Local Therapy Improves Survival for Early Recurrence After Resection of Colorectal Liver Metastases.

BACKGROUND: Early recurrence following hepatectomy for colorectal liver metastases (CLM) is associated with worse survival; yet, impact of further local therapy is unclear. We sought to evaluate whether local therapy benefits patients with early recurrence following hepatectomy for CLM. METHODS: Clinicopathologic and survival outcomes of patients managed with hepatectomy for CLM (1/2001-12/2020) were queried from a prospectively maintained database. Timing of recurrence was stratified as early (recurrence-free survival [RFS] < 6 months), intermediate (RFS 6-12 months), and later (RFS > 12 months). Local therapy was defined as ablation, resection, or radiation. RESULTS: Of 671 patients, 541 (81%) recurred with 189 (28%) early, 180 (27%) intermediate, and 172 (26%) later recurrences. Local therapy for recurrence resulted in improved survival, regardless of recurrence timing (early 78 vs. 32 months, intermediate 72 vs. 39 months, later 132 vs. 65 months, all p < 0.001). Following recurrence, treatment with local therapy (hazard ratio [HR] = 0.24), liver and extrahepatic recurrence (HR = 1.81), RAS + TP53 co-mutation (HR = 1.52), and SMAD4 mutation (HR = 1.92) were independently associated with overall survival (all p ≤ 0.002). Among patients with recurrence treated by local therapy, patients older than 65 years (HR 1.79), liver and extrahepatic recurrence (HR 2.05), primary site or other recurrence (HR 1.90), RAS-TP53 co-mutation (HR 1.63), and SMAD4 mutation (HR 2.06) had shorter post-local therapy survival (all p ≤ 0.04). CONCLUSIONS: While most patients recur after hepatectomy for CLM, local therapy may result in long-term survival despite early recurrence. Somatic mutational profiling may help to guide the multidisciplinary consideration of local therapy after recurrence.

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.

Targeted exome-based predictors of patterns of progression of colorectal liver metastasis after percutaneous thermal ablation.

BACKGROUND: Percutaneous thermal ablation is a curative-intent locoregional therapy (LRT) for selected patients with unresectable colorectal liver metastasis (CLM). Several factors have been identified that contribute to local tumour control after ablation. However, factors contributing to disease progression outside the ablation zone after ablation are poorly understood. METHODS: In this retrospective study, using next-generation sequencing, we identified genetic biomarkers associated with different patterns of progression following thermal ablation of CLM. RESULTS: A total of 191 ablation naïve patients between January 2011 and March 2020 were included in the analysis, and 101 had genomic profiling available. Alterations in the TGFß pathway were associated with increased risk of development of new intrahepatic tumours (hazard ratio [HR], 2.75, 95% confidence interval [95% CI] 1.39-5.45, P = 0.004); and alterations in the Wnt pathway were associated with increased probability of receiving salvage LRT for any intrahepatic progression (HR, 5.8, 95% CI 1.94-19.5, P = 0.003). CONCLUSIONS: Our findings indicate that genomic alterations in cancer-related signalling pathways can predict different progression patterns and the likelihood of receiving salvage LRT following percutaneous thermal ablation of CLM.

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.

Conditional recurrence analysis of intrahepatic cholangiocarcinoma: Changes in recurrence rate and survival after recurrence resection by disease-free interval.

AIM: The prognosis of patients with resected intrahepatic cholangiocarcinoma (ICC) is still unsatisfactory, with a high recurrence rate. We aimed to evaluate risks of recurrence changing over time and the survival benefit of resection for recurrent ICC. METHODS: This study included patients who underwent hepatectomy for ICC during 1995-2020. Risk factors for recurrence-free survival (RFS) in patients undergoing initial resection and overall survival (OS) in patients who developed recurrence after initial resection were analyzed. Conditional cumulative incidence of recurrence was assessed. RESULTS: A total of 169 patients were included in the study and 114 patients (67.5%) developed recurrence. Cumulative analyses showed that the 5-year recurrence rate was 69.3% at the time of initial resection but decreased to 24.8% in patients free from recurrence at 2 years after initial resection and 2.6% in patients free from recurrence at 4 years. Re-resection was carried out in 26 (22.8%) of 114 patients who developed recurrence. Multivariable Cox proportional hazards model analysis indicated re-resection (hazard ratio [HR] 0.19; 95% confidence interval [CI] 0.11-0.40, p < 0.001), microvascular invasion (MVI) (HR 2.39; 95% CI 1.05-5.40, p = 0.037), and disease-free interval (months) (HR 0.97; 95% CI 0.95-1.00, p = 0.067) were significantly associated with longer OS after recurrence. CONCLUSIONS: Although the rate of recurrence remains high, conditional cumulative recurrence rate analysis showed that the rate of recurrence decreased by disease-free interval. Resection of recurrent ICC was associated with improved OS, particularly among patients with longer disease-free interval and absence of MVI after initial hepatectomy.

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.

Clinical evaluation of the aberrant left hepatic artery arising from the left gastric artery in esophagectomy.

PURPOSE: The left gastric artery (LGA) is commonly severed when the gastric tube is made for esophageal reconstruction. Sacrifice of the LGA can cause liver ischemic necrosis in patients with an aberrant left hepatic artery (ALHA) arising from the LGA. We experienced a case of life-threatening hepatic abscess after severing the ALHA. Therefore, the purpose of this study is to evaluate clinical outcomes of severing the ALHA. METHODS: We retrospectively enrolled 176 consecutive patients who underwent esophagectomy with gastric tube reconstruction. They were classified into the ALHA (N = 16, 9.1%) and non-ALHA (N = 160, 90.9%) groups. Univariate analysis was performed to compare the clinicopathological variables. Long-term survival was analyzed using the Kaplan-Meier method in matched pair case-control analysis. RESULTS: The postoperative morbidities were not statistically different between the two groups, although serum alanine aminotransferase levels on postoperative days 1 and 3 were significantly higher in the ALHA group (36 IU/L, 14-515; 32 IU/L, 13-295) than in the non-ALHA group (24 IU/L, 8-163; 19 IU/L, 6-180), respectively (p = 0.0055; p = 0.0073). Overall survival was not statistically different between the two groups (p = 0.26). CONCLUSIONS: Severe hepatic abscess occurred in 6.3% of the patients with the ALHA after esophagectomy, even though the results presented here found no statistical differences in morbidity or mortality with or without the ALHA. Surgeons should probably attempt to preserve the ALHA especially in patients with altered liver function while making a gastric tube for esophageal reconstruction.

Influence of outflow-obstructed liver volume and venous communication development: A three-dimensional volume study in living donors.

Living donor liver transplantation using the left liver graft with the middle hepatic vein (MHV) is a well-established procedure. Following such procedures, outflow obstruction occurs in remnant livers. However, the effects of the outflow-obstructed liver volume (LVOut-Ob ), with or without venous communication development, remain unclear. The aim of the study is to investigate effects of outflow-obstructed regions by focusing on short-term outcomes and remnant liver hypertrophy in left liver procurement donors. Of 532 donors, we collected data from 119 undergoing left liver procurement with the MHV. Postoperative hepatic parameters, venous communication development, and liver hypertrophy were evaluated in 2 donor groups based on LVOut-Ob . The left liver was procured with the MHV in 119 donors, who formed 2 more groups based on the median LVOut-Ob : large-outflow-obstruction group (n = 60; LVOut-Ob ≥ 263 mL) and small-outflow-obstruction (n = 59; LVOut-Ob < 263 mL) group. Postoperative liver function parameters were significantly impaired in the large-outflow-obstruction group compared with the small-outflow-obstruction group. Postoperative venous communication developed in 52 (66.7%) of 78 donors analyzed. Hypertrophy ratios in remnant right livers and right paramedian sectors were significantly higher in the small-outflow-obstruction group than in the large-outflow-obstruction group (P = 0.01 and P = 0.02, respectively). The liver hypertrophy ratio of outflow-obstructed regions was better, especially in small regions developing venous communication (P = 0.001). The postoperative morbidity rate did not differ significantly (P = 0.66). In conclusion, the procurement of the left liver graft with the MHV was safely performed with minimal morbidity by assessing the donor remnant right liver volume with and without outflow obstruction. Attention should be paid that postoperative hepatic parameters and remnant liver hypertrophy were impaired in the remnant livers with large outflow-obstructed regions compared with those with small outflow-obstructed regions. Liver Transplantation 23 1531-1540 2017 AASLD.

Real-time confocal laser endomicroscopic evaluation of primary liver cancer based on human liver autofluorescence.

BACKGROUND: Confocal laser endomicroscopy (CLE) is available for real-time microscopic examination. This study aims to evaluate the usefulness of intraoperative CLE examination as a modality to evaluate surgical margins in surgery for primary liver cancer. METHODS: A probe-based CLE system (Cellvizio 100, Mauna Kea Technologies, Paris, France) was used. The subjects comprised seven specimens obtained from six patients with primary liver cancer in November 2015. The probe was manually attached to the surfaces of specimens, and images were collected without external fluorophores. CLE images were compared with hematoxylin and eosin-stained slides. Fluorescence intensity (FI) values of the CLE images were assessed using luminance-analyzing software. RESULTS: CLE examination visualized non-cancerous regions in the background liver as regular structures with high fluorescence because of human liver autofluorescence. Conversely, hepatocellular carcinoma and intrahepatic cholangiocarcinoma were depicted as irregular structures with low fluorescence. The median FI values of the non-cancerous regions and the cancerous regions were 104 (79.8-156) and 74.9 (60.6-106), respectively, and were significantly different (P = 0.031). CONCLUSIONS: The probe-based CLE enables real-time differentiation of cancerous regions from non-cancerous tissues in surgical specimens because of human liver autofluorescence. CLE can be used to confirm negative surgical margins in the operating room. J. Surg. Oncol. 2017;115:151-157. © 2016 Wiley Periodicals, Inc.

Evolving survival gains in patients with young-onset colorectal cancer and synchronous resectable liver metastases.

We aimed to evaluate the practice and the associated outcomes of surgical treatment for young-onset colorectal cancer (YOCRC) patients presenting with synchronous liver metastases. The study cohort was divided into two groups according to surgery date: 131 patients in the early era (EE, 1998-2011) and 179 in the contemporary era (CE, 2012-2020). The CE had a higher rate of node-positive primary tumors, higher carcinoembryonic antigen level, and lower rate of RAS/BRAF mutations. The CE had higher rates of reverse or combined resection, multi-drug prehepatectomy chemotherapy, and two-stage hepatectomy. The median survival was 8.4 years in the CE and 4.3 years in the EE (p = 0.011). On multivariate analysis, hepatectomy in the CE was independently associated with improved overall survival (HR 0.48, p = 0.001). With a combination of perioperative systemic therapy, careful selection of treatment approach, and coordinated resections, durable cure can be achieved in YOCRC patients.

Liver volumetry and liver-regenerative interventions: history, rationale, and emerging tools.

BACKGROUND: Postoperative hepatic insufficiency (PHI) is the most feared complication after hepatectomy. Volume of the future liver remnant (FLR) is one objectively measurable indicator to identify patients at risk of PHI. In this review, we summarized the development and rationale for the use of liver volumetry and liver-regenerative interventions and highlighted emerging tools that could yield new advancements in liver volumetry. METHODS: A review of MEDLINE/PubMed, Embase, and Cochrane Library databases was conducted to identify literature related to liver volumetry. The references of relevant articles were reviewed to identify additional publications. RESULTS: Liver volumetry based on radiologic imaging was developed in the 1980s to identify patients at risk of PHI and later used in the 1990s to evaluate grafts for living donor living transplantation. The field evolved in the 2000s by the introduction of standardized FLR based on the hepatic metabolic demands and in the 2010s by the introduction of the degree of hypertrophy and kinetic growth rate as measures of the FLR regenerative and functional capacity. Several liver-regenerative interventions, most notably portal vein embolization, are used to increase resectability and reduce the risk of PHI. In parallel with the increase in automation and machine assistance to physicians, many semi- and fully automated tools are being developed to facilitate liver volumetry. CONCLUSION: Liver volumetry is the most reliable tool to detect patients at risk of PHI. Advances in imaging analysis technologies, newly developed functional measures, and liver-regenerative interventions have been improving our ability to perform safe hepatectomy.

Biliary Anatomy 2.0 Quiz: Test Your Knowledge.

Anatomy has remained an interest of physicians throughout the ages. The biliary tract spans from the liver to the hepatoduodenal mesentery, pancreas, and into the duodenum. Therefore, it is important for not only hepatobiliary surgeons but also general gastrointestinal surgeons, gastroenterologists, radiologists, and pathologists to be familiar with biliary anatomy and its variants. While surgery for hilar cholangiocarcinoma is one of the most challenging procedures, cholecystectomy is one of the most common procedures done from the beginning of surgical training. We hope that by answering the following questions, you will gain a comprehensive understanding of biliary anatomy and a greater appreciation for it.

Liver Anatomy 2.0 Quiz: Test Your Knowledge.

The liver is one the largest organs in the abdomen and the most frequent site of metastases for gastrointestinal tumors. Surgery on this complex and highly vascularized organ can be associated with high morbidity even in experienced hands. A thorough understanding of liver anatomy is key to approaching liver surgery with confidence and preventing complications. The aim of this quiz is to provide an active learning tool for a comprehensive understanding of liver anatomy and its integration into clinical practice.

Locoregional treatment for colorectal liver metastases aiming for precision medicine.

In patients with colorectal liver metastases (CLM), surgery is potentially curative. The use of novel surgical techniques and complementary percutaneous ablation allows for curative-intent treatment even in marginally resectable cases. Resection is used as part of a multidisciplinary approach, which for nearly all patients will include perioperative chemotherapy. Small CLM can be treated with parenchymal-sparing hepatectomy (PSH) and/or ablation. For small CLM, PSH results in better survival and higher rates of resectability of recurrent CLM than non-PSH. For patients with extensive bilateral distribution of CLM, two-stage hepatectomy or fast-track two-stage hepatectomy is effective. Our increasing knowledge of genetic alterations allows us to use them as prognostic factors alongside traditional risk factors (e.g. tumor diameter and tumor number) to select patients with CLM for resection and guide surveillance after resection. Alteration in RAS family genes (hereafter referred to as "RAS alteration") is an important negative prognostic factor, as are alterations in the TP53, SMAD4, FBXW7, and BRAF genes. However, APC alteration appears to improve prognosis. RAS alteration, increased number and diameter of CLM, and primary lymph node metastasis are well-known risk factors for recurrence after CLM resection. In patients free of recurrence 2 y after CLM resection, only RAS alteration is associated with recurrence. Thus, surveillance intensity can be stratified by RAS alteration status after 2 y. Novel diagnostic instruments and tools, such as circulating tumor DNA, may lead to further evolution of patient selection, prognostication, and treatment algorithms for CLM.

TP53 Alteration and Its Effect on Pathologic Response Are Associated with Survival after Resection of Colorectal Liver Metastases.

The aims of this study were to assess the effect of known gene alterations (RAS, TP53, APC, SMAD4, BRAF, and FBXW7) on pathologic response (PR) and their combined association with survival in patients with colorectal liver metastases (CLM). From a prospectively maintained database, we collected data on 458 patients who underwent curative-intent hepatectomy after receiving the first-line preoperative chemotherapy between 2004 and 2020. Major PR was defined as tumor viability of less than 50% in all tumors. Multivariate logistic regression revealed that oxaliplatin-containing regimen (OR: 2.54, 95% CI: 1.58-4.07, P < 0.001), bevacizumab-containing regimen (OR: 2.15, 95%CI: 1.36-3.39, P = 0.001), and TP53 alteration (OR: 0.42, 95%CI: 0.27-0.66, P < 0.001) were independently associated with major PR. Multivariate Cox regression also revealed that patients with TP53 wild-type and major PR (HR: 0.49, 95%CI: 0.31-0.77, P = 0.002) and those with TP53 alteration and major PR (HR: 0.70, 95%CI: 0.49-1.00, P = 0.048) had significantly better overall survival compared to those with minor PR. Further studies targeting the association of TP53 with PR and survival can help clarify the role of TP53 in CLM.

Safety and usefulness of fluorescence imaging using methylene blue as a fluorophore in a Japanese population with hepatobiliary and pancreatic diseases: A phase I study.

BACKGROUND: Methylene blue (MB) has been used to treat methemoglobinemia. Recently, a fluorescence imaging technique using MB as a fluorophore was used in several region but still not in hepatobiliary and pancreatic surgery; thus, information on the safety of intraoperative fluorescence imaging using MB in a healthy Japanese population is lacking. We aimed to evaluate the usefulness of MB fluorescence imaging in patients undergoing hepatobiliary and pancreatic surgery and the safety of intraoperative administration of MB in patients without methemoglobinemia. METHODS: Eighteen patients undergoing hepatobiliary and pancreatic surgery were enrolled. We developed and used a fluorescence imaging system to visualize MB as fluorescence. The fluorescence intensity of the blood vessels, tumors, liver, and intestine were measured. The primary endpoint was the ability of the MB fluorescence imaging to visualize vessels and tumors with fluorescence. The secondary endpoint was the safety of fluorescence imaging using MB in patients without methemoglobinemia. RESULTS: For the 18 patients undergoing MB fluorescence imaging, no intraoperative and postoperative complications related to MB administration occurred. Seventeen patients (94%) successfully visualized the target object as fluorescence by MB fluorescence imaging, including 100% of neuroendocrine tumors (four tumors) and peripancreatic vessels (n = 13). CONCLUSION: The administration of MB and application of fluorescence imaging using MB can visualize blood vessels and pancreatic neuroendocrine neoplasms. And it also showed the safety of using MB as a fluorophore in Japanese patients without methemoglobinemia.

Probe-based confocal laser endomicroscopy for real-time evaluation of colorectal liver metastasis in resected surgical specimens.

Probe-based confocal laser endomicroscopy (pCLE) enables real-time examination of tissue structure. This study investigated pCLE with or without fluorescein sodium for the intraoperative diagnosis of colorectal liver metastasis (CLM) and detection of surgical margins. Thirty-four specimens of CLM and adjacent noncancerous tissue were obtained from 21 patients and examined by pCLE between May 2017 and March 2018. Images were obtained both without and with fluorescein sodium applied to the cut surface and compared with hematoxylin and eosin-stained tissue. Fluorescence intensity (FI) was measured by luminance-analysis software. Without external fluorophores, pCLE visualized 91.2% of CLM tissues as an irregular structure with low autofluorescence and 90.5% of noncancerous liver tissues as a regular structure with high autofluorescence. The median FI was significantly lower in cancer than in benign tissue in patients without chemotherapy [70.4 (51.6-110) vs. 48.3 (39.0-59.4), p = 0.002] and with chemotherapy [67.9 (54.6-89.2) vs. 48.6 (28.8-82.1), p < 0.001]. The border was clearly visible; pCLE with fluorescein sodium clearly showed their morphologies. In summary, our study demonstrated real-time pCLE distinguished CLM and noncancerous tissue by differences in structure and FI regardless of prehepatectomy chemotherapy. Fluorescein spray facilitated clear visualization of differences in the morphology.