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Background As part of a randomized phase II trial in patients with isolated resectable colorectal peritoneal metastases (CPMs), the present study compared patient-reported outcomes (PROs) of patients treated with perioperative systemic therapy versus cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS–HIPEC) alone. Also, PROs of patients receiving perioperative systemic therapy were explored. Patients and Methods Eligible patients were randomized to perioperative systemic therapy (experimental) or CRS–HIPEC alone (control). PROs were assessed using EORTC QLQ-C30, QLQ-CR29, and EQ-5D-5L questionnaires at baseline, after neoadjuvant treatment (experimental), and at 3 and 6 months postoperatively. Linear mixed modeling was used to compare five predefined PROs (visual analog scale, global health status, physical functioning, fatigue, C30 summary score) between arms and to longitudinally analyze PROs in the experimental arm. Results Of 79 analyzed patients, 37 (47%) received perioperative systemic therapy. All predefined PROs were comparable between arms at all timepoints and returned to baseline at 3 or 6 months postoperatively. The experimental arm had worsening of fatigue [mean difference (MD) + 14, p = 0.001], loss of appetite (MD + 15, p = 0.003), hair loss (MD + 18, p

INTRODUCTION: The oral fluoropyrimidine S-1 has shown comparable efficacy to capecitabine in Asian and some Western studies on metastatic colorectal cancer. S-1 is associated with a lower incidence of hand-foot syndrome (HFS) and cardiac toxicity. We assessed the long-term tolerability of S-1 in patients who discontinued capecitabine for reasons of HFS or cardiac toxicity.PATIENTS AND METHODS: Patients with metastatic colorectal cancer who switched from capecitabine to S-1, given as monotherapy or in combination with other agents, were identified in a Dutch prospective cohort study (2016-2021). The incidence and severity of HFS, cardiotoxicity and other toxicities were assessed.RESULTS: Forty-seven patients were identified. The median duration of capecitabine treatment was 81 days (range 4-454). In 19 patients (40%) a dose reduction was applied prior to switch to S-1. Reasons for discontinuation of capecitabine were HFS in 36 (77%) patients, coronary artery vasospasms in 10 (21%) patients, and gastrointestinal toxicities in 1 patient (2%). The median number of S-1 cycles was 6 (range 1-36). The median time between last dose of capecitabine and first dose of S-1 was 11 days (range 1-49). After switch to S-1, all patients with prior HFS developed a lower grade or complete resolution of symptoms, and in all other patients symptoms did not recur. Other S-1-related adverse events were limited to grade 1-2. Six patients (13%) discontinued S-1 due to either known fluoropyrimidine-related or bevacizumab-related toxicities. Switch to S-1 did not appear to compromise treatment efficacy.CONCLUSION: S-1 is a valid alternative to capecitabine in case HFS or cardiotoxicity occurs.

INTRODUCTION: The RECOURSE trial demonstrated a modest benefit in overall survival (OS) for trifluridine/tipiracil (FTD/TPI) versus placebo in pretreated metastatic colorectal cancer (mCRC) patients. Unfortunately, quality of life (QoL) was not assessed. We evaluated QoL and survival of patients treated with FTD/TPI in daily practice.PATIENTS AND METHODS: QUALITAS is a substudy of the Prospective Dutch CRC cohort (PLCRC). From 150 mCRC patients treated with FTD/TPI, QoL (EORTC QLQ-C30 and QLQ-CR29) was assessed monthly from study entry, and linked to clinical data of the Netherlands Cancer Registry. Joint models were constructed combining mixed effects models with Cox PH models. Primary endpoint was difference in QoL over time (which was deemed clinically relevant if ≥10 points). Secondary endpoints were progression-free survival (PFS), time to treatment failure (TTF), and OS. We analyzed the association between QLQ-C30 Summary Score (QoL-SS) at FTD/TPI initiation (baseline) and survival.RESULTS: There was no clinically relevant change in QoL-SS from baseline to 10 months post-baseline (i.e. the cut-off point after which 90% of patients had discontinued FTD/TPI treatment): -5.3 [95% CI -8.7;-1.5]. Patients who were treated with FTD/TPI for ≥ 3 months (n = 85) reported 6.3 [1.6;11.1] points higher baseline QoL, compared to patients treated < 3 months (n = 65, "poor responders"). In the latter, time to a clinically relevant QoL deterioration was < 2 months. Median PFS, TTF and OS were 2.9 [2.7;3.1], 3.1 [2.9;3.2] and 7.7 [6.6;8.8] months, respectively. Worse baseline QoL-SS was independently associated with shorter OS (HR 0.45 [0.32;0.63]), PFS (0.63 [0.48;0.83]), and TTF (0.64 [0.47;0.86]).CONCLUSION: The maintenance of QoL during FTD/TPI treatment in daily practice supports its use. The QoL deterioration in "poor responders" is likely due to disease progression. The strong association between worse baseline QoL and shorter survival suggests that clinicians should take QoL into account when determining prognosis and treatment strategy for individual patients.

This retrospective multicenter cohort study compared the feasibility and safety of oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-Ox) with or without intraoperative intravenous 5-fluorouracil (5-FU) and leucovorin (L). Our study included consecutive patients with histologically proven unresectable and isolated colorectal peritoneal metastases (cPM) treated with PIPAC-Ox in seven tertiary referral centers between January 2015 and April 2020. Toxicity events and oncological outcomes (histological response, progression-free survival, and overall survival) were compared between patients who received intraoperative intravenous 5-FU/L (PIPAC-Ox + 5-FU/L group) and patients who did not (PIPAC-Ox group). In total, 101 patients (263 procedures) were included in the PIPAC-Ox group and 30 patients (80 procedures) were included in the PIPAC-Ox + 5-FU/L group. Common Terminology Criteria for Adverse Events v4.0 grade 2 or higher adverse events occurred in 48 of 101 (47.5%) patients in the PIPAC-Ox group and in 13 of 30 (43.3%) patients in the PIPAC-Ox + 5-FU/L group (p = 0.73). The complete histological response rates according to the peritoneal regression grading score were 27% for the PIPAC-Ox + 5-FU/L group and 18% for the PIPAC-Ox group (p = 0.74). No statistically significant differences were observed in overall or progression-free survival between the two groups. The safety and feasibility of PIPAC-Ox + 5-FU/L appears to be similar to the safety and feasibility of PIPAC-Ox alone in patients with unresectable cPM. Oncological outcomes must be evaluated in larger studies.

Background: Outcome after colorectal liver metastases (CRLM) resection has improved over time, despite increased resection rates. Hence, it's crucial to identify all patients possible to treat with curative intent. The objectives of this study were to map recurrence pattern, treatment strategy and survival depending on treatment and follow-up strategy.Methods: In the COLOFOL-trial, patients with radically resected stage II-III colorectal cancer were randomized to high-frequency (6, 12, 18, 24 and 36 months; HF) or low-frequency (12 and 36 months; LF) follow-up. In this study, all CRLM within 5 years were identified and medical files scrutinized. Overall survival (OS) was analysed in uni- and multivariable analyses. Primary endpoint was 5-year OS.Results: Of 2442 patients, 235 (9.6%) developed metachronous CRLM of which 123 (52.3%) underwent treatment with curative intent, resulting in 5-year OS of 58%. Five-year OS for patients with CRLM was 43% after HF versus 24% after LF. The survival benefit was confirmed for HF 8 years from resection of the primary tumour, HR 0.63 (CI 0.46-0.85).Conclusion: A high proportion of metachronous CRLM was possible to treat with curative intent, yielding high survival rates. More intense follow-up after colorectal cancer resection might be of value in high-risk patients. Background: Outcome after colorectal liver metastases (CRLM) resection has improved over time, despite increased resection rates. Hence, it's crucial to identify all patients possible to treat with curative intent. The objectives of this study were to map recurrence pattern, treatment strategy and survival depending on treatment and follow-up strategy.Methods: In the COLOFOL-trial, patients with radically resected stage II-III colorectal cancer were randomized to high-frequency (6, 12, 18, 24 and 36 months; HF) or low-frequency (12 and 36 months; LF) follow-up. In this study, all CRLM within 5 years were identified and medical files scrutinized. Overall survival (OS) was analysed in uni- and multivariable analyses. Primary endpoint was 5-year OS.Results: Of 2442 patients, 235 (9.6%) developed metachronous CRLM of which 123 (52.3%) underwent treatment with curative intent, resulting in 5-year OS of 58%. Five-year OS for patients with CRLM was 43% after HF versus 24% after LF. The survival benefit was confirmed for HF 8 years from resection of the primary tumour, HR 0.63 (CI 0.46-0.85).Conclusion: A high proportion of metachronous CRLM was possible to treat with curative intent, yielding high survival rates. More intense follow-up after colorectal cancer resection might be of value in high-risk patients.

Background As part of a randomized phase II trial in patients with isolated resectable colorectal peritoneal metastases (CPMs), the present study compared patient-reported outcomes (PROs) of patients treated with perioperative systemic therapy versus cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS–HIPEC) alone. Also, PROs of patients receiving perioperative systemic therapy were explored. Patients and Methods Eligible patients were randomized to perioperative systemic therapy (experimental) or CRS–HIPEC alone (control). PROs were assessed using EORTC QLQ-C30, QLQ-CR29, and EQ-5D-5L questionnaires at baseline, after neoadjuvant treatment (experimental), and at 3 and 6 months postoperatively. Linear mixed modeling was used to compare five predefined PROs (visual analog scale, global health status, physical functioning, fatigue, C30 summary score) between arms and to longitudinally analyze PROs in the experimental arm. Results Of 79 analyzed patients, 37 (47%) received perioperative systemic therapy. All predefined PROs were comparable between arms at all timepoints and returned to baseline at 3 or 6 months postoperatively. The experimental arm had worsening of fatigue [mean difference (MD) + 14, p = 0.001], loss of appetite (MD + 15, p = 0.003), hair loss (MD + 18, p

BACKGROUND: T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization. METHODS/DESIGN: In this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate. DISCUSSION: Since the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Trial registration Nederlands Trial Register, NL 7879, 16 July 2019 ( https://trialregister.nl/trial/7879 ).

Contains fulltext : 238268.pdf (Publisher’s version ) (Closed access) 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.

A significant proportion of colorectal cancer (CRC) patients develop peritoneal metastases (PM) in the course of their disease. PMs are associated with a poor quality of life, significant morbidity and dismal disease outcome. To improve care for this patient group, a better understanding of the molecular characteristics of CRC-PM is required. Here we present a comprehensive molecular characterization of a cohort of 52 patients. This reveals that CRC-PM represent a distinct CRC molecular subtype, CMS4, but can be further divided in three separate categories, each presenting with unique features. We uncover that the CMS4-associated structural protein Moesin plays a key role in peritoneal dissemination. Finally, we define specific evolutionary features of CRC-PM which indicate that polyclonal metastatic seeding underlies these lesions. Together our results suggest that CRC-PM should be perceived as a distinct disease entity.

Background: Trifluridine–tipiracil plus bevacizumab has shown efficacy in previous phase 2 studies including patients with unresectable metastatic colorectal cancer. We aimed to investigate first-line trifluridine–tipiracil plus bevacizumab versus capecitabine plus bevacizumab in patients with unresectable metastatic colorectal cancer ineligible for intensive treatment. Methods: In this open-label, randomised, phase 3 study, we enrolled patients aged 18 years and older with histologically confirmed metastatic colorectal cancer, ineligible for full-dose doublet or triplet chemotherapy and curative resection across 25 countries and regions. Participants were randomly allocated (1:1) to trifluridine–tipiracil plus bevacizumab or capecitabine plus bevacizumab until disease progression or unacceptable toxicity using an interactive web response system, stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 vs 2), primary tumour location (right vs left colon), and the main reason for not being a candidate for intensive therapy (clinical condition vs non-clinical condition). The primary endpoint was investigator-assessed progression-free survival, defined as the time from randomisation to radiological progression or death from any cause, in the intention-to-treat population. Safety was assessed in all patients having taken at least one dose of the study drug. The trial is ongoing, findings presented here are those of the primary analysis of progression-free survival, conducted after 629 events had occurred. This study is registered with ClinicalTrials.gov, NCT03869892. Findings: Between March 21, 2019, and Sept 14, 2020, 856 patients (54% male, 46% female) were randomly assigned to trifluridine–tipiracil plus bevacizumab (n=426) or capecitabine plus bevacizumab (n=430). After a median follow-up of 16·6 months (95% CI 16·5–17·1), the hazard ratio for progression-free survival for trifluridine–tipiracil plus bevacizumab versus capecitabine plus bevacizumab was 0·87 (0·75–1·02; p=0·0464; protocol-defined significance level of p=0·021 not met). Investigator-assessed median progression-free survival was 9·4 months (95% CI 9·1–10·9) with trifluridine–tipiracil plus bevacizumab versus 9·3 months (8·9–9·8) with capecitabine plus bevacizumab. The most common grade 3 and higher treatment-emergent adverse events were neutropenia (220 [52%] of 423 patients in the trifluridine–tipiracil plus bevacizumab group vs six [1%] of 427 in the capecitabine plus bevacizumab group), decreased neutrophil count (78 [18%] vs four [

BACKGROUND: In thermal ablation of malignant liver tumors, ablation dimensions remain poorly predictable. This study aimed to investigate factors influencing volumetric ablation dimensions in patients treated with stereotactic microwave ablation (SMWA) for colorectal liver metastases (CRLM).METHODS: Ablation volumes from CRLM ≤3 cm treated with SMWA within a prospective European multicentre trial were segmented. Correlations between applied ablation energies and resulting effective ablation volumes (EAV) and ablation volume irregularities (AVI) were investigated. A novel measure for AVI, including minimum enclosing and maximum inscribed ellipsoid ablation volumes, and a surrogate parameter for the expansion of ablation energy (EAV per applied energy), was introduced. Potential influences of tumor and patient-specific factors on EAV per applied energy and AVI were analyzed using multivariable mixed-effects models.RESULTS: A total of 116 ablations from 71 patients were included for analyses. Correlations of EAV or AVI and ablation energy were weak to moderate, with a maximum of 25% of the variability in EAV and 13% in AVI explained by the applied ablation energy. On multivariable analysis, ablation expansion (EAV per applied ablation energy) was influenced mainly by the tumor radius (B = -0.03, [CI -0.04, -0.007]). AVI was significantly larger with higher applied ablation energies (B = 0.002 [CI 0.0007, 0.002]]); liver steatosis, KRAS mutation, subcapsular location or proximity to major blood vessels had no influence.CONCLUSIONS: This study confirmed that factors beyond the applied ablation energy might affect volumetric ablation dimensions, resulting in poor predictability. Further clinical trials including tissue sampling are needed to relate physical tissue properties to ablation expansion.

Contains fulltext : 288035.pdf (Publisher’s version ) (Open Access) BACKGROUND: T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization. METHODS/DESIGN: In this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate. DISCUSSION: Since the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Trial registration Nederlands Trial Register, NL 7879, 16 July 2019 ( https://trialregister.nl/trial/7879 ).

Patients with inflammatory bowel disease are at an increased risk of cancer secondary to long-standing intestinal inflammation. Surgical options must take into account the significant risk of synchronous disease at other colonic sites. Ileal pouch anal anastomosis is a viable option for patients with ulcerative colitis, but this should be restricted to early cancers that are unlikely to require preoperative or postoperative radiation treatment.

Introduction: Peritoneal metastases (PM) originating from colorectal cancer (CRC) and pseudomyxoma peritonei (PMP) can be treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Certain sites in the peritoneal cavity are prone to contain PM and are, therefore, routinely resected. The aim of this study is to investigate the frequency of disease in CRS specimens routinely resected. Secondly, to investigate if the risk of finding PM in routinely resected specimen is associated with involvement of anatomic related peritoneal areas. Materials and methods: This study investigated 433 patients diagnosed with PMP (n = 119) or PM from CRC (n = 314) and operated with CRS + HIPEC between June 2006 and November 2020 at a national center. Baseline data were prospectively registered. Pathology reports were reviewed for the presence of metastases in the routinely resected umbilicus, ligamentum teres hepatis, ovaries and greater omentum. Tumor extent was estimated using the Dutch region count. Results: PM was found in 14.7% of umbilical resections, in 17.4% of the resected ligamentum teres hepatis, in 48.2% of the resected ovaries and in 49.5% of the greater omentum specimens. We found an association between macroscopic disease involvement of the nearest region and risk of PM found in the related resections. Seven of 31 women with no macroscopically visible disease in the pelvis had PM diagnosed in the resected ovaries. Conclusions: A substantial proportion of routine resections held histologic verified PM. Our results may advocate for a routinely performed resection of the umbilicus, ligamentum teres hepatis, ovaries and greater omentum.

Image based biomarker discovery typically requires an accurate segmentation of histologic structures (e.g., cell nuclei, tubules, epithelial regions) in digital pathology Whole Slide Images (WSI). Unfortunately, annotating each structure of interest is laborious and often intractable even in moderately sized cohorts. Here, we present an open-source tool, Quick Annotator (QA), designed to improve annotation efficiency of histologic structures by orders of magnitude. While the user annotates regions of interest (ROI) via an intuitive web interface, a deep learning (DL) model is concurrently optimized using these annotations and applied to the ROI. The user iteratively reviews DL results to either (a) accept accurately annotated regions, or (b) correct erroneously segmented structures to improve subsequent model suggestions, before transitioning to other ROIs. We demonstrate the effectiveness of QA over comparable manual efforts via three use cases. These include annotating (a) 337,386 nuclei in 5 pancreatic WSIs, (b) 5,692 tubules in 10 colorectal WSIs, and (c) 14,187 regions of epithelium in 10 breast WSIs. Efficiency gains in terms of annotations per second of 102x, 9x, and 39x were respectively witnessed while retaining f-scores >.95, suggesting QA may be a valuable tool for efficiently fully annotating WSIs employed in downstream biomarker studies., The submission includes 14 pages, 7 figures, 2 tables,and 21 references. It is a new submission

Importance: The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer.Observations: Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts.Conclusions and Relevance: The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.

