Impact of pancreas transection site on incidence of pancreatic fistula after distal pancreatectomy: a propensity score matched study.

BACKGROUND: Distal pancreatectomy (DP) is performed for lesions in the body and tail of the pancreas. The morbidity profile is considerable, mainly due to clinically relevant postoperative pancreatic fistula (CR-POPF). This study aims to investigate potential differences in CR-POPF related to transection site. METHODS: An observational cohort study from a prospectively maintained database was performed. Subtotal distal pancreatectomy (SDP) was defined as transection over the superior mesenteric vein, and DP was defined as transection lateral to this point. Propensity score matching (PSM) in 1:1 fashion was applied based on demographical and perioperative variables. RESULTS: Six hundred and six patients were included in the analysis (1997-2020). Four hundred twenty (69.3%) underwent DP, while 186 (30.7%) underwent SDP. The rate of CR-POPF was 19.3% after DP and 20.4% after SDP (p = 0.74). SDP was associated with older age (63.1 vs 60.1 years, p = 0.016), higher occurrence of ductal adenocarcinoma (37.1 vs 17.6%, p = 0.001) and more frequent use of neoadjuvant chemotherapy (3.8 vs 0.7%, p = 0.012). After PSM, 155 patients were left in each group. The difference in CR-POPF between DP and SDP remained statistically non-significant (20.6 vs 18.7%, p = 0.67). CONCLUSION: This study found no difference in CR-POPF related to transection site during distal pancreatectomy.

Health Economic Evaluation of Patients With Colorectal Liver Metastases Randomized to ALPPS or TSH: Analysis From the LIGRO Trial.

Objective: This is a preplanned, health economic evaluation from the LIGRO trial. One hundred patients with colorectal liver metastases (CRLM) and standardized future liver remnant <30% were randomized to associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) or two-staged hepatectomy (TSH). Summary Background Data: TSH, is an established method in advanced CRLM. ALPPS has emerged providing improved resection rate and survival. The health care costs and health outcomes, combining health-related quality of life (HRQoL) and survival into quality-adjusted life years (QALYs), of ALPPS and TSH have not previously been evaluated and compared. Methods: Costs and QALYs were compared from treatment start up to 2 years. Costs are estimated from resource use, including all surgical interventions, length of stay after interventions, diagnostic procedures and chemotherapy, and applying Swedish unit costs. QALYs were estimated by combining survival and HRQoL data, the latter being assessed with EQ-5D 3L. Estimated costs and QALYs for each treatment strategy were combined into an incremental cost-effectiveness ratio (ICER). Nonparametric bootstrapping was used to assess the joint distribution of incremental costs and QALYs. Results: The mean cost difference between ALPPS and TSH was 12,662€, [95% confidence interval (CI): -10,728-36,051; P = 0.283]. Corresponding mean difference in life years and QALYs was 0.1296 (95% CI: -0.12-0.38; P = 0.314) and 0.1285 (95% CI: -0.11-0.36; P = 0.28), respectively. The ICER was 93,186 and 92,414 for QALYs and life years as outcomes, respectively. Conclusions: Based on the 2-year data, the cost-effectiveness of ALPPS is uncertain. Further research, exploring cost and health outcomes beyond 2 years is needed.

Laparoscopic parenchyma-sparing liver resection for large (≥ 50 mm) colorectal metastases.

BACKGROUND: Traditionally, patients with large liver tumors (≥ 50 mm) have been considered for anatomic major hepatectomy. Laparoscopic resection of large liver lesions is technically challenging and often performed by surgeons with extensive experience. The current study aimed to evaluate the surgical and oncologic safety of laparoscopic parenchyma-sparing liver resection in patients with large colorectal metastases. METHODS: Patients who primarily underwent laparoscopic parenchyma-sparing liver resection (less than 3 consecutive liver segments) for colorectal liver metastases between 1999 and 2019 at Oslo University Hospital were analyzed. In some recent cases, a computer-assisted surgical planning system was used to better visualize and understand the patients' liver anatomy, as well as a tool to further improve the resection strategy. The surgical and oncologic outcomes of patients with large (≥ 50 mm) and small (< 50 mm) tumors were compared. Multivariable Cox-regression analysis was performed to identify risk factors for survival. RESULTS: In total 587 patients met the inclusion criteria (large tumor group, n = 59; and small tumor group, n = 528). Median tumor size was 60 mm (range, 50-110) in the large tumor group and 21 mm (3-48) in the small tumor group (p < 0.001). Patient age and CEA level were higher in the large tumor group (8.4 µg/L vs. 4.6 µg/L, p < 0.001). Operation time and conversion rate were similar, while median blood loss was higher in the large tumor group (500 ml vs. 200 ml, p < 0.001). Patients in the large tumor group had shorter 5 year overall survival (34% vs 49%, p = 0.027). However, in the multivariable Cox-regression analysis tumor size did not impact survival, unlike parameters such as age, ASA score, CEA level, extrahepatic disease at liver surgery, and positive lymph nodes in the primary tumor. CONCLUSION: Laparoscopic parenchyma-sparing resections for large colorectal liver metastases provide satisfactory short and long-term outcomes.

Implementation and training with laparoscopic distal pancreatectomy: 23-year experience from a high-volume center.

BACKGROUND: Distal pancreatectomy is the most common procedure in minimally-invasive pancreatic surgery. Data in the literature suggest that the learning curve flattens after performing up to 30 procedures. However, the exact number remains unclear. METHODS: The implementation and training with laparoscopic distal pancreatectomy (LDP) in a high-volume center were studied between 1997 and 2020. Perioperative outcomes and factors related to conversion were assessed. The individual experiences of four different surgeons (pioneer and adopters) performing LDP on a regular basis were examined. RESULTS: Six hundred forty LDPs were done accounting for 95% of all distal pancreatectomies performed throughout the study period. Conversion was needed in 14 (2.2%) patients due to intraoperative bleeding or tumor adherence to the major vasculature. Overall morbidity and mortality rates were 35 and 0.6%, respectively. Intra- and postoperative outcomes did not change for any of the surgeons within their first 40 cases. Operative time significantly decreased after the first 80 cases for the pioneer surgeon and did not change afterwards although the proportion of ductal adenocarcinoma increased. Tumor size increased after the first 80 cases for the first adopter without affecting the operative time. CONCLUSIONS: In this nearly unselected cohort, no significant changes in surgical outcomes were observed throughout the first 40 LDPs for different surgeons. The exact number of procedures required to overcome the learning curve is difficult to determine as it seems to depend on patient selection policy and specifics of surgical training at the corresponding center.

Prognostic Impact of Resection Margin Status in Distal Pancreatectomy for Ductal Adenocarcinoma.

BACKGROUND: Resection margin status is considered one of the few surgeon-controlled parameters affecting prognosis in pancreatic ductal adenocarcinoma (PDAC). While studies mostly focus on resection margins in pancreatoduodenectomy, little is known about their role in distal pancreatectomy (DP). This study aimed to investigate resection margins in DP for PDAC. METHODS: Patients who underwent DP for PDAC between October 2004 and February 2020 were included (n = 124). Resection margins and associated parameters were studied in two consecutive time periods during which different pathology examination protocols were used: non-standardized (period 1: 2004-2014) and standardized (period 2: 2015-2020). Microscopic margin involvement (R1) was defined as ≤1 mm clearance. RESULTS: Laparoscopic and open resections were performed in 117 (94.4%) and 7 (5.6%) patients, respectively. The R1 rate for the entire cohort was 73.4%, increasing from 60.4% in period 1 to 83.1% in period 2 (p = 0.005). A significantly higher R1 rate was observed for the posterior margin (35.8 vs. 70.4%, p < 0.001) and anterior pancreatic surface (based on a 0 mm clearance; 18.9 vs. 35.4%, p = 0.045). Pathology examination period, poorly differentiated PDAC, and vascular invasion were associated with R1 in the multivariable model. Extended DP, positive anterior pancreatic surface, lymph node ratio, perineural invasion, and adjuvant chemotherapy, but not R1, were significant prognostic factors for overall survival in the entire cohort. CONCLUSIONS: Pathology examination is a key determinant of resection margin status following DP for PDAC. A high R1 rate is to be expected when pathology examination is meticulous and standardized. Involvement of the anterior pancreatic surface affects prognosis.

The expressed mutational landscape of microsatellite stable colorectal cancers.

BACKGROUND: Colorectal cancer is the 2nd leading cause of cancer-related deaths with few patients benefiting from biomarker-guided therapy. Mutation expression is essential for accurate interpretation of mutations as biomarkers, but surprisingly, little has been done to analyze somatic cancer mutations on the expression level. We report a large-scale analysis of allele-specific mutation expression. METHODS: Whole-exome and total RNA sequencing was performed on 137 samples from 121 microsatellite stable colorectal cancers, including multiregional samples of primary and metastatic tumors from 4 patients. Data were integrated with allele-specific resolution. Results were validated in an independent set of 241 colon cancers. Therapeutic associations were explored by pharmacogenomic profiling of 15 cell lines or patient-derived organoids. RESULTS: The median proportion of expressed mutations per tumor was 34%. Cancer-critical mutations had the highest expression frequency (gene-wise mean of 58%), independent of frequent allelic imbalance. Systematic deviation from the general pattern of expression levels according to allelic frequencies was detected, including preferential expression of mutated alleles dependent on the mutation type and target gene. Translational relevance was suggested by correlations of KRAS/NRAS or TP53 mutation expression levels with downstream oncogenic signatures (p < 0.03), overall survival among patients with stage II and III cancer (KRAS/NRAS: hazard ratio 6.1, p = 0.0070), and targeted drug sensitivity. The latter was demonstrated for EGFR and MDM2 inhibition in pre-clinical models. CONCLUSIONS: Only a subset of mutations in microsatellite stable colorectal cancers were expressed, and the "expressed mutation dose" may provide an opportunity for more fine-tuned biomarker interpretations.

De novo transcriptomic subtyping of colorectal cancer liver metastases in the context of tumor heterogeneity.

BACKGROUND: Gene expression-based subtyping has the potential to form a new paradigm for stratified treatment of colorectal cancer. However, current frameworks are based on the transcriptomic profiles of primary tumors, and metastatic heterogeneity is a challenge. Here we aimed to develop a de novo metastasis-oriented framework. METHODS: In total, 829 transcriptomic profiles from patients with colorectal cancer were analyzed, including primary tumors, liver metastases, and non-malignant liver samples. High-resolution microarray gene expression profiling was performed of 283 liver metastases from 171 patients treated by hepatic resection, including multiregional and/or multi-metastatic samples from each of 47 patients. A single randomly selected liver metastasis sample from each patient was used for unsupervised subtype discovery by nonnegative matrix factorization, and a random forest prediction model was trained to classify multi-metastatic samples, as well as liver metastases from two independent series of 308 additional patients. RESULTS: Initial comparisons with non-malignant liver samples and primary colorectal tumors showed a highly variable degree of influence from the liver microenvironment in metastases, which contributed to inter-metastatic transcriptomic heterogeneity, but did not define subtype distinctions. The de novo liver metastasis subtype (LMS) framework recapitulated the main distinction between epithelial-like and mesenchymal-like tumors, with a strong immune and stromal component only in the latter. We also identified biologically distinct epithelial-like subtypes originating from different progenitor cell types. LMS1 metastases had several transcriptomic features of cancer aggressiveness, including secretory progenitor cell origin, oncogenic addictions, and microsatellite instability in a microsatellite stable background, as well as frequent RAS/TP53 co-mutations. The poor-prognostic association of LMS1 metastases was independent of mutation status, clinicopathological variables, and current subtyping frameworks (consensus molecular subtypes and colorectal cancer intrinsic subtypes). LMS1 was also the least heterogeneous subtype in comparisons of multiple metastases per patient, and tumor heterogeneity did not confound the prognostic value of LMS1. CONCLUSIONS: We report the first large study of multi-metastatic gene expression profiling of colorectal cancer. The new metastasis-oriented subtyping framework showed potential for clinically relevant transcriptomic classification in the context of metastatic heterogeneity, and an LMS1 mini-classifier was constructed to facilitate prognostic stratification and further clinical testing.

Metastatic heterogeneity of the consensus molecular subtypes of colorectal cancer.

Gene expression-based subtypes of colorectal cancer have clinical relevance, but the representativeness of primary tumors and the consensus molecular subtypes (CMS) for metastatic cancers is not well known. We investigated the metastatic heterogeneity of CMS. The best approach to subtype translation was delineated by comparisons of transcriptomic profiles from 317 primary tumors and 295 liver metastases, including multi-metastatic samples from 45 patients and 14 primary-metastasis sets. Associations were validated in an external data set (n = 618). Projection of metastases onto principal components of primary tumors showed that metastases were depleted of CMS1-immune/CMS3-metabolic signals, enriched for CMS4-mesenchymal/stromal signals, and heavily influenced by the microenvironment. The tailored CMS classifier (available in an updated version of the R package CMScaller) therefore implemented an approach to regress out the liver tissue background. The majority of classified metastases were either CMS2 or CMS4. Nonetheless, subtype switching and inter-metastatic CMS heterogeneity were frequent and increased with sampling intensity. Poor-prognostic value of CMS1/3 metastases was consistent in the context of intra-patient tumor heterogeneity.

Genomic and prognostic heterogeneity among RAS/BRAFV600E /TP53 co-mutated resectable colorectal liver metastases.

Hepatic resection is potentially curative for patients with colorectal liver metastases, but the treatment benefit varies. KRAS/NRAS (RAS)/TP53 co-mutations are associated with a poor prognosis after resection, but there is large variation in patient outcome within the mutation groups, and genetic testing is currently not used to evaluate benefit from surgery. We have investigated the potential for improved prognostic stratification by combined biomarker analysis with DNA copy number aberrations (CNAs), and taking tumor heterogeneity into account. We determined the mutation status of RAS, BRAFV600 , and TP53 in 441 liver lesions from 171 patients treated by partial hepatectomy for metastatic colorectal cancer. CNAs were profiled in 232 tumors from 67 of the patients. Mutations and high-level amplifications of cancer-critical genes, the latter including ERBB2 and EGFR, were predominantly homogeneous within patients. RAS/BRAFV600E and TP53 co-mutations were associated with a poor patient outcome (hazard ratio, HR, 3.9, 95% confidence interval, CI, 1.3-11.1, P = 0.012) in multivariable analyses with clinicopathological variables. The genome-wide CNA burden and intrapatient intermetastatic CNA heterogeneity varied within the mutation groups, and the CNA burden had prognostic associations in univariable analysis. Combined prognostic analyses of RAS/BRAFV600E /TP53 mutations and CNAs, either as a high CNA burden or high intermetastatic CNA heterogeneity, identified patients with a particularly poor outcome (co-mutation/high CNA burden: HR 2.7, 95% CI 1.2-5.9, P = 0.013; co-mutation/high CNA heterogeneity: HR 2.5, 95% CI 1.1-5.6, P = 0.022). In conclusion, DNA copy number profiling identified genomic and prognostic heterogeneity among patients with resectable colorectal liver metastases with co-mutated RAS/BRAFV600E /TP53.

Laparoscopic distal pancreatectomy in patients with poor physical status.

BACKGROUND: Laparoscopic distal pancreatectomy (LDP) is advantageous over open surgery in the treatment of benign pancreatic lesions and low-grade malignancies. Yet the evidence on the relationship between comorbidities and the outcomes of LDP remains scarce. METHODS: Patients who had undergone LDP for all indications between April 1997 and December 2019 were included. Preoperative physical status was defined according to the American Society of Anesthesiology (ASA) criteria. Perioperative outcomes were compared between the patients with high (ASA III-IV) and low/moderate anesthetic risk (ASA I-II). RESULTS: A total of 605 patients were eligible for analysis including 190 with ASA III-IV and 415 with ASA I-II. The former was associated with older age, male gender, preexisting medical conditions, greater total number of comorbidities and red blood cell transfusion. The rate of medical complications was significantly higher in high-risk patients. Multivariable analysis identified ASA III-IV and operative time as independent predictors for medical complications. Overall/severe morbidity, surgical complications and mortality rates were similar. CONCLUSIONS: Poor physical status defined as ASA grades III-IV predicts medical complications, but has a limited impact on surgical complications and severe morbidity of LDP. Thus, it should not be considered as a contraindication for LDP.

ALPPS Improves Survival Compared With TSH in Patients Affected of CRLM: Survival Analysis From the Randomized Controlled Trial LIGRO.

OBJECTIVE: To evaluate the oncological outcome for patients with colorectal liver metastases (CRLM) randomized to associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) or 2-stage hepatectomy (TSH). BACKGROUND: TSH with portal vein occlusion is an established method for patients with CRLM and a low volume of the future liver remnant (FLR). ALPPS is a less established method. The oncological outcome of these methods has not been previously compared in a randomized controlled trial. METHODS: One hundred patients with CRLM and standardized FLR (sFLR) <30% were included and randomized to resection by ALPPS or TSH, with the option of rescue ALPPS in the TSH group, if the criteria for volume increase was not met. The first radiological follow-up was performed approximately 4 weeks postoperatively and then after 4, 8, 12, 18, and 24 months. At all the follow-ups, the remaining/recurrent tumor was noted. After the first follow-up, chemotherapy was administered, if indicated. RESULTS: The resection rate, according to the intention-to-treat principle, was 92% (44 patients) for patients randomized to ALPPS compared with 80% (39 patients) for patients randomized to TSH (P = 0.091), including rescue ALPPS. At the first postoperative follow-up, 37 patients randomized to ALPPS were assessed as tumor free in the liver, and also 28 patients randomized to TSH (P = 0.028). The estimated median survival for patients randomized to ALPPS was 46 months compared with 26 months for patients randomized to TSH (P = 0.028). CONCLUSIONS: ALPPS seems to improve survival in patients with CRLM and sFLR <30% compared with TSH.

Long-Term Oncologic Outcomes After Laparoscopic Versus Open Resection for Colorectal Liver Metastases : A Randomized Trial.

BACKGROUND: Despite the recent worldwide dissemination of laparoscopic liver surgery, no high-level evidence supports the oncologic safety of this approach. OBJECTIVE: To evaluate long-term oncologic outcomes after laparoscopic versus open liver resection in patients with colorectal metastases. DESIGN: A single-center, assessor-blinded, randomized controlled trial (OSLO-COMET [Oslo Randomized Laparoscopic Versus Open Liver Resection for Colorectal Metastases Trial]). (ClinicalTrials.gov: NCT01516710). SETTING: Oslo University Hospital, the only provider of liver surgery for the 3 million inhabitants of southeastern Norway. PARTICIPANTS: Patients with resectable colorectal liver metastases were randomly assigned to have open or laparoscopic liver resection. INTERVENTION: From February 2012 to January 2016, a total of 280 patients were included in the trial (laparoscopic surgery: n = 133; open surgery: n = 147). MEASUREMENTS: The primary outcome was postoperative morbidity within 30 days. Five-year rates of overall and recurrence-free survival were predefined secondary end points. RESULTS: At a median follow-up of 70 months, rates of 5-year overall survival were 54% in the laparoscopic group and 55% in the open group (between-group difference, 0.5 percentage point [95% CI, -11.3 to 12.3 percentage points]; hazard ratio, 0.93 [CI, 0.67 to 1.30]; P = 0.67). Rates of 5-year recurrence-free survival were 30% in the laparoscopic group and 36% in the open group (between-group difference, 6.0 percentage points [CI, -6.7 to 18.7 percentage points]; hazard ratio, 1.09 [CI, 0.80 to 1.49]; P = 0.57). LIMITATION: The trial was not powered to detect differences in secondary end points and was not designed to address a noninferiority hypothesis for survival outcomes. CONCLUSION: In this randomized trial of laparoscopic and open liver surgery, no difference in survival outcomes was found between the treatment groups. However, differences in 5-year overall survival up to about 10 percentage points in either direction cannot be excluded. This trial should be followed by pragmatic multicenter trials and international registries. PRIMARY FUNDING SOURCE: The South-Eastern Norway Regional Health Authority.

High Concordance and Negative Prognostic Impact of RAS/BRAF/PIK3CA Mutations in Multiple Resected Colorectal Liver Metastases.

BACKGROUND: The prevalence and clinical implications of genetic heterogeneity in patients with multiple colorectal liver metastases remain largely unknown. In a prospective series of patients undergoing resection of colorectal liver metastases, the aim was to investigate the inter-metastatic and primary-to-metastatic heterogeneity of mutations in KRAS, NRAS, BRAF, and PIK3CA and their prognostic impact. PATIENTS AND METHODS: We analyzed the mutation status among 372 liver metastases and 78 primary tumors from 106 patients by methods used in clinical routine testing, by Sanger sequencing, by next-generation sequencing (NGS), and/or by droplet digital polymerase chain reaction. The 3-year cancer-specific survival (CSS) was analyzed using the Kaplan-Meier method. RESULTS: Although Sanger sequencing indicated inter-metastatic mutation heterogeneity in 14 of 97 patients (14%), almost all cases were refuted by high-sensitive NGS. Also, heterogeneity among metastatic deposits was concluded only for PIK3CA in 2 patients. Similarly, primary-to-metastatic heterogeneity was indicated in 8 of 78 patients (10%) using Sanger sequencing but for only 2 patients after NGS, showing the emergence of 1 KRAS and 1 PIK3CA mutation in the metastatic lesions. KRAS mutations were present in 53 of 106 patients (50%) and were associated with poorer 3-year CSS after liver resection (37% vs. 61% for KRAS wild-type; P = .004). Poor prognostic associations were found also for the combination of KRAS/NRAS/BRAF mutations compared with triple wild-type (P = .002). CONCLUSION: Intra-patient mutation heterogeneity was virtually undetected, both between the primary tumor and the liver metastases and among the metastatic deposits. KRAS mutations separately, and KRAS/NRAS/BRAF mutations combined, were associated with poor patient survival after partial liver resection.

Laparoscopic liver resection for non-colorectal non-neuroendocrine metastases: perioperative and oncologic outcomes.

BACKGROUND: Liver resection is a treatment of choice for colorectal and neuroendocrine liver metastases, and laparoscopy is an accepted approach for surgical treatment of these patients. The role of liver resection for patients with non-colorectal non-neuroendocrine liver metastases (NCNNLM), however, is still disputable. Outcomes of laparoscopic liver resection for this group of patients have not been analyzed. MATERIAL AND METHODS: In this retrospective study, patients who underwent laparoscopic liver resection for NCNNLM at Oslo University Hospital between April 2000 and January 2018 were analyzed. Perioperative and oncologic data of these patients were examined. Postoperative morbidity was classified using the Accordion classification. Kaplan-Meier method was used for survival analysis. Median follow-up was 26 (IQR, 12-41) months. RESULTS: Fifty-one patients were identified from a prospectively collected database. The histology of primary tumors was classified as adenocarcinoma (n = 16), sarcoma (n = 4), squamous cell carcinoma (n = 4), melanoma (n = 16), gastrointestinal stromal tumor (n = 9), and adrenocortical carcinoma (n = 2). The median operative time was 147 (IQR, 95-225) min, while the median blood loss was 200 (IQR, 50-500) ml. Nine (18%) patients experienced postoperative complications. There was no 90-day mortality in this study. Thirty-five (68%) patients developed disease recurrence or progression. Seven (14%) patients underwent repeat surgical procedure for recurrent liver metastases. One-, three-, and five-year overall survival rates were 85%, 52%, and 38%, respectively. The median overall survival was 37 (95%CI, 25 to 49) months. CONCLUSION: Laparoscopic liver resection for NCNNLM results in good outcomes and should be considered in patients selected for surgical treatment.

Heterogeneous radiological response to neoadjuvant therapy is associated with poor prognosis after resection of colorectal liver metastases.

INTRODUCTION: Surgery combined with perioperative chemotherapy has become standard of care in patients with resectable colorectal liver metastases. However, poor outcome is expected for a significant subgroup. The clinical implications of inter-metastatic heterogeneity remain largely unknown. In a prospective, population-based series of patients undergoing resection of multiple colorectal liver metastases, the aim was to investigate the prevalence and prognostic impact of heterogeneous response to neoadjuvant chemotherapy. MATERIALS AND METHODS: Radiological response to treatment was evaluated in a lesion-specific manner in 2-5 metastases per patient. Change of lesion diameter was evaluated and response/progression was classified according to three different size thresholds; 3, 4 and 5 mm. A heterogeneous response was defined as progression and response of different metastases in the same patient. RESULTS: In total, 142 patients with 585 liver metastases were examined with the same radiological method (MRI or CT) before and after neoadjuvant treatment. Heterogeneous response to treatment was seen in 16 patients (11%) using the 3 mm size change threshold, and this group had a 5-year cancer-specific survival of 19% compared to 49% for patients with response in all lesions (p = 0.003). Cut-off values of 4-5 mm were less sensitive for detecting a heterogeneous response, but the survival difference was similar and significant. CONCLUSION: A subgroup of patients with multiple colorectal liver metastases had heterogeneous radiological response to neoadjuvant chemotherapy and poor prognosis. The evaluation of response pattern is easy to perform, feasible in clinical practice and, if validated, a promising biomarker for treatment decisions.