Resection and reconstruction of the largest abdominal vein system (the inferior vena cava, hepatic, and portal vein): a narrative review.

Background and Objective: As tumors invade major abdominal veins, surgical procedures are transformed from simple and basic to complicated and challenging. In this narrative review, we focus on what is currently known and not known regarding the technical aspects of major abdominal venous resection and its reconstruction, patency, and oncologic benefit in a cross-cutting perspective. Methods: A systematic literature search was performed in PubMed and Semantic Scholar from inception up to October 18, 2023. We reviewed 106 papers by title, abstract, and full text regarding resection or reconstruction of the inferior vena cava, hepatic vein confluence, portal vein (PV), and middle hepatic vein (MHV) tributaries in living donor liver transplantation (LDLT) in a cross-cutting perspective. Key Content and Findings: The oncologic benefit of aggressive hepatic vein resection with suitable reconstruction against adenocarcinoma remains unclear, and further studies are required to clarify this point. A superior mesenteric/PV resection is now a universal, indispensable, and effective procedure for pancreatic ductal adenocarcinoma. Although many case series using tailor-made autologous venous grafts have been reported, not only size mismatch but also additional surgical incisions and a longer operation time remain obstacles for venous reconstruction. The use of autologous alternative tissue remains only an alternative procedure because the patency rate of customized tubular conduit type to interpose or replace the resected vein is not known. Unlike arterial replacement, venous replacement using synthetic vascular grafts is still rarely reported and there are several inherent limitations except for reconstruction of tributaries of MHV in LDLT. Conclusions: Various approaches to abdominal vein resection and replacement or reconstruction are technically feasible with satisfactory results. Synthetic vascular grafts may be appropriate but have a certain rate of complications.

Reproducibility and efficiency of liver volumetry using manual method and liver analysis software.

BACKGROUND: For liver volumetry, manual tracing on computed tomography (CT) images is time-consuming and operator dependent. To overcome these disadvantages, several three-dimensional simulation software programs have been developed; however, their efficacy has not fully been evaluated. METHODS: Three physicians performed liver volumetry on preoperative CT images on 30 patients who underwent formal right hepatectomy, using manual tracing volumetry and two simulation software programs, SYNAPSE and syngo.via. The future liver remnant (FLR) was calculated using each method of volumetry. The primary endpoint was reproducibility and secondary outcomes were calculation time and learning curve. RESULTS: The mean FLR was significantly lower for manual volumetry than for SYNAPSE or syngo.via; there was no significant difference in mean FLR between the two software-based methods. Reproducibility was lower for the manual method than for the software-based methods. Mean calculation time was shortest for SYNAPSE. For the two physicians unfamiliar with the software, no obvious learning curve was observed for using SYNAPSE, whereas learning curves were observed for using syngo.via. CONCLUSIONS: Liver volumetry was more reproducible and faster with three-dimensional simulation software, especially SYNAPSE software, than with the conventional manual tracing method. Software can help even inexperienced physicians learn quickly how to perform liver volumetry.

Hepatectomy Before Primary Tumor Resection as Preferred Approach for Synchronous Liver Metastases from Rectal Cancer.

BACKGROUND: For patients with synchronous liver metastases (LM) from rectal cancer, a consensus on surgical sequencing is lacking. We compared outcomes between the reverse (hepatectomy first), classic (primary tumor resection first), and combined (simultaneous hepatectomy and primary tumor resection) approaches. METHODS: A prospectively maintained database was queried for patients with rectal cancer LM diagnosed before primary tumor resection who underwent hepatectomy for LM from January 2004 to April 2021. Clinicopathological factors and survival were compared between the three approaches. RESULTS: Among 274 patients, 141 (51%) underwent the reverse approach; 73 (27%), the classic approach; and 60 (22%), the combined approach. Higher carcinoembryonic antigen level at LM diagnosis and higher number of LM were associated with the reverse approach. Combined approach patients had smaller tumors and underwent less complex hepatectomies. More than eight cycles of pre-hepatectomy chemotherapy and maximum diameter of LM > 5 cm were independently associated with worse overall survival (OS) (p = 0.002 and 0.027, respectively). Although 35% of reverse-approach patients did not undergo primary tumor resection, OS did not differ between groups. Additionally, 82% of incomplete reverse-approach patients ultimately did not require diversion during follow-up. RAS/TP53 co-mutation was independently associated with lack of primary resection with the reverse approach (odds ratio: 0.16, 95% CI 0.038-0.64, p = 0.010). CONCLUSIONS: The reverse approach results in survival similar to that of combined and classic approaches and may obviate primary rectal tumor resections and diversions. RAS/TP53 co-mutation is associated with a lower rate of completion of the reverse approach.

Prospective Study of Perioperative Circulating Tumor DNA Dynamics in Patients Undergoing Hepatectomy for Colorectal Liver Metastases.

OBJECTIVE: To evaluate the association of perioperative ctDNA dynamics on outcomes after hepatectomy for CLM. SUMMARY BACKGROUND DATA: Prognostication is imprecise for patients undergoing hepatectomy for CLM, and ctDNA is a promising biomarker. However, clinical implications of perioperative ctDNA dynamics are not well established. METHODS: Patients underwent curative-intent hepatectomy after preoperative chemotherapy for CLM (2013-2017) with paired prehepatectomy/postoperative ctDNA analyses via plasma-only assay. Positivity was determined using a proprietary variant classifier. Primary endpoint was recurrence-free survival (RFS). Median follow-up was 55 months. RESULTS: Forty-eight patients were included. ctDNA was detected before and after surgery (ctDNA+/+) in 14 (29%), before but not after surgery (ctDNA+/-) in 19 (40%), and not at all (ctDNA-/-) in 11 (23%). Adverse tissue somatic mutations were detected in TP53 (n = 26; 54%), RAS (n = 23; 48%), SMAD4 (n = 5; 10%), FBXW7 (n = 3; 6%), and BRAF (n = 2; 4%). ctDNA+/+ was associated with worse RFS (median: ctDNA+/+, 6.0 months; ctDNA+/-, not reached; ctDNA-/-, 33.0 months; P = 0.001). Compared to ctDNA+/+, ctDNA+/- was associated with improved RFS [hazard ratio (HR) 0.24 (95% confidence interval (CI) 0.1-0.58)] and overall survival [HR 0.24 (95% CI 0.08-0.74)]. Adverse somatic mutations were not associated with survival. After adjustment for prehepatectomy chemotherapy, synchronous disease, and ≥2 CLM, ctDNA+/- and ctDNA-/- were independently associated with improved RFS compared to ctDNA+/+ (ctDNA+/-: HR 0.21, 95% CI 0.08-0.53; ctDNA-/-: HR 0.21, 95% CI 0.08-0.56). CONCLUSIONS: Perioperative ctDNA dynamics are associated with survival, identify patients with high recurrence risk, and may be used to guide treatment decisions and surveillance after hepatectomy for patients with CLM.

The impact of the covalently closed circular DNA level on recurrence of hepatocellular carcinoma after initial hepatectomy: an analysis of patients with resolved hepatitis B virus infection.

BACKGROUND: We assessed whether or not covalently closed circular DNA (cccDNA) levels in the background liver influence the recurrence of hepatocellular carcinoma (HCC) in patients with resolved hepatitis B virus (HBV) infection. METHODS: Among 425 patients who underwent initial hepatectomy for HCC between 2010 and 2018, a retrospective review was performed in 44 with resolved HBV infection. The clinicopathologic characteristics were analyzed for correlation with tumor recurrence. The HBV cccDNA levels were tested via a droplet digital polymerase chain reaction assay. RESULTS: HBV cccDNA was detected in 27 of 44 patients (61%), and the median level was 1.0 copies/1000 ng (range, 0-931.3 copies/1000 ng). Anti-HBc ≥8.9 S/CO was associated with cccDNA detection (odds ratio, 11.08; 95% confidence interval [95% CI], 2.48-49.46; P = 0.002). Twenty-eight patients (64%) developed HCC recurrence after hepatectomy. The overall 3- and 5-year recurrence-free survival rates were 45.7% and 34.3%, respectively.19 HBV cccDNA levels was not significantly associated with HCC recurrence, while the presence of multiple tumors was an independent risk fact or (hazard ratio, 6.53; 95% CI, 2.48-17.19; P < 0.001. CONCLUSION: HBV cccDNA levels did not influence HCC recurrence after hepatectomy. Anti-HBc levels may be used as a surrogate marker for cccDNA.

Preoperative Predictive Features of Invasive Carcinoma Among Intraductal Papillary Mucinous Neoplasm of the Pancreas.

OBJECTIVE: Noninvasive intraductal papillary mucinous neoplasms (IPMNs) theoretically do not metastasize. The purpose of this study is to preoperatively distinguish invasive carcinomas associated with IPMN from noninvasive IPMN. METHODS: A total of 131 patients who underwent surgical resection for IPMN were retrospectively analyzed to identify the predictors of invasive carcinoma, based on the International Association of Pancreatology Consensus Guidelines. RESULTS: Of the 131 patients, 29 (22%) had invasive carcinomas and 102 (78%) had noninvasive IPMN. An enhancing mural nodule (MN) greater than or equal to 5 mm, obstructive jaundice, an abrupt change in the caliber of the pancreatic duct (PD) with distal pancreatic atrophy, and lymphadenopathy were the significant predictors of invasive carcinoma in univariate analysis. The optimal cutoff value for the size of the enhancing MN to differentiate invasive carcinoma was 13 mm. In multivariate analysis, enhancing MN greater than or equal to 13 mm, obstructive jaundice, and an abrupt change in the PD caliber were the independent predictors. When all these factors were absent, only 17% were invasive carcinomas. CONCLUSIONS: Enhancing MN greater than or equal to 13 mm, obstructive jaundice, and an abrupt change in the PD caliber were predictive factors for invasive carcinoma. Systematic lymph node dissection may be omitted when a high-risk patient has none of these factors.

Colorectal Liver Micrometastases: Association with RAS/TP53 Co-Mutation and Prognosis after Surgery.

BACKGROUND: Micrometastases, defined as microscopic cancer cells spatially separated from the macroscopically evident metastasis, are identified in 24% to 56% of resected colorectal liver metastases (CLMs). Somatic gene mutations have emerged as independent prognostic factors in CLM. This study aimed to determine the prognostic impact and risk factors for the presence of micrometastases, including somatic gene mutations. STUDY DESIGN: Prospective evaluation for micrometastases was performed at 2 centers in the US and France from 2015 to 2019. CLM specimens were cut radially from the tumor margin to surrounding grossly normal liver for a distance of 2 cm. Depending on CLM size, 3 to 8 specimens per patient were submitted for microscopic analysis. Somatic gene mutations were detected by next-generation sequencing. RESULTS: Among 140 patients undergoing CLM resection in the US (n = 84) and France (n = 56), 36 (26%) patients were found to have micrometastases. Five-year overall and recurrence-free survival rates with micrometastases were 39% and 0%, respectively, compared with 61% and 20% without micrometastases (both p < 0.05). In multivariable analyses, the presence of micrometastases was an independent risk factor for worse overall survival (hazard ratio 2.88, 95% CI 1.46 to 5.70, p = 0.002) and recurrence-free survival (hazard ratio 1.56, 95% CI 1.01 to 2.41, p = 0.046). In binary logistic regression analysis, RAS/TP53 co-mutation was found to significantly increase the risk of micrometastases (odds ratio 2.77, 95% CI 1.15 to 6.71, p = 0.024). CONCLUSIONS: Micrometastases are associated with significantly worse survival after CLM resection. RAS/TP53 co-mutation correlated with increased risk of micrometastases. Further studies are needed to determine strategies to eradicate micrometastases.

Outcomes of Mixed Pathologic Response in Patients with Multiple Colorectal Liver Metastases Treated with Neoadjuvant Chemotherapy and Liver Resection.

BACKGROUND: Pathologic response to preoperative chemotherapy predicts survival in patients with colorectal liver metastases (CLMs) who undergo hepatectomy. In multiple CLMs, mixed pathologic response, wherein tumors exhibit different degrees of treatment response, is possible. We sought to evaluate survival outcomes of mixed response in patients with multiple CLMs. METHODS: We conducted a retrospective cohort study using a single-institution database of patients with two or more CLMs who underwent preoperative chemotherapy and hepatectomy (2010-2018). Pathologic response of each tumor was measured on pathology. Patients were stratified by pathologic response as complete (pCR) = 0-1% viability; major (pMajR) = 2-49% viability; minor (pMinR) = 50-99% viability; or mixed (pMixR) = at least one pCR/MajR tumor and one pMinR. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and adjusted risk of death was evaluated using Cox regression. RESULTS: Among 444 patients, 6% had pCR, 34% had pMajR, 36% had pMinR, and 24% had pMixR. Median and 5-year RFS for patients with pMixR was 10.4 months and 16%, respectively, compared with pMajR (11.3 months and 18%, respectively), pMinR (7.7 months and 13%, respectively), and pCR (23.1 months and 38%, respectively) [log-rank p < 0.001]. Median and 5-year OS for patients with pMixR was 77.4 months and 60%, respectively, compared with pMajR (80.5 months and 63%, respectively), pMinR (49.9 months and 39%, respectively), and pCR (median OS not reached; median follow-up of 37.1 months and 5-year OS of 65%) [log-rank p = 0.002]. pMixR was associated with a 52% risk of death reduction (hazard ratio 0.48, 95% confidence interval 0.30-0.78 vs. pMinR). CONCLUSIONS: One-quarter of patients with multiple CLMs have pMixR following preoperative chemotherapy and hepatectomy. OS and RFS for patients with pMixR mirror those of pMajR rather than pMinR, suggesting the greatest response achieved in any metastasis best predicts survival.

Histological growth patterns of colorectal cancer liver metastases: a strong prognostic marker associated with invasive patterns of the primary tumor and p53 alteration.

The histological growth pattern of liver metastases (desmoplastic, pushing, and replacement patterns) at the tumor-liver parenchymal interface is a prognostic factor in patients with colorectal cancer. However, data regarding its association with the primary tumor characteristics and molecular alterations are limited. This study evaluated the histological growth pattern in 136 cases of colorectal cancer liver metastases without preoperative treatment, comparing it with the clinicopathological features of the primary tumor. Liver metastasis exhibiting predominantly non-desmoplastic pattern (<50%), observed in 74 cases (54%), was associated with hepatic vein invasion (P = 0.025), worse recurrence-free survival (P < 0.001) and overall survival (P = 0.008). In multivariate analyses, multiple tumors (P < 0.001) and non-desmoplastic patterns (P = 0.009) were associated with worse recurrence-free survival, and tumor size (P = 0.025) and non-desmoplastic pattern (P = 0.025) were associated with worse overall survival. In 88 patients with available primary tumor tissue slides, non-desmoplastic pattern in the liver metastasis was associated with high-grade tumor budding (P = 0.002), high-grade poorly differentiated cluster (P = 0.021), absence of mucinous histology (P = 0.016), and aberrant p53 expression (complete loss or overexpression; P  0.001) of the primary colorectal cancer. In conclusion, the histological growth pattern in liver metastasis was a strong and independent prognostic factor for colorectal cancer. Our observations highlight the significant associations between histological growth patterns in liver metastases and histopathological features of the primary tumor, especially invasive front morphology and p53 aberration.

Effect of Co-mutation of RAS and TP53 on Postoperative ctDNA Detection and Early Recurrence after Hepatectomy for Colorectal Liver Metastases.

BACKGROUND: Circulating tumor DNA (ctDNA) is a promising biomarker for patients undergoing hepatectomy for colorectal liver metastases (CLM). We hypothesized that post-hepatectomy ctDNA detection would identify patients at highest risk for early recurrence of CLM. STUDY DESIGN: Patients with CLM who underwent curative-intent hepatectomy with ctDNA analysis within 180 days postoperatively (1/2013 and 6/2020) were included. Tissue somatic mutations and ctDNA analyses were performed by next-generation sequencing panels. Survival analyses determined factors associated with clinical recurrence 1 year or earlier after hepatectomy. Patients with primary tumors in situ and without 1-year follow-up were excluded. Median follow-up was 28.3 months. RESULTS: Of 105 patients, 32 (30%) were ctDNA positive (ctDNA+) after curative-intent hepatectomy. Compared with ctDNA-negative patients, ctDNA+ patients had multiple CLM (84% vs 55%, p = 0.002) and co-mutated RAS/TP53 (47% vs 23%, p = 0.018). Multiple CLM (odds ration (OR), 5.43; p = 0.005) and co-mutated RAS/TP53 (OR, 3.30; p = 0.019) were independently associated with post-hepatectomy ctDNA. Although perioperative carcinoembryonic antigen levels were not prognostic, postoperative ctDNA+ (hazard ratio (HR), 2.04; p = 0.011) and extrahepatic disease (HR, 2.45, p = 0.004) were independently associated with worse recurrence-free survival. After adjusting for extrahepatic disease, preoperative chemotherapy, multiple CLM, tumor viability of 50% or greater, and co-mutated RAS/TP53, ctDNA+ within 180 days was the only independent risk factor for recurrence 1 year or earlier after hepatectomy (94% vs 49%; HR, 11.8; p = 0.003). CONCLUSION: Postoperative ctDNA detection is associated with early recurrence 1 year or earlier after curative-intent hepatectomy for CLM, and RAS/TP53 co-mutations result in a more than 3-fold increased risk for postoperative ctDNA positivity. This highlights the complementary effect of tumor tissue and circulating mutational profiling for patients with CLM.

A multicenter phase II trial evaluating the efficacy of bevacizumab plus mFOLFOX6 for R0 surgical resection in advanced colorectal liver metastases harboring mutant-type KRAS: NEXTO-mt trial.

BACKGROUND: The effect of bevacizumab plus mFOLFOX6 on downsizing of liver metastases for curative resection has not been well assessed for patients with advanced colorectal liver metastases (CRLMs). This multicenter phase II trial aimed to examine the efficacy and safety of bevacizumab plus mFOLFOX6 for advanced CRLMs harboring mutant-type KRAS. METHODS: Patients with advanced CRLMs (tumor number of ≥5 and/or technically unresectable) harboring mutant-type KRAS were included. Surgical indication was evaluated every 4 cycles of bevacizumab plus mFOLFOX6. Liver resection was planned if the CRLMs were resectable. The primary endpoint was R0 resection rate. The secondary endpoints included overall survival (OS), recurrence-free survival, progression-free survival, and safety. RESULTS: Between 2013 and 2017, 29 patients from six centers were registered. The rates of complete and partial responses were 0% and 62.1%, respectively. R0 and R1 resections were performed in 19 and 1 patient, respectively (R0 resection rate: 65.5%). No mortality occurred. During the median follow-up of 30.7 months, the 3-year OS rate for all the patients was 64.4% with the median survival of 49.1 months. CONCLUSION: For advanced CRLMs harboring mutant-type KRAS, bevacizumab plus mFOLFOX6 achieved a high R0 resection rate, leading to favorable survival.

Preoperative portal vein embolization: a comparison of ethanol and coils versus ethanol alone.

PURPOSE: To compare the efficacy and safety of preoperative portal vein embolization (PVE) with ethanol and coils versus ethanol alone. MATERIAL AND METHODS: Between April 2014 and May 2019, 45 patients underwent right preoperative PVE with ethanol and coils (n = 19; EthCo group) or ethanol alone (n = 26; Eth group). RESULTS: The change in % future liver remnant (FLR) was not significantly different between the EthCo and Eth groups (11.2 ± 4.3% versus 11.3 ± 4.1%, p = .98). Less ethanol was used in the EthCo group (9.7 ± 3.5 mL versus 11.9 ± 4.4 mL, p = .02). Recanalization was observed in eight patients only in the Eth group (p < .01). There were no differences in the pre-/post-PVE laboratory data between the two groups, except for post-PVE albumin. The volume of ethanol used was positively correlated with the post-PVE total bilirubin (p = .01), aspartate aminotransferase (AST) (p < .01) and alanine aminotransferase (ALT) (p < .01) levels. CONCLUSION: The efficacy of PVE did not differ between the EthCo and Eth groups. The use of ethanol and coils was associated with less recanalization and liver damage compared with ethanol alone.

Neither Surgical Margin Status nor Somatic Mutation Predicts Local Recurrence After R0-intent Resection for Colorectal Liver Metastases.

BACKGROUND: We evaluated the associations of surgical margin status and somatic mutations with the incidence of local recurrence (LR) and oncologic outcomes in patients undergoing R0-intent (microscopically negative margin) resection of colorectal liver metastases (CLM). METHODS: Patients with CLM who underwent initial R0-intent resection and analysis of tumor tissue using next-generation sequencing during 2001-2018 were analyzed. Recurrences were classified as LR (at the resection margin), other intrahepatic recurrence, or extrahepatic recurrence. Predictors and survival effect of LR were evaluated using univariate and multivariate analysis. RESULTS: Of 552 patients analyzed, 415 (75%) had R0 resection (margin width ≥ 1.0 mm), and 38 (7%) had LR. LR incidence was not affected by surgical margin width. RAS/TP53 co-mutation was associated with increased risk of intrahepatic recurrence (67% vs. 49%; p < 0.001) and overall recurrence (p < 0.001). However, incidence of LR did not differ significantly by RAS/TP53, BRAF, SMAD4, or FBXW7 mutation. Extrahepatic disease (hazard ratio [HR], 1.47; p = 0.034), > 8 cycles of preoperative chemotherapy (HR, 1.98; p = 0.033), tumor viability ≥ 50% (HR, 1.55; p = 0.007), RAS/TP53 co-mutation (HR, 1.69; p = 0.001), and SMAD4 mutation (HR, 2.44; p < 0.001) were independently associated with poor overall survival, but surgical margin status was not. CONCLUSIONS: Although somatic mutations were associated with overall recurrence, neither surgical margin width nor somatic mutations affected LR risk after R0-intent hepatectomy for CLM. LR and prognosis were likely driven by individual tumor biology rather than surgical margins.

Fast-track two-stage hepatectomy by concurrent portal vein embolization at first-stage hepatectomy in hybrid interventional radiology / operating suite.

OBJECTIVES: In two-stage hepatectomy for bilateral liver metastases, patient dropout between stages is a major issue. We recently proposed a novel approach of fast-track two-staged hepatectomy (FT-TSH), in which patients undergo concurrent first-stage hepatectomy (FSH) with portal vein embolization (PVE) in a hybrid interventional radiology surgical suite. However, its efficacy remains unclear. METHODS: Patients with bilateral liver metastases scheduled for FT-TSH at MD Anderson Cancer Center between October 2017 and December 2020 were included on a prospective registry. The effectiveness and feasibility were evaluated. RESULTS: Nineteen patients were scheduled for FT-TSH. Primary site of tumor was colon/rectum in 18 patients and ovary in one patient. Median number of tumors was 10 and median size of largest tumor before surgery was 2.4 cm. Two (11%) patients did not undergo PVE and seventeen patients (89%) completed FSH + PVE. None of the patients had a major complication (Clavien-Dindo grade ≥ III) after FSH + PVE. Median kinetic growth rate after FSH + PVE was 2.9%/week (range 0.8-5.6). Twelve patients (71%) among the seventeen who underwent FSH + PVE proceeded to second-stage hepatectomy, and ten patients (59%) finally completed second-stage hepatectomy. Median interval between stages was 5.6 weeks (4.0-20.1). One patient (10%) had a major morbidity after SSH, and there was no 90-day mortality. CONCLUSIONS: FT-TSH is safe and allows for short intervals between hepatectomy stages while achieving favorable liver hypertrophy. Further investigation is needed to evaluate the true efficacy of FT-TSH.