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.

Discontinuation of imatinib in patients with oligometastatic gastrointestinal stromal tumour who are in complete radiological remission: a prospective multicentre phase II study.

INTRODUCTION: Metastatic gastrointestinal stromal tumour (GIST) is considered incurable, and life-long treatment with tyrosine kinase inhibitors is recommended. We investigated whether selected patients with metastatic GIST may remain in durable remission despite imatinib discontinuation. PATIENTS: In this 1-group, prospective, multicentre phase II trial selected patients with oligometastatic (≤3 metastases) GIST discontinued imatinib treatment. Eligible patients had been treated with imatinib >5 years without progression and had no radiologically detectable metastases after metastasectomy, radiofrequency ablation (RFA) or complete response to imatinib. The primary endpoint was progression-free survival (PFS) 3-years after stopping imatinib. Overall survival (OS) and quality of life (QoL) were secondary endpoints. RESULTS: The trial closed prematurely due to slow accrual. Between January 5, 2017, and June 5, 2019, 13 patients were enrolled, of whom 12 discontinued imatinib. The median follow-up time was 55 months (range, 36 to 69) after study entry. Five (42%) of the 12 eligible patients remained progression free, and seven (58%) progressed with a median time to progression 10 months. Median PFS was 23 months and the estimated 3-year PFS 41%. Six of the seven patients who progressed restarted imatinib, and all six responded. Three-year OS was 100%, and all patients were alive at the time of the study analysis. QoL measured 5 and 11 months after discontinuation of imatinib demonstrated improvement compared to the baseline. INTERPRETATION: A substantial proportion of selected patients with oligometastatic GIST treated with imatinib and metastasis surgery/RFA may remain disease-free for ≥3 years with improved QoL after stopping of imatinib.

Pancreatic duct occlusion with polychloroprene-based glue for the management of postoperative pancreatic fistula after pancreatoduodenectomy-an outdated approach?

Background: Managing postoperative pancreatic fistula (POPF) presents a formidable challenge after pancreatoduodenectomy. Some centers consider pancreatic duct occlusion (PDO) in reoperations following pancreatoduodenectomy as a pancreas-preserving procedure, aiming to control a severe POPF. The aim of the current study was to evaluate the short- and long-term outcomes of employing PDO for the management of the pancreatic stump during relaparotomy for POPF subsequent to pancreatoduodenectomy. Methods: Retrospective review of consecutive patients at Oslo University Hospital undergoing pancreatoduodenectomy and PDO during relaparotomy. Pancreatic stump management during relaparotomy consisted of occlusion of the main pancreatic duct with polychloroprene Faxan-Latex, after resecting the dehiscent jejunal loop previously constituting the pancreaticojejunostomy. Results: Between July 2005 and September 2015, 826 pancreatoduodenectomies were performed. Overall reoperation rate was 13.2% (n = 109). POPF grade B/C developed in 113 (13.7%) patients. PDO during relaparotomy was performed in 17 (2.1%) patients, whereas completion pancreatectomy was performed in 22 (2.7%) patients. Thirteen (76%) of the 17 patients had a persistent POPF after PDO, and the time from PDO until removal of the last abdominal drain was median 35 days. Of the PDO patients, 13 (76%) patients required further drainage procedures (n = 12) or an additional reoperation (n = 1). In-hospital mortality occurred in one patient (5.9%). Five (29%) patients developed new-onset diabetes mellitus, and 16 (94%) patients acquired exocrine pancreatic insufficiency. Conclusions: PDO is a safe and feasible approach for managing severe POPF during reoperation following pancreatoduodenectomy. A significant proportion of patients experience persistent POPF post-procedure, necessitating supplementary drainage interventions. The findings suggest that it is advisable to explore alternative pancreas-preserving methods before opting for PDO in the management of POPF subsequent to pancreatoduodenectomy.

Results from the european survey on preoperative management and optimization protocols for PeriHilar cholangiocarcinoma.

BACKGROUND: Major surgery, along with preoperative cholestasis-related complications, are responsible for the increased risk of morbidity and mortality in perihilar cholangiocarcinoma (pCCA). The aim of the present survey is to provide a snapshot of current preoperative management and optimization strategies in Europe. METHODS: 61 European centers, experienced in hepato-biliary surgery completed a 59-questions survey regarding pCCA preoperative management. Centers were stratified according to surgical caseload (<5 and ≥ 5 cases/year) and preoperative management protocols' application. RESULTS: The overall case volume consisted of 6333 patients. Multidisciplinary discussion was routinely performed in 91.8% of centers. Most respondents (96.7%) recognized the importance of a well-structured preoperative protocol. The preferred method for biliary drainage was percutaneous transhepatic biliary drainage (60.7%) while portal vein embolization was the preferred technique for liver hypertrophy (90.2%). Differences in preoperative pathologic confirmation of malignancy (35.8% vs 28.7%; p < 0.001), number of mismanaged referred patients (88.2% vs 50.8%; p < 0.001), biliary drainage (65.1% vs 55.6%; p = 0.015) and liver function evaluation (37.2% vs 5.6%; p = 0.001) were found between centers according to groups' stratification. CONCLUSION: The importance of a correct preoperative management is recognized. Nevertheless, the current lack of guidelines leads to wide heterogeneity of behaviors among centers. This survey can provide recommendations to improve pCCA perioperative outcomes.

Laparoscopic versus open liver resection for intrahepatic cholangiocarcinoma: a multicenter propensity score-matched study.

BACKGROUND: The role of laparoscopy in the treatment of intrahepatic cholangiocarcinoma (ICC) remains unclear. This multicenter study examined the outcomes of laparoscopic liver resection for ICC. METHODS: Patients with ICC who had undergone laparoscopic or open liver resection between 2012 and 2019 at four European expert centers were included in the study. Laparoscopic and open approaches were compared in terms of surgical and oncological outcomes. Propensity score matching was used for minimizing treatment selection bias and adjusting for confounders (age, ASA grade, tumor size, location, number of tumors and underlying liver disease). RESULTS: Of 136 patients, 50 (36.7%) underwent laparoscopic resection, whereas 86 (63.3%) had open surgery. Median tumor size was larger (73.6 vs 55.1 mm, p = 0.01) and the incidence of bi-lobar tumors was higher (36.6 vs 6%, p < 0.01) in patients undergoing open surgery. After propensity score matching baseline characteristics were comparable although open surgery was associated with a larger fraction of major liver resections (74 vs 38%, p < 0.01), lymphadenectomy (60 vs 20%, p < 0.01) and longer operative time (294 vs 209 min, p < 0.01). Tumor characteristics were similar. Laparoscopic resection resulted in less complications (30 vs 52%, p = 0.025), fewer reoperations (4 vs 16%, p = 0.046) and shorter hospital stay (5 vs 8 days, p < 0.01). No differences were found in terms of recurrence, recurrence-free and overall survival. CONCLUSION: Laparoscopic resection seems to be associated with improved short-term and with similar long-term outcomes compared with open surgery in patients with ICC. However, possible selection criteria for laparoscopic surgery are yet to be defined.

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.

Minimally Invasive Pancreatoduodenectomy: Contemporary Practice, Evidence, and Knowledge Gaps.

Minimally invasive pancreatoduodenectomy has gained popularity throughout the last decade. For laparoscopic pancreatoduodenectomy, some high-level evidence exists, but with conflicting results. There are currently no published randomized controlled trials comparing robotic and open pancreatoduodenectomy. Comparative long-term data for patients with pancreatic ductal adenocarcinoma is lacking to date. Based on the existing evidence, current observed benefits of minimally invasive pancreatoduodenectomy over open pancreatoduodenectomy seem scarce, but retrospective data indicate the safety of these procedures in selected patients. As familiarity with the robotic platform increases, studies have shown an expansion in indications, also including patients with vascular involvement and even indicating favorable results in patients with obesity and high-risk morphometric features. Several ongoing randomized controlled trials aim to investigate potential differences in short- and long-term outcomes between minimally invasive and open pancreatoduodenectomy. Their results are much awaited.

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.

Evolution of laparoscopic liver surgery: 20-year experience of a Norwegian high-volume referral center.

BACKGROUND: Laparoscopic liver surgery has evolved to become a standard surgical approach in many specialized centers worldwide. In this study we present the evolution of laparoscopic liver surgery at a single high-volume referral center since its introduction in 1998. METHODS: Patients who underwent laparoscopic liver resection (LLR) between August 1998 and December 2018 at the Oslo University Hospital were analyzed. Perioperative outcomes were compared between three time periods: early (1998 to 2004), middle (2005 to 2012) and recent (2013-2018). RESULTS: Up to December 2020, 1533 LLRs have been performed. A total of 1232 procedures were examined (early period, n = 62; middle period, n = 367 and recent period, n = 803). Colorectal liver metastasis was the main indication for surgery (68%). The rates of conversion to laparotomy and hand-assisted laparoscopy were 3.2% and 1.4%. The median operative time and blood loss were 130 min [interquartile range (IQR), 85-190] and 220 ml (IQR, 50-600), respectively. The total postoperative complications rate was 20.3% and the 30-day mortality was 0.3%. The median postoperative stay was two (IQR, 2-4) days. When comparing perioperative outcomes between the three time periods, shorter operation time (median, from 182 to 120 min, p < 0.001), less blood loss (median, from 550 to 200 ml, p = 0.023), decreased rate of conversions to laparotomy (from 8 to 3%) and shorter postoperative hospital stay (median, from 3 to 2 days, p < 0.001) was observed in the later periods, while the number of more complex liver resections had increased. CONCLUSION: During the last two decades, the indications, the number of patients and the complexity of laparoscopic liver procedures have expanded significantly. Initially being an experimental approach, laparoscopic liver surgery is now safely implemented across our unit and has become the method of choice for surgical treatment of most liver tumors.

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.

Portal Vein Embolization Using N-Butyl Cyanoacrylate-Glue: What Impact Does a Central Vascular Plug Have?

PURPOSE: To examine if the addition of a central vascular plug (CVP) to portal vein embolization (PVE) with N-butyl cyanoacrylate-glue (NBCA) increases future liver remnant (FLR) growth. MATERIAL AND METHODS: This is a single-center retrospective study of 115 consecutive patients with colorectal liver metastases undergoing PVE in 2013-2019. All patients were embolized with NBCA as the main embolic agent. In 2017-2019 NBCA was combined with a CVP in the central part of the right portal vein. Growth of the FLR and standardized FLR (sFLR) including degree of hypertrophy (DH) and kinetic growth rate (KGR) were analyzed, as well as procedure data such as use of cone-beam CT (CBCT), dose area product (DAP), fluoroscopy time and contrast dose. RESULTS: A total of 40 patients (35%) underwent PVE with a combination of CVP and NBCA. The DH was higher in these patients after 4 weeks, mean 13.6% (SD 7.8) vs. 10.5% (SD 6.4; p = 0.022), verified in multivariate analysis (coefficient 4.1, p = 0.015). A CVP did not significantly increase the resection rate (90% vs 82%, p = 0.4). Cone beam CT was used in 65 patients (57%). Use of CBCT did not affect FLR growth, and fluoroscopy time and contrast doses were not different in patients having a CBCT or not. Slightly lower DAP (median 3375 vs. 4499 cGy*cm2; p = 0.09) was seen in procedures where CBCT was used. CONCLUSION: A CVP in addition to NBCA embolization was associated with increased growth of the FLR compared to NBCA alone.

Treatment of relapse and survival outcomes after liver transplantation in patients with colorectal liver metastases.

Liver transplantation (LT) in selected colorectal cancer (CRC) patients with nonresectable liver-only metastases may result in 5-year overall survival of up to about 70-100%. However, the majority will have recurrent disease. All patients included in this report were included in prospective studies. Forty-four out of 56 patients had a relapse, and all 44 patients received treatment for recurrent disease. The organ of the first relapse was lung metastases in 23 of the 44 patients. The first treatment modality of the relapse was the treatment with curative intent in 55.8% of the patients, and chemotherapy was the first treatment administered to 25.6% of the patients. Patients receiving surgery of lung metastases had a 5-year overall survival of 66.5% from the time of metastasectomy. Patients receiving treatment with curative intent for metastases to other organs had a 5-year overall survival of 24.8%. Nine of the 44 patients had no evidence of disease (NED) at the end of the follow-up. Median time of NED in these patients was 54.3 months, and median overall survival from the time of LT was 8.4 years. Because of the high incidence of recurrent disease, these patients should have a systematic long-term follow-up since many of the relapses may be treated with curative intent.

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.

How should liver hypertrophy be stimulated? A comparison of upfront associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) and portal vein embolization (PVE) with rescue possibility.

BACKGROUND: The role of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in comparison to portal vein embolization (PVE) is debated. The aim of this study was to compare successful resection rates (RR) with upfront ALPPS vs. PVE with rescue ALPPS on demand and to compare the hypertrophy of the liver between ALPPS and PVE plus subsequent rescue ALPPS. METHODS: A retrospective analysis of all patients treated with PVE for colorectal liver metastasis (CRLM) or ALPPS (any diagnosis, rescue ALPPS included) at five Scandinavian university hospitals during the years 2013-2016 was conducted. A Chi-square test and a Mann-Whitney U test were used to assess the difference between the groups. A successful RR was defined as liver resection without a 90-day mortality. RESULTS: A total of 189 patients were included. Successful RR was in 84.5% of the patients with ALPPS upfront and in 73.3% of the patients with PVE and rescue ALPPS on demand (P=0.080). The hypertrophy of the future liver remnants (FLRs) with ALPPS upfront was 71% (48-97%) compared to 96% (82-113%) after PVE and rescue ALPPS (P=0.010). CONCLUSIONS: Upfront ALPPS offers a somewhat higher successful RR than PVE with rescue ALPPS on demand. The sequential combination of PVE and ALPPS leads to a higher overall degree of hypertrophy than upfront ALPPS.

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.