Living donor liver transplantation for colorectal cancer liver metastases: Midterm outcomes at a single center in North America.

In recent years, liver transplantation has emerged as a treatment for patients with stage IV colorectal liver metastases (CRLM). Given the limited number of available deceased donor grafts, the use of living donor liver transplantation (LDLT) can be an important option. We performed a retrospective analysis of 10 patients that underwent LDLT for CRLM at our institution. A total of 90% of patients were male, with median age of 58 years and median model for end-stage liver disease score of 11 (range: 6-32). The rectum was the most common primary location (40%). Synchronous liver tumors were found in 50%. Pretransplant patients underwent resection (60%), hepatic-artery infusion pumping (50%), and/or radiofrequency ablation (50%). Everybody underwent adjuvant chemotherapy. Median cold ischemia time was 103 minutes (range: 93-207 minutes), and median total OR time was 11.5 hours (range: 8.5-13.9 hours). In total, 30% of patients had postoperative complications requiring reoperation. Mean recurrence-free survival was 2.2 years (95% confidence interval, 1.2-3.2 years), and mean overall survival was 3.0 years (95% confidence interval, 2.5-3.6 years). In total, 30% of patients suffered a recurrence, and 90% of patients are currently alive. This study represents the largest single-center analysis in North America of patients undergoing LDLT for CRLM. LDLT is a safe and effective alternative for patients with CRLM who do not have progressive disease or extrahepatic metastasis.

Riboflavin-LSD1 axis participates in the in vivo tumor-associated macrophage morphology in human colorectal liver metastases.

Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME). In colorectal liver metastasis (CLM), TAM morphology correlates with prognosis, with smaller TAMs (S-TAMs) conferring a more favorable prognosis than larger TAMs (L-TAMs). However, the metabolic profile of in vivo human TAM populations remains unknown. Multiparametric flow cytometry was used to freshly isolate S- and L-TAMs from surgically resected CLM patients (n = 14S-, 14L-TAMs). Mass spectrometry-based metabolomics analyses were implemented for the metabolic characterization of TAM populations. Gene expression analysis and protein activity were used to support the biochemical effects of the enzyme-substrate link between riboflavin and (lysine-specific demethylase 1A, LSD1) with TAM morphologies. L-TAMs were characterized by a positive correlation and a strong association between riboflavin and TAM morphologies. Riboflavin in both L-TAMs and in-vitro M2 polarized macrophages modulates LSD1 protein expression and activity. The inflammatory stimuli promoted by TNFα induced the increased expression of riboflavin transporter SLC52A3 and LSD1 in M2 macrophages. The modulation of the riboflavin-LSD1 axis represents a potential target for reprogramming TAM subtypes, paving the way for promising anti-tumor therapeutic strategies.

An integrated framework for prognosis prediction and drug response modeling in colorectal liver metastasis drug discovery.

BACKGROUND: Colorectal cancer (CRC) is the third most prevalent cancer globally, and liver metastasis (CRLM) is the primary cause of death. Hence, it is essential to discover novel prognostic biomarkers and therapeutic drugs for CRLM. METHODS: This study developed two liver metastasis-associated prognostic signatures based on differentially expressed genes (DEGs) in CRLM. Additionally, we employed an interpretable deep learning model utilizing drug sensitivity databases to identify potential therapeutic drugs for high-risk CRLM patients. Subsequently, in vitro and in vivo experiments were performed to verify the efficacy of these compounds. RESULTS: These two prognostic models exhibited superior performance compared to previously reported ones. Obatoclax, a BCL-2 inhibitor, showed significant differential responses between high and low risk groups classified by prognostic models, and demonstrated remarkable effectiveness in both Transwell assay and CT26 colorectal liver metastasis mouse model. CONCLUSIONS: This study highlights the significance of developing specialized prognostication approaches and investigating effective therapeutic drugs for patients with CRLM. The application of a deep learning drug response model provides a new drug discovery strategy for translational medicine in precision oncology.

Laparoscopically Limited Anatomic Liver Resections: A Single-Center Analysis for Oncologic Outcomes of the Conceptual Procedure.

BACKGROUND: Limited anatomic resections (LARs), such as segmentectomies, performed using a fully laparoscopic approach, have gained popularity for liver malignancies. However, the oncologic efficacy of laparoscopic LARs (Lap-LARs) needs further investigation. This cohort study evaluated the oncologic outcomes of Lap-LAR for hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM). METHODS: At a Japanese referral center, 112 patients underwent Lap-LAR using the Glissonean approach and indocyanine green (ICG) fluorescence navigation. Recurrence-free survival (RFS), overall survival (OS), time to interventional failure (TIF), and time to surgical failure (TSF) were assessed. RESULTS: Among the 112 patients (median age, 74 years [range, 66-80 years]; 80 men [71.4 %]), Lap-LAR showed promising results. The median operative time was 348 min (range, 280-460 min), and the median blood loss was 190 mL (range, 95.5-452.0 mL). The median error between the estimated and actual liver volumes was 2 % (1.2-4.8 %). Complications greater than Clavien-Dindo 3a were observed in 11.6 % of the patients. The 5-year RFS, OS, and TIF rates for HCC were 45.1 % ± 7.9 %, 73.1 % ± 6.7 %, and 74.2 % ± 6 .6 %, respectively. The 5-year RFS, OS, and TSF rates for CRLM were 36.8 % ± 8.7 %, 60.1 % ± 13.3 %, and 63.6 % ± 10.4 %, respectively. CONCLUSIONS: Lap-LAR showed favorable oncologic outcomes for HCC and CRLM. Its precise technique makes it a promising therapeutic option for liver malignancies. Further comparisons with conventional approaches are warranted.

Tuning Tumor Targeting and Ratiometric Photoacoustic Imaging by Fine-Tuning Torsion Angle for Colorectal Liver Metastasis Diagnosis.

Photoacoustic (PA) tomography is an emerging biomedical imaging technology for precision cancer medicine. Conventional small-molecule PA probes usually exhibit a single PA signal and poor tumor targeting that lack the imaging reliability. Here, we introduce a series of cyanine/hemicyanine interconversion dyes (denoted Cy-HCy) for PA/fluorescent dual-mode probe development that features optimized ratiometric PA imaging and tunable tumor-targeting ability for precise diagnosis and resection of colorectal cancer (CRC). Importantly, Cy-HCy can be presented in cyanine (inherent tumor targeting and long NIR PA wavelength) and hemicyanine (poor tumor targeting and short NIR PA wavelength) by fine-tuning torsion angle and the ingenious transformation between cyanine and hemicyanine through regulation optically tunable group endows the NIR ratiometric PA and tunable tumor-targeting properties. To demonstrate the applicability of Cy-HCy dyes, we designed the first small-molecule tumor-targeting and NIR ratiometric PA probe Cy-HCy-H2S for precise CRC liver metastasis diagnosis, activated by H2S (a CRC biomarker). Using this probe, we not only visualized the subcutaneous tumor and liver metastatic cancers in CRC mouse models but also realized PA and fluorescence image-guided tumor excision. We expect that Cy-HCy will be generalized for creating a wide variety of inherently tumor-targeting NIR ratiometric PA probes in oncological research and practice.

Dense tumor-infiltrating lymphocytes (TILs) in liver metastasis from colorectal cancer are related to improved overall survival.

BACKGROUND AND OBJECTIVES: Tumor-infiltrating lymphocytes (TILs) represent a host-tumor interaction, frequently signifying an augmented immunological response. Nonetheless, implications with survival outcomes in patients with colorectal carcinoma liver metastasis (CRLM) warrant rigorous validation. The objective was to demonstrate the association between TILs and survival in patients with CRLM. METHOD: In a retrospective evaluation conducted in a single institution, we assessed all patients who underwent hepatectomy due to CRLM between 2014 and 2018. Comprehensive medical documentation reviews were executed. TILs were assessed by a liver pathologist, blinded to the clinical information, in all surgical slides. RESULTS: This retrospective cohort included 112 patients. Median overall survival (OS) was 58 months and disease-free survival (DFS) was 12 months for the entire cohort. Comparison between groups showed a median OS of 81 months in the dense TILs group and 40 months in the weak/absent group (p = 0.001), and DFS was 14 months versus 9 months (p = 0.041). Multivariable analysis showed that TILs were an independent predictor of OS (HR 1.95; p = 0.031). CONCLUSIONS: Dense TILs are a pivotal prognostic indicator, correlating with enhanced OS. Including TILs information in histopathological evaluations should refine the clinical decision-making process for this group of patients.

Prognostic implications of margin status in association with systemic treatment in a cohort study of patients with resection of colorectal liver metastases.

BACKGROUND: This study investigates the impact of margin status after colorectal liver metastasis (CLM) resection on outcomes of patients after neoadjuvant treatment versus those who underwent upfront resection. METHODS: An international collaborative database of CLM patients who underwent surgical resection was used. Proportional hazard regression models were created for single and multivariable models to assess the relationship between independent measures and median overall survival (mOS). RESULTS: R1 was associated with worse OS in the neoadjuvant group (mOS: 51.8 m for R0 vs. 26.0 m for R1; HR: 2.18). In the patients who underwent upfront surgery, R1 was not associated with OS. (mOS: 46.7 m for R0 vs. 42.6 m for R1). When patients with R1 in each group were stratified by adjuvant treatment, there was no significant difference in the neoadjuvant group, while in the upfront surgery group with R1, adjuvant treatment was associated with significant improvement in OS (mOS: 42.6 m for adjuvant vs. 25.0 m for no adjuvant treatment; HR: 0.21). CONCLUSION: R1 is associated with worse outcomes in the patients who receive neoadjuvant treatment with no significant improvement with the addition of adjuvant therapy, likely representing an aggressive tumor biology. R1 did not impact OS in patients with upfront surgery who received postoperative chemotherapy.

Resection versus resection with ablation: Analysis from the colorectal liver operative metastasis international collaborative.

BACKGROUND: Thermal ablation has recently become a key therapy for the treatment of colorectal liver metastasis (CLM). However, the role of ablation in combination with resection has not yet been firmly established. We hypothesize that in patients with CLM, those who undergo liver resection with ablation (RA) have similar outcomes compared with those who undergo liver resection only. METHODS: We reviewed a multicenter international database of 906 surgical procedures for CLM from 5 high volume hepatobiliary surgical units. Patients undergoing RA (n = 63) were matched based on the number of lesions and tumor size using a 1:1 balanced propensity score analysis with those having resection only (n = 63). Our primary outcomes were overall survival (OS) and disease-free survival (DFS). RESULTS: The mean age of our cohort was 58 ± 11 years, with 43% females. With a median follow-up of 70.8 months, patients in the resection and RA group had a median OS of 45.1 and 54.8 months (p = 0.71), respectively. The median DFS was 22.7 and 14.2 months (p = 0.045), respectively. Using a multivariate Cox proportional hazards regression model, the treatment approach was not associated with OS (p = 0.94) or DFS (p = 0.059). A higher number of lesions is independently associated with worse DFS (hazard ratio: 1.12, p < 0.01). When there was disease recurrence, the region of recurrence was similar between the RA versus resection only groups (p = 0.27), but there was a shorter time to recurrence in the RA group (p = 0.002). CONCLUSION: For CLM, the treatment approach was not significantly associated with OS or DFS, while tumor biology likely played an important role. Prospective research on the quality and effectiveness of thermal ablation combined with hepatic resection is warranted.

Recurrence patterns after complex multimodality therapy and hepatic arterial infusion for colorectal liver metastases: A reflection of biology and technique.

BACKGROUND AND METHODS: We characterized colorectal liver metastasis recurrence and survival patterns after surgical resection and intraoperative ablation ± hepatic arterial infusion pump (HAIP) placement. We estimated patterns of recurrence and survival in patients undergoing contemporary multimodal treatments. Between 2017 and 2021, patient, tumor characteristics, and recurrence data were collected. Primary outcomes included recurrence patterns and survival data based on operative intervention. RESULTS: There were 184 patients who underwent hepatectomy and intraoperative ablation. Sixty patients (32.6%) underwent HAIP placement. A total of 513 metastases were ablated, median total of 2 ablations per patient. Median time to recurrence was 31 [22-40] months. Recurrence patterns included tumor at ablative margin on first scheduled postoperative imaging (8, 4.3%), local tumor recurrence at ablative site (69, 37.5%), and non-ablated liver tumor recurrence (38, 20.6%). In patients who underwent HAIP placement, the rate of liver recurrence was reduced (45% vs 70.9%, p = 0.0001). Median overall survival was 64 [41-58] months and prolonged survival was associated with HAIP treatment (85 [66-109] vs 60 [51-70] months. CONCLUSIONS AND DISCUSSION: Hepatic recurrence is common and combination of intraoperative ablation and HAIP treatments were associated with prolonged survival. These data may reflect patient selection however, future work will clarify preoperative tumor and patient characteristics that may better predict recurrence expectations.

Implementation of Hepatic Artery Infusion Pump Therapy: Real-World Single-Center Experience.

BACKGROUND AND OBJECTIVES: Hepatic artery infusion pump (HAIP) therapy is an available option at highly specialized centers to treat unresectable liver tumors (e.g., colorectal liver metastases [CRLM]). This study describes the safety and outcomes of HAIP program implementation at an academic-based cancer center. METHODS: Patients who underwent HAIP placement (2021-2023) were included. Categorical and continuous variables were compared using Chi-square and Kruska-Wallis tests, respectively. Survival and variables associated with survival were calculated using the Kaplan-Meier method and Cox proportional hazards model, respectively. RESULTS: Of the 26 HAIP procedures for unresectable CRLM, four were done as adjuvant therapy. Median duration of HAIP therapy was 9.2 months and four patients subsequently underwent hepatectomy. Complication rate was 37.5%, with biliary complication rate of 23.1%. Median overall survival (OS) from date of diagnosis was 55.2 months. Concurrent primary tumor resection was associated with inferior OS (p = 0.030). Multivariable regression did not identify independent predictors of OS. Progression-free survival from time of HAIP placement was 7.8 months. CONCLUSIONS: HAIP placement was technically successful in most patients with an acceptable complication rate. Survival outcomes were comparable with those described in the literature for HAIP therapy in combination with systemic therapy. The significant difference in outcomes for those with concurrent colectomy warrants further investigation.

Proposal of "borderline resectable" colorectal liver metastases based on analysis of risk factors for early surgical failure.

PURPOSE: We aimed to define borderline resectable colorectal liver metastases (CRLM) based on the analysis of risk factors for early surgical failure and investigate the efficacy of neoadjuvant chemotherapy in these patients. METHODS: This was a retrospective analysis of a multi-institutional cohort of patients diagnosed with technically resectable CRLM. Early surgical failure within 6 months of liver surgery was defined as ESF6. We classified CRLM into three grades (A, B, and C) according to the definition of the Japanese Society for Cancer of the Colon and Rectum. RESULTS: Among the 249 patients with technically resectable CRLM, 46 (18.5%) developed ESF6. The survival rate of these patients was significantly lower than that of the patients without ESF6. In the multivariate analysis of synchronous CRLM patients, no neoadjuvant chemotherapy, Grade B/C, and Charlson comorbidity index ≥ 3 were independent predictors of ESF6. Among patients with synchronous and Grade B/C CRLM, ESF6 rates, surgical failure-free survival, and overall survival in the neoadjuvant chemotherapy group were significantly better relative to the upfront surgery group. CONCLUSIONS: Patients with synchronous and Grade B/C CRLM are at a high risk of early surgical failure, have a poor long-term prognosis, and can be defined as borderline resectable and good candidates for neoadjuvant chemotherapy.

The KRAS G12D mutation increases the risk of unresectable recurrence of resectable colorectal liver-only metastasis.

PURPOSE: Unresectable recurrence is a critical predictor of outcomes for colorectal cancer patients. We attempted to identify the prognostic factors, especially for unresectable recurrence-free survival (URFS) as a new endpoint, in patients with resectable colorectal liver-only metastasis (CRLOM). METHODS: We investigated patients with resectable CRLOM, who underwent an R0 resection for both CRC and CRLOM between January, 2014 and March, 2019 at a single institution. The exclusion criteria were patients who received neoadjuvant treatment, the absence of data for genetic analyses, and the presence of multiple cancers, synchronous CRC, or familial adenomatous polyposis. The prognostic factors were examined retrospectively using data on pre-hepatectomy factors, including primary tumor molecular profiling results. RESULTS: We analyzed the data of 101 patients who underwent curative-intent surgery for CRLOM. Multivariate analysis revealed that KRAS G12D mutation-positivity (hazard ratio [HR]: 7.69; p < 0.01), RYR2 mutation-positivity (HR: 4.03; p < 0.01), and KRAS G12S mutation-positivity (HR: 3.96; p = 0.03), CA19-9 > 37 U/ml before hepatectomy (HR: 3.62; p < 0.01), and primary tumor pN2 stage (HR: 3.22; p = 0.03) were significant predictors of the URFS. CONCLUSIONS: This is the first study to show that specific KRAS and RYR2 mutations were associated with the URFS.

Onyx®, A New Tool for Intraoperative Localization of Liver Lesions.

BACKGROUND: Precise preoperative localization of liver tumors facilitates successful surgical procedures, Intraoperative ultrasonography is a sensitive imaging modality. However, the presence of small non-palpable isoechoic intraparenchymal lesions may be challenging intraoperatively. METHODOLOGY AND MATERIAL DESCRIPTION: Onyx® is a non-adhesive liquid agent comprised of ethylene-vinyl alcohol usually used dissolved in dimethyl-sulfoxide and suspended micronized tantalum powder to provide contrast for visualization under fluoroscopy and ultrasonography and a macroscopic black shape. This embolization material has been increasingly used for the embolization of intracranial arteriovenous malformations. We present the novel application of Onyx® on liver surgery. CURRENT STATUS: We present the case of a female, 55 years-old, whose medical history revealed an elective sigmoidectomy (pT3N1a). After 17 months of follow up, by PET-CT scan, the patient was diagnosed of a small intraparenchymal hypo-attenuated 13 mm tumor located at segment V consistent with metachronous colorectal liver metastasis. Open metastasectomy was performed, ultrasonography-guided Onyx® infusion was delivered the day after, intraoperative ultrasonography showed a palpable hyperechoic material with a posterior acoustic shadowing artifact around the lesion. Onyx® is a promising new tool, without any previous application on liver surgery, feasible with advantages in small not palpable intraparenchymal liver lesions.

Renin-Angiotensin Inhibitor, Captopril, Attenuates Growth of Patient-Derived Colorectal Liver Metastasis Organoids.

The recurrence of colorectal liver metastasis (CRLM) following liver resection is common; approximately 40% of patients will experience tumor recurrence post-surgery. Renin-angiotensin inhibitors (RASis) have been shown to attenuate the growth and progression of CRLM in pre-clinical models following liver resection. This study examined the efficacy of the RASi captopril on patient-derived colorectal liver metastasis organoids. Patient-derived organoids (PDOs) were established using fresh samples of colorectal liver metastasis from appropriately consented patients undergoing liver resection. To mimic the regenerating liver post-CRLM liver resection, PDOs were cultured under hepatocyte regeneration conditions in vitro. CRLM PDOs were established from three patients' parent tissue. CRLM PDOs and parent tissue expressed markers of colorectal cancer, CDX2 and CK20, consistently. Furthermore, CRLM PDOs treated with captopril showed a dose dependent reduction in their expansion in vitro. In conclusion, CRLM PDOs recapitulate in vivo disease and displayed a dose-dependent response to treatment with captopril. RASis may be an additional viable treatment for patients with CRLM.

Evolution of Liver Transplantation Indications: Expanding Horizons.

Liver transplantation (LT) has significantly transformed the prognosis of patients with end-stage liver disease and hepatocellular carcinoma (HCC). The traditional epidemiology of liver diseases has undergone a remarkable shift in indications for LT, marked by a decline in viral hepatitis and an increase in metabolic dysfunction-associated steatotic liver disease (MASLD), along with expanded indications for HCC. Recent advancements in surgical techniques, organ preservation and post-transplant patients' management have opened new possibilities for LT. Conditions that were historically considered absolute contraindications have emerged as potential new indications, demonstrating promising results in terms of patient survival. While these expanding indications provide newfound hope, the ethical dilemma of organ scarcity persists. Addressing this requires careful consideration and international collaboration to ensure equitable access to LT. Multidisciplinary approaches and ongoing research efforts are crucial to navigate the evolving landscape of LT. This review aims to offer a current overview of the primary emerging indications for LT, focusing on acute-on-chronic liver failure (ACLF), acute alcoholic hepatitis (AH), intrahepatic and perihilar cholangiocarcinoma (i- and p-CCA), colorectal liver metastasis (CRLM), and neuroendocrine tumