients scheduled for CRS and HIPEC between 2009 and 2017, 111 subjects with peritoneal metastases from primaries of the appendix, colon, or rectum were analyzed for KRAS mutation and 92 for BRAF mutation., Results: Mutation in KRAS was present in 51/111 (46%), and mutated BRAF was found in 10/92 (11%). There was no difference in overall survival between KRAS mutation tumors and KRAS wild type, whereas BRAF mutation was associated with short survival. No subject with BRAF mutation survived 2 years. On multivariate analysis, completeness of cytoreduction score (CCS, p = 0.000001), presence of signet cell differentiation (p = 0.000001), and BRAF mutation (p = 0.0021) were linked with poor prognosis., Conclusions: BRAF mutation is a marker of poor prognosis in patients with appendiceal and colorectal peritoneal metastases scheduled for CRS and HIPEC, whereas survival outcome in subjects with mutated KRAS does not differ from wild-type KRAS. This finding suggests that those with BRAF mutation should be considered for alternative treatment options.

Purpose: Genetic alterations in colorectal peritoneal metastases (PM) are largely unknown. This study was designed to analyze whole-genome copy number alterations (CNA) in colorectal PM and to identify alterations associated with prognosis after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)., Methods: All patients with PM, originating from a colorectal adenocarcinoma, who were treated with CRS and HIPEC in Uppsala Sweden, between 2004 and 2015, were included (n = 114). DNA derived from formalin-fixed paraffin-embedded (FFPE) specimens were analyzed for CNA using molecular inversion probe arrays., Results: There were extensive but varying degrees of CNA, ranging from minimal CNA to total aneuploidy. In particular, gain of parts of chromosome 1p and major parts of 15q were associated with poor survival. A combination of gains of 1p and 15q was associated with poor survival, also after adjustment for differences in peritoneal cancer index and completeness of cytoreduction score [hazard ratio (HR) 5.96; 95% confidence interval (CI) 2.19-16.18]. These patients had a mean copy number (CN) of 3.19 compared with 2.24 in patients without gains. Complete CN analysis was performed in 53 patients. Analysis was unsuccessful for the remaining patients due to insufficient amounts of DNA and signals caused by interstitial components and normal cells. There was no difference in survival between patients with successful and unsuccessful CN analysis., Conclusions: This study shows that gains of parts of chromosome 1p and of major parts of chromosome 15q were significantly associated with poor survival after CRS and HIPEC, which could represent future prognostic biomarkers.

Background: Selecting colorectal patients for HIPEC-surgery needs improvement. The study aim was to improve the colorectal peritoneal score (COREP) and to compare it with three other scores: peritoneal-surface disease-severity score (PSDS), colorectal-peritoneal metastases prognostic-surgical-score (COMPASS), and the CEA/PCI ratio., Method: Twelve preoperative factors were chosen to evaluate for COREP score modification. Criteria from logistical analyses were set to qualify for the modified COREP score (mCOREP). Odds ratios were used to assign score points for the eligible factors with open/close laparotomy prediction as endpoint. mCOREP was applied internally and compared with the original COREP, PSDS, COMPASS, and CEA/PCI ratio. Odds ratios, hazard ratios, and Kaplan-Meier curves were used for comparison., Results: Seven factors qualified for mCOREP: CEA, CA 19-9, CA-125, C-reactive protein, albumin, platelet count and signet-cell histology. mCOREP was superior to the original COREP. mCOREP and COMPASS scores were the only scores with independent prognostic value. The mCOREP had the best discriminatory ability between its prognostic groupings. mCOREP 11 + had 9 months survival with half of patients being open/close surgery., Conclusion: The mCOREP has successfully been simplified while still improving its prognostic ability. The mCOREP and COMPASS scores have independent prognostic value. Patients with mCOREP 11 + may not benefit from treatment.

Background: Early diagnosis to target minimal volume disease has received increased attention in the management of appendiceal and colorectal peritoneal metastases (PM). This study aimed to identify risk factors for appendiceal, colon and rectal PM., Methods: Data were retrieved from the Swedish Colorectal Cancer Registry for all patients undergoing bowel resection of appendiceal and colorectal tumours, in Sweden, 2007-2015. Risk factors for synchronous and metachronous PM were analysed with multivariate logistic and Cox proportional hazard regression models., Results: Synchronous PM was most common in appendiceal cancer (23.5%), followed by colon (3.1%) and rectal (0.6%) cancer. The 5-year cumulative incidence was 9.0% for appendiceal, 2.5% for right colon, 1.8% for left colon and 1.2% for rectal cancer. In appendiceal cancer (n = 327), T4, N2, mucinous tumour, and non-radical surgery were associated with PM. In colon cancer (n = 24,399), synchronous PM were primarily associated with T4 (OR 18.37, 95% CI 8.12-41.53), T3 and N2 but also with N1, right-sided tumour, mucinous tumour, vascular and perineural invasion, female gender, age <60 and emergency surgery. These factors were also associated with metachronous PM. In rectal cancer (n = 10,394), T4 (OR 19.12, 95% CI 5.52-66.24), proximal tumour and mucinous tumour were associated with synchronous PM and T4 and mucinous tumour with metachronous PM., Conclusions: This study shows that appendiceal cancer, right-sided colon cancer, advanced tumour and node stages and mucinous histopathology are the main high-risk features for PM and should increase the awareness of current or future PM., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: The importance of absent neoplastic epithelium in specimens from cytoreductive surgery (CRS) is unknown. This study aimed to investigate the prevalence and prognostic value of histopathology without neoplastic epithelium in patients treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC)., Methods: Data were extracted from medical records and histopathology reports for patients treated with initial CRS and HIPEC at Uppsala University Hospital, Sweden, between 2004 and 2012. Patients with inoperable disease and patients undergoing palliative non-CRS surgery were excluded from the study. Patients lacking neoplastic epithelium in surgical specimens from CRS, with or without mucin, were classified as "neoplastic epithelium absent" (NEA), and patients with neoplastic epithelium were classified as "neoplastic epithelium present" (NEP)., Results: The study observed NEA in 78 of 353 patients (22 %). Mucin was found in 28 of the patients with NEA. For low-grade appendiceal mucinous neoplasms and adenomas, the 5-year overall survival rate was 100 % for NEA and 84 % for NEP, and the 5-year recurrence-free survival rate was 100 % for NEA and 59 % for NEP. For appendiceal/colorectal adenocarcinomas (including tumors of the small intestine), the 5-year overall survival rate was 61 % for NEA and 38 % for NEP, and the 5-year recurrence-free survival rate was 60 % for NEA and 14 % for NEP. Carcinoembryonic antigen level, peritoneal cancer index, and completeness of the cytoreduction score were lower in patients with NEA., Conclusions: A substantial proportion of patients undergoing CRS and HIPEC have NEA. These patients have a favorable prognosis and a decreased risk of recurrence. Differences in patient selection can affect the proportion of NEA and hence explain differences in survival rates between reported series.