Background: At present, selected patients with resectable colorectal peritoneal metastases (CRC-PM) are increasingly treated with a combination therapy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this study was to investigate the current worldwide practice.Methods: HIPEC experts from 19 countries were invited through the Peritoneal Surface Oncology Group International (PSOGI) to complete an online survey concerning their personal expertise and current hospital and country wide practice.Results: It is estimated that currently more than 3800 patients with CRC-PM (synchronous and metachronous) are annually treated with CRS and HIPEC in 430 centers. Integration of CRS and HIPEC in national guidelines varies, resulting in large treatment disparities between countries. Amongst the experts, there was general agreement on issues related to indication, surgical technique and follow up but less on systemic chemotherapy or proactive strategies.Conclusion: This international survey demonstrates that CRS and HIPEC is now performed on a large scale for CRC-PM patients. Variation in treatment may result in heterogeneity in surgical and oncological outcomes, emphasising the necessity to reach consensus on several issues of this comprehensive procedure. Future initiatives directed at achieving an international consensus statement are needed. (C) 2018 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Background: RECIST 1.1 presents challenges when evaluating treatment response to angiogenesis inhibitors. The objective response rate, when evaluating the treatment effect of regorafenib, using RECIST 1.1, is < 2% and beneficial treatment could erroneously be terminated. Dynamic contrast-enhanced computed tomography (DCE-CT) has potential as a non-invasive functional imaging biomarker, by quantifying the treatment effect of this targeted therapy. Purpose: To evaluate three-dimensional (3D) tumor dynamic parameters representing tumor microcirculation assessed by DCE-CT during the treatment with regorafenib in a cohort of patients with treatment-refractory metastatic colorectal cancer. Material and Methods: Thirty-three patients with colorectal metastases (27 liver lesions, three abdominal lesions, and three pulmonary lesions) were treated with regorafenib and evaluated using DCE-CT. A total of 112 DCE-CT scans were analyzed using Advanced Perfusion and Permeability Application and correlated to standard contrast-enhanced computed tomography (CE-CT) evaluated using RECIST 1.1. Results: A significant decrease in most DCE-CT parameters, a simultaneous decrease in tumor attenuation and an increase in tumor volume were detected during treatment. However, no associations were found between the DCE-CT parameters and PFS or OS using simple COX proportional hazards regression. Conclusion: In this exploratory study, a significant decrease in most dynamic parameters suggests an overall treatment effect of regorafenib in tumor vasculature. DCE-CT may assist in an objective evaluation of these responses compared to RECIST. The anti-angiogenic changes could not be associated with treatment outcome in terms of PFS and OS, which might be due to the small cohort or a rather limited survival benefit in this pre-medicated treatment-refractory group of patients.

To compare local recurrence (LR) rate in patients with colorectal cancer liver metastasis (CRCLM) after surgical wedge resection (WR) or radiofrequency ablation (RFA) and to investigate predictive factors of LR. This single-centre, retrospective, institutional review board-approved study including 43 consecutive patients with 121 metastases treated by WR and 60 patients with 110 metastases treated by RFA between 2007 and 2014 with 23 and 18.5 months of follow-up, respectively. Demographics and tumour characteristics were compared using the unpaired t-test and chi-square test. Predictive factors for LR (lesion size, depth, relation to hepatic vessels, intervention, margin status) were investigated in uni- and multivariate analyses. Patient and CRCLM characteristics were similar in both groups. Mean lesion size and depth in the WR and RFA groups were 18 mm and 15 mm (p = 0.03), and 19 mm and 26 mm (p < 0.001), respectively. LR showed a trend towards difference in favour of RFA (19% and 10% in the WR and RFA groups, respectively, p = 0.06). Positive margins and lesion depth were predictive factors of LR in the WR group (p = 0.03 and p = 0.02, respectively, on uni- and multivariable analyses). Lesion depth and proximity to a vein increased the risk of positive margins on pathology after WR (p = 0.04 and p < 0.001, respectively). Our analysis did not identify any predictive factors of LR following RFA. Our study showed a trend towards a lower LR rate with RFA compared to WR. Lesions located deep in the liver and/or close to large vessels are at high risk of LR following WR, while curative treatment can be obtained with RFA.

Aims of the Study: The present survey aimed to evaluate current opinion and practice regarding peritoneal metastasis (PM), satisfaction with available treatment options, and need for new therapeutic approaches. Methods: This was a qualitative study conducted between October 2016 and October 2017 in the Réseau Suisse Romand d’Oncologie including 101 members of various oncological specialties. Participants’ demographics, current practice, knowledge, and satisfaction regarding available treatment options and need for new treatment options were assessed by semantic differential scales through 33 closed questions with automatic reminders at 4-, 8-, 12-, and 16-week intervals. Results: Twenty-seven participants (27%) completed the survey. Participants were gastrointestinal or gynecologic oncologists and surgeons. Most participants (67%) evaluated their knowledge on PM as moderate, while 22% considered themselves as experts. Clinical usefulness of systemic chemotherapy and hyperthermic intraperitoneal chemotherapy was judged to be moderate to high for PM of ovarian and colorectal origin and moderate to poor for gastric origin. Satisfaction with available treatment options was 6/10 (interquartile range [IQR] 4–7) for ovarian, 5/10 (IQR 3–7) for colorectal, and 3/10 (IQR 1–3) for gastric PM. Treatment strategies varied widely for typical case vignettes. The need for new treatment modalities was rated as 8/10 (IQR 6–10). Conclusion: Usefulness of and satisfaction with available treatment options for PM were rated as moderate at best by oncological experts, and treatment strategies differed importantly among participants. There appears to be a clear need for standardization and new treatment modalities.

Background The management of patients with colorectal cancer (CRC) with peritoneal metastases is challenging, and the roles of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are unclear and debated among experts. Materials and Methods The experts of the Swiss Peritoneal Cancer Group were contacted and agreed to participate in this analysis. Experts from 9 centers in Switzerland provided their decision algorithms for CRS/HIPEC for patients with or at high risk for peritoneal metastases from CRC. Their responses were converted into decision trees on the basis of objective consensus methodology. The decision trees were used as a basis to identify consensus and discrepancies. Results The final treatment algorithms included a total of 5 decision criteria (age, Peritoneal Cancer Index [PCI], extraperitoneal metastases, Peritoneal Surface Disease Severity Score, and various risk factors [RF]) and 2 treatment options (HIPEC, yes or no). HIPEC was never recommended for patients without peritoneal metastases in the absence of RF for peritoneal metastases. For patients with a PCI ≤15 without organ metastases, all centers recommended CRS/HIPEC. There was also a consensus not to perform CRS/HIPEC in elderly patients (80 years and older), those with a PCI >20, and those with unresectable metastases. For patients with a PCI = 16 to 20, there was no consensus. Conclusion Multiple decision criteria relevant to all participating centers were identified. Because patient selection for CRS/HIPEC remains difficult, uniform criteria for the term “high risk” for peritoneal metastases and systemic metastases are helpful. Future trials and guidelines should take these criteria into account.

Contains fulltext : 215755.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Shared decision making is not always commonplace in advanced colorectal or lung cancer care. Decision aids (DAs) might be helpful. This review aimed (a) to provide an overview of DAs for patients with advanced colorectal or lung cancer and assess their availability; and (b) to assess their effectiveness if possible. METHODS: A systematic literature search (PubMed/EMBASE/PsycINFO/CINAHL) and Internet and expert searches were carried out to identify relevant DAs. Data from the DAs included were extracted and the quality of studies, evidence (Grading of Recommendations Assessment, Development and Evaluation) and effectiveness (International Patient Decision Aid Standards) of DAs were determined. RESULTS: Ten of the 12 DAs included (four colorectal cancer, four lung cancer and four generic) are still available. Most (9/12) were applicable throughout the disease pathway and usable for all decisions, or to the decision for supportive care with/without anti-cancer therapy. Seven studies tested effectiveness. Effects on patient outcomes varied, but were generally weakly positive (e.g., DAs improved patient satisfaction) with low evidence. Study quality was fair to good. CONCLUSION: There is a lack of readily available DAs that have been demonstrated to be effective in advanced colorectal or lung cancer. Rigorous testing of the effects of currently available and future DAs, to improve patient outcomes, is urgently needed.

Background A major concern following ablation treatment is the risk of insufficient heating leaving vital tumor tissue at the treatment site, leading to recurrent disease and reduced survival. Dynamic contrast-enhanced computed tomography (DCE-CT) has the potential to evaluate the treatment site in an objective and standardized manner and provide a marker of recurrent disease. Purpose To evaluate the feasibility of measuring changes in the dynamic parameters of the treatment site following ablation of colorectal liver metastases, assessed by DCE-CT using a novel evaluation method, applying a circumferential semi-automated attenuation-restricted volume of interest (VOI). Material and Methods Forty-three treatment sites following ablation in 39 patients with colorectal liver metastases were evaluated using DCE-CT. A total of 159 DCE-CT scans were analyzed using the circumferential semi-automatized VOI. Results We found no significant differences in the dynamic parameters over time between a group of patients with recurrent disease and a group without. No consistent associations between time to recurrence and the dynamic histogram parameters were identified. Conclusion In this exploratory feasibility study, we were not able to differentiate between the two groups (recurrence/no recurrence) using the dynamic parameters derived from the standardized circumferential VOI. In time, the method may have potential to evaluate the treatment site following ablation in an objective and standardized manner. Currently, the method needs further refinement before clinical implementation.

Background and Aims To optimize therapeutic decision-making in early invasive colorectal cancer (T1 CRC) patients, it is important to elicit the patient's perspective next to considering medical outcome. Because empirical data on patient-reported impact of different treatment options are lacking, we evaluated patients' quality of life, perceived time to recovery, and fear of cancer recurrence after endoscopic or surgical treatment for T1 CRC. Methods In this cross-sectional study, we selected patients with histologically confirmed T1 CRC who participated in the Dutch Bowel Cancer Screening Programme and received endoscopic or surgical treatment between January 2014 and July 2017. Quality of life was measured using the European Organization for Research and Treatment 30-item Core Quality of Life Questionnaire and the 5-level EuroQoL 5-dimension questionnaire. We used the Cancer Worry Scale (CWS) to evaluate patients' fear of cancer recurrence. A question on perceived time to recovery after treatment was also included in the set of questionnaires sent to patients. Results Of all 119 eligible patients, 92.4% responded to the questionnaire (endoscopy group, 55/62; surgery group, 55/57). Compared with the surgery group, perceived time to recovery was on average 3 months shorter in endoscopically treated patients after adjustment for confounders (19.9 days vs 111.3 days; P = .001). The 2 treatment groups were comparable with regard to global quality of life, functioning domains, and symptom severity scores. Moreover, patients in the endoscopy group did not report more fear of cancer recurrence than those in the surgery group (CWS score, 0-40; endoscopy 7.6 vs surgery 9.7; P = .140). Conclusions From the patient's perspective, endoscopic treatment provides a quicker recovery than surgery, without provoking more fear of cancer recurrence or any deterioration in quality of life. These results contribute to the shared therapeutic decision-making process of clinicians and T1 CRC patients.

Socioeconomic inequalities in cancer stage at diagnosis and survival are important public health issues. This study investigates the association between socioeconomic position (SEP) and colorectal cancer (CRC) stage at diagnosis and survival in Switzerland, a European country with highest level of medical facilities and life expectancy. We used population‐based CRC data from seven Swiss cantonal cancer registries 2001–2008 (N = 10,088) linked to the Swiss National Cohort (SNC). Follow‐up information was available until the end of 2013. SEP was estimated based on education. The association between cancer stage and SEP was assessed using logistic regression models including cancer localization (colon/rectum), sex, age, civil status, urbanity of residence, language region, and nationality (Swiss/non‐Swiss). Survival was analyzed using competing risk regressions reporting subhazard ratios (SHRs) for the risk of dying due to CRC. We observed a social gradient for later stage CRC with adjusted odds ratios (ORs) of 1.11 (95% CI: 0.97–1.19) and 1.28 (95% CI: 1.08–1.50) for middle and low SEP compared to high SEP. Further, single compared to married people had elevated odds of being diagnosed at later stages. Survival was lower in patients with CRC with low SEP in the unadjusted model (SHR: 1.18, 95% CI: 1.07–1.30). After adjustment for stage at diagnosis and further sociodemographic characteristics, significant survival inequalities by SEP disappeared but remained for non‐Swiss compared to Swiss citizens and for patients living in nonurban areas compared to their urban counterparts. Swiss public health strategies should facilitate equal access to CRC screening and optimal CRC care for all social groups and in all regions of Switzerland.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new drug delivery method offered in selected patients suffering from non-resectable peritoneal carcinomatosis (PC). As reported experience is still limited, we conducted a survey among active PIPAC centers aiming to report their technical approach and clinical findings. An online survey was sent to active PIPAC centers worldwide. The questionnaire consisted of 34 closed questions and was conducted over a period of 3 months beginning in March 2017. Nine out of 15 contacted centers completed the questionnaire totaling 832 PIPAC procedures in 349 patients. Most common indications for PIPAC were PC from gastric, ovarian and colorectal origin. The mean time between each PIPAC procedure was 6-8 weeks. Seven of nine (77.8%) centers evaluate the PCI at every PIPAC procedure. At least four tissue samples for histopathology analysis were retrieved in 5 (55.6%). All centers (100%) use the same chemotherapy protocol: oxaliplatin at a dosage of 92mg/m 2 for PC of colorectal origin and a combination of cisplatin and doxorubicin at a dosage of 7.5mg/m 2 and 1.5mg/m 2 , respectively, for other types of PC. Eight centers (88.9%) perform routine radiological evaluation before first PIPAC and after third PIPAC. These data confirm that PIPAC procedures are homogeneously performed in established centers. Standardization of the procedure will facilitate future international multicenter prospective clinical trials.

Immune cells infiltrating tumors can have important impact on tumor progression and response to therapy. We present an efficient algorithm to simultaneously estimate the fraction of cancer and immune cell types from bulk tumor gene expression data. Our method integrates novel gene expression profiles from each major non-malignant cell type found in tumors, renormalization based on cell-type-specific mRNA content, and the ability to consider uncharacterized and possibly highly variable cell types. Feasibility is demonstrated by validation with flow cytometry, immunohistochemistry and single-cell RNA-Seq analyses of human melanoma and colorectal tumor specimens. Altogether, our work not only improves accuracy but also broadens the scope of absolute cell fraction predictions from tumor gene expression data, and provides a unique novel experimental benchmark for immunogenomics analyses in cancer research (http://epic.gfellerlab.org)., eLife digest Malignant tumors do not only contain cancer cells. Normal cells from the body also infiltrate tumors. These often include a variety of immune cells that can help detect and kill cancer cells. Many evidences suggest that the proportion of different immune cell types in a tumor can affect tumor growth and which treatments are effective. Researchers often study tumors by measuring the expression of genes, i.e., which genes are active in tumors. However, the proportion of different cell types in the tumor is often not measured for tumors studied at the gene expression level. Racle et al. have now demonstrated that a new computer-based tool can accurately detect all the main cell types in a tumor directly from the expression of genes in this tumor. The tool is called “Estimating the Proportion of Immune and Cancer cells” – or EPIC for short. It compares the level of expression of genes in a tumor with a library of the gene expression profiles from specific cell types that can be found in tumors and uses this information to predict how many of each type of cell are present. Experimental measurements of several human tumors confirmed that EPIC’s predictions are accurate. EPIC is freely available online. Since the active genes in tumors from many patients have already been documented together with clinical data, researchers could use EPIC to investigate whether the cell types in a tumor affect how harmful it is or how well a particular treatment works on it. In the future, this information could help to identify the best treatment for a particular patient and may reveal new genes that cause malignant tumors to develop and grow.

INTRODUCTION:VMS is a Dutch risk assessment tool for hospitalized older adults that includes a short evaluation of four geriatric domains: risk for delirium, risk for undernutrition, risk for physical impairments, and fall risk. We investigated whether the information derived from this tool has prognostic value for outcomes of colorectal surgery.METHODS:All consecutive patients over age 70 years who underwent elective colorectal cancer surgery in three Dutch hospitals (2014-2016) were studied. The presence of risk was scored prior to surgery and per geriatric domain as either 0 (risk absent) or 1 (risk present). The total number of geriatric risk factors was summed. The primary outcome was long-term survival. Secondary outcomes were postoperative complications, including delirium. Cox proportional hazards models were used to evaluate the sumscore and risk factors associated with overall survival.RESULTS:Five hundred fifty patients were included. Median age was 76.5 years, and median follow-up was 870 days. Patients with intermediate (1-2) or high (3-4) sumscore were independently associated with lower overall survival, with hazard ratio (HR) of 1.9 [95% confidence interval (CI) 1.1-3.5; p = 0.03] and 8.7 (95% CI 4.0-19.2; p CONCLUSIONS:This easy-to-use geriatric sumscore has strong associations with long-term outcome and morbidity after colorectal cancer surgery. This information may be included in risk models for morbidity and mortality and can be used in shared decision-making.

The aim of this study was to compare combined gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA)-enhanced and diffusion-weighted (DW) MRI with IV contrast-enhanced F-FDG PET/CT to detect and assess the viability of colorectal liver metastases (CLMs) after neoadjuvant chemotherapy (NAC). After NAC, 45 patients with CLMs were prospectively enrolled and underwent combined Gd-EOB-DTPA-enhanced and DW-MRI and contrast-enhanced F-FDG PET/CT. Forty patients subsequently underwent surgery based on intraoperative ultrasound, which served as the reference standard for the presence of CLMs. The number of metastases detected by each technique was then compared. In 69 resected metastases, the SUVmean and SUVmax, mean and maximum target-to-background ratio (TBR), total lesion glycolysis, metabolic tumor volume, and mean and minimum apparent diffusion coefficient (ADC) were examined to identify correlations with the corresponding tumor viability (TV) determined from histological specimens. Intraoperative ultrasound revealed 153 CLMs, 122 of which were resected. The detection rate of MRI and contrast-enhanced F-FDG PET/CT were similar (P = 0.61). The SUVmax and minimum ADC were negatively correlated (r = -0.34, P = 0.005) on preoperative imaging after NAC. However, TV was significantly correlated with the maximum TBR (r = 0.33, P = 0.006) and mean TBR (r = 0.37, P = 0.002), but not with the minimum ADC (r = -0.02, P = 0.9) or mean ADC (r = 0.01, P = 0.9). Combined Gd-EOB-DTPA-enhanced and DW-MRI and contrast-enhanced F-FDG PET/CT allow confident detection of CLMs, but only F-FDG PET metrics are associated with TV after NAC.

Background Reduced muscle density is associated with an increased risk of postoperative complications. We examined the prognostic value of muscle density as a predictor of postoperative complications in elderly patients undergoing surgery for colorectal cancer. Methods Patients (≥70 years) who underwent surgery for colorectal cancer between 2006 and 2013 were selected from a prospective single centre database. The Hounsfield Unit Average (HUA or HU/mm 2 ) of the psoas muscles at the level of the third lumbar vertebra was calculated on the scan. High and low muscle density groups were identified based on the lowest gender specific HUAC quartile. Major postoperative complications (Clavien-Dindo (CD) ≥3) within 30 days after surgery were retrospectively documented. Logistic regression analysis was used to identify risk factors for postoperative complications. Results A total of 373 patients (median age = 78 years) were included in this study. The mean muscle density score was 24.5 ± 4.3 HU/mm 2 for males and 26.3 ± 5.0 HU/mm 2 for females. The cut-off point for the lowest gender specific quartile was ≤22.0 HU/mm 2 for males and ≤23.5 HU/mm 2 for females. After multivariable regression, there was a statistically significant association between muscle density and CD ≥ 3 (OR = 1.84 (95% CI 1.11–3.06), p = 0.019). Anastomotic leakage in patients with a primary anastomosis (n = 287) occurred more often in patients with low muscle density (11.7% vs 23.3%, p = 0.016). The associations remained significant after correction for confounders. Conclusion Low muscle density is associated with major postoperative complications in older patients who undergo surgery for colorectal cancer.

In this article, the authors review the current status of biomarker research in the adjuvant treatment of colon cancer, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era., The number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups of patients will benefit from a specific treatment. Despite more than two decades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive molecular biomarkers with proven utility in this setting. A secondary objective of the Pan European Trials in Adjuvant Colon Cancer-3 trial, which compared irinotecan in combination with 5-fluorouracil and leucovorin in the postoperative treatment of stage III and stage II colon cancer patients, was to undertake a translational research study to assess a panel of putative prognostic and predictive markers in a large colon cancer patient cohort. The Cancer and Leukemia Group B 89803 trial, in a similar design, also investigated the use of prognostic and predictive biomarkers in this setting. In this article, the authors, who are coinvestigators from these trials and performed similar investigations of biomarker discovery in the adjuvant treatment of colon cancer, review the current status of biomarker research in this field, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era.

// Peter D. Caie 1, 2 , Ying Zhou 3 , Arran K. Turnbull 3 , Anca Oniscu 1, 2 , David J. Harrison 1, 2 1 Quantitative and Digital Pathology, School of Medicine, University of St Andrews, St Andrews, KY16 9TF, UK 2 Digital Pathology Unit, Laboratory Medicine, Royal Infirmary of Edinburgh, Edinburgh, EH16 4SA, UK 3 Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK Correspondence to: Peter D. Caie, email: pdc5@st-andrews.ac.uk Keywords: digital pathology, big-data, tumor buds, poorly differentiated clusters, data mining Received: January 13, 2016 Accepted: June 01, 2016 Published: June 15, 2016 ABSTRACT A number of candidate histopathologic factors show promise in identifying stage II colorectal cancer (CRC) patients at a high risk of disease-specific death, however they can suffer from low reproducibility and none have replaced classical pathologic staging. We developed an image analysis algorithm which standardized the quantification of specific histopathologic features and exported a multi-parametric feature-set captured without bias. The image analysis algorithm was executed across a training set ( n = 50) and the resultant big data was distilled through decision tree modelling to identify the most informative parameters to sub-categorize stage II CRC patients. The most significant, and novel, parameter identified was the ‘sum area of poorly differentiated clusters’ (AreaPDC). This feature was validated across a second cohort of stage II CRC patients ( n = 134) (HR = 4; 95% CI, 1.5– 11). Finally, the AreaPDC was integrated with the significant features within the clinical pathology report, pT stage and differentiation, into a novel prognostic index (HR = 7.5; 95% CI, 3–18.5) which improved upon current clinical staging (HR = 4.26; 95% CI, 1.7– 10.3). The identification of poorly differentiated clusters as being highly significant in disease progression presents evidence to suggest that these features could be the source of novel targets to decrease the risk of disease specific death.

In many cancers, the establishment of a patient’s future treatment regime often relies on histopathological assessment of tumor tissue specimens in order to determine the extent of the ‘pathological response’ to a given therapy. However, histopathological assessment of pathological response remains subjective. Here we use MALDI mass spectrometry imaging to generate lipid signatures from colorectal cancer liver metastasis specimens resected from patients preoperatively treated with chemotherapy. Using these signatures we obtained a unique pathological response score that correlates with prognosis. In addition, we identify single lipid moieties that are overexpressed in different histopathological features of the tumor, which have potential as new biomarkers for assessing response to therapy. These data show that computational methods, focusing on the lipidome, can be used to determine prognostic markers for response to chemotherapy and may potentially improve risk assessment and patient care.

The counting of poorly differentiated clusters of 5 or more cancer cells lacking a gland-like structure in a tumor mass has recently been identified among the histological features predictive of poor prognosis in colorectal cancer. Poorly differentiated clusters can easily be recognized in the histological sections of colorectal cancer routinely stained with haematoxylin and eosin. Despite some limitations related to specimen fragmentation, counting can also be assessed in endoscopic biopsies. Based on the number of poorly differentiated clusters that appear under a microscopic field of a ×20 objective lens (i.e., a microscopic field with a major axis of 1 mm), colorectal cancer can be graded into malignancies as follows: tumors with

To examine clinical features and outcome of patients who underwent hepatic resection for colorectal liver metastases (LM) involving the caudate lobe.Consecutive patients who underwent hepatic resection for LM from May 1990 to September 2004 were analyzed from a multicenter database. Demographics, operative data, pathologic margin status, recurrence, and survival were analyzed.Of 580 patients, 40 (7%) had LM involving the caudate. Six had isolated caudate LM and 34 had LM involving the caudate plus one or more other hepatic segments. Patients with caudate LM were more likely to have synchronous primary colorectal cancer (63% vs. 36%; P = 0.01), multiple LM (70% vs. 51%; P = 0.02) and required extended hepatic resection more often than patients with non-caudate LM (60% vs. 18%; P0.001). Only four patients with caudate LM underwent a vascular resection; three at first operation, one after recurrence of a resected caudate tumor. All had primary repair (vena cava, n = 3; portal vein, n = 1). Perioperative complications (43% vs. 28%) and 60-day operative mortality (0% vs. 1%) were similar (caudate vs. non-caudate LM, both P0.05). Pathological margins were positive in 15 (38%) patients with caudate LM and in 43 (8%) with non-caudate LM (P0.001). At a median follow-up of 40 months, 25 (64%) patients with caudate LM recurred compared with 219 (40%) patients with non-caudate LM (P = 0.01). Patients with caudate LM were more likely to have intrahepatic disease as a component of recurrence (caudate: 51% vs. non-caudate: 25%; P = 0.001). No patient recurred on the vena cava or portal vein. Patients with caudate LM had shorter 5-year disease-free and overall survival than patients with non-caudate LM (disease-free: 24% vs. 44%; P = 0.02; overall: 41% vs. 58%; P = 0.02).Patients who undergo hepatic resection for caudate LM often present with multiple hepatic tumors and tumors in proximity to the major hepatic veins. Extended hepatectomy is required in the majority, although vascular resection is not frequently necessary; when performed, primary repair is usually possible. Despite resection in this population of patients with multiple and bilateral tumors, and despite close-margin and positive-margin resection in a significant proportion, recurrence on the portal vein or vena cava was not observed, and long-term survival is accomplished (41% 5-year overall survival).

A dutch national evidence-based guideline on the diagnosis and treatment of patients with colorectal liver metastases has been developed. The most important recommendations are as follows. For synchronous liver metastases, spiral computed tomography (CT) or magnetic resonance imaging (MRI) should be used as imaging. For evaluation of lung metastases, imaging can be limited to chest radiography. For detection of metachronous liver metastases, ultrasonography could be performed as initial modality if the entire liver is adequately visualised. In doubtful cases or potential candidates for surgery, CT or MRI should be performed as additional imaging. For evaluation of extrahepatic disease, abdominal and chest CT could be performed. Fluorodeoxyglucose positron emission tomography could be valuable in patients selected for surgery based on CT (liver/abdomen/chest), for identifying additional extrahepatic disease. Surgical resection is the treatment of choice with a five-year survival of 30 to 40%. Variation in selection criteria for surgery is caused by inconclusive data in the literature concerning surgical margins.

Background The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. Methods/Design STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies. Discussion The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. Trial registration STRATEGIC-1 is registered at Clinicaltrials.gov: NCT01910610, 23 July, 2013. STRATEGIC-1 is registered at EudraCT-No.: 2013-001928-19, 25 April, 2013. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1503-7) contains supplementary material, which is available to authorized users.

Chemotherapy treatment of cancer remains a challenge due to the molecular and functional heterogeneity displayed by tumours originating from the same cell type. The pronounced heterogeneity makes it difficult for oncologists to devise an effective therapeutic strategy for the patient. One approach for increasing treatment efficacy is to test the chemosensitivity of cancer cells obtained from the patient's tumour. 3D culture represents a promising method for modelling patient tumours in vitro. The aim of this study was therefore to evaluate how closely short-term spheroid cultures of primary colorectal cancer cells resemble the original tumour. Colorectal cancer cells were isolated from human tumour tissue and cultured as spheroids. Spheroid cultures were established with a high success rate and remained viable for at least 10 days. The spheroids exhibited significant growth over a period of 7 days and no difference in growth rate was observed for spheroids of different sizes. Comparison of spheroids with the original tumour revealed that spheroid culture generally preserved adenocarcinoma histology and expression patterns of cytokeratin 20 and carcinoembryonic antigen. Interestingly, spheroids had a tendency to resemble tumour protein expression more closely after 10 days of culture compared to 3 days. Chemosensitivity screening using spheroids from five patients demonstrated individual response profiles. This indicates that the spheroids maintained patient-to-patient differences in sensitivity towards the drugs and combinations most commonly used for treatment of colorectal cancer. In summary, short-term spheroid culture of primary colorectal adenocarcinoma cells represents a promising in vitro model for use in personalized medicine.

Tumor budding in colorectal cancer (CRC) is recognized as a valuable prognostic factor but its translation into daily histopathology practice has been delayed by lack of agreement on the optimal method of assessment. Within the context of the Swiss Association of Gastrointestinal Pathology (SAGIP), we performed a multicenter interobserver study on tumor budding, comparing hematoxylin and eosin (H&E) with pan-cytokeratin staining using a 10 high power field (10HPF) and hotspot (1HPF) method. Two serial sections of 50 TNM stage II-IV surgically treated CRC were stained for H&E and pan-cytokeratin. Tumor buds were scored by independent observers at six participating centers in Switzerland and Austria using the 10HPF and 1HPF method on a digital pathology platform. Pearson correlation (r) and intra-class correlation coefficients (ICC) comparing scores between centers were calculated. Three to four times more tumor buds were detected in pan-cytokeratin compared to H&E slides. Correlation coefficients for tumor budding counts between centers ranged from r = 0.46 to r = 0.91 for H&E and from r = 0.73 to r = 0.95 for pan-cytokeratin slides. Interobserver agreement across all centers was excellent for pan-cytokeratin [10HPF: ICC = 0.83 and 1HPF: ICC = 0.8]. In contrast, assessment of tumor budding on H&E slides reached only moderate agreement [10HPF: ICC = 0.58 and 1HPF: ICC = 0.49]. Based on previous literature and our findings, we recommend (1) pan-cytokeratin staining whenever possible, (2) 10HPF method for resection specimens, and (3) 1HPF method for limited material (preoperative biopsy or pT1). Since tumor budding counts can be used to determine probabilities of relevant outcomes and as such more optimally complement clinical decision making, we advocate the avoidance of cutoff scores.

Multidisciplinary management of colorectal liver metastases allows an increase of about 20% in the resection rate of liver metastases. It includes chemotherapy, interventional radiology and surgery. In 2013, the preliminary results of the in-situ split of the liver associated with portal vein ligation (ALLPS) are promising with unprecedented mean hypertrophy up to 70% at day 9. However, the related morbidity of this procedure is about 40% and hence should be performed in the setting of study protocol only. For pancreatic cancer, the future belongs to the use of adjuvant and neo adjuvant therapies in order to increase the resection rate. Laparoscopic and robot-assisted surgery is still in evolution with significant benefits in the reduction of cost, hospital stay, and postoperative morbidity. Finally, enhanced recovery pathways (ERAS) have been validated for colorectal surgery and are currently assessed in other fields of surgery like HPB and upper GI surgery.

BACKGROUND: To determine the dose-limiting toxicity (DLT), maximum tolerated dose, recommended dose (RD) and preliminary evidence of activity of escalating doses of irinotecan (CPT-11) fixed-dose-rate infusional gemcitabine (FDR-GMB) and bevacizumab in pretreated metastatic colorectal cancer (mCRC) patients. Pharmacogenomic analysis was performed to investigate the association between VEGF single-nucleotide polymorphisms and clinical outcome. PATIENTS AND METHODS: A total of 89 mCRC patients were recruited in a two-step study design; 28 were included in the dose-finding study and 59 in the pharmacogenomic analysis. The FDR-GMB of 1000 mg m⁻², bevacizumab 5 mg kg⁻¹ and CPT-11 doses ranging from 100 to 160 mg m⁻² were explored. The VEGF protein serum levels were quantified by EIA. Allelic discrimination was performed to genotype polymorphisms in the VEGF gene. RESULTS: CPT-11 RD was 150 mg m⁻². Diarrhoea and neutropenia were the DLT. After a median follow-up of 42 months, the median time to progression (TTP) and overall survival were 5.2 and 19.9 months, respectively. VEGF levels were significantly correlated with VEGF-2578AA and VEGF-460CC genotypes, and a trend was observed with VEGF+405GG genotype. The presence of any of these genotypes correlated with a longer median TTP (8.8 vs 4.5 months, P=0.04). CONCLUSION: The triplet combination tested in this study is effective and well tolerated. A possible predictive role for VEGF gene polymorphisms and baseline VEGF circulating levels is suggested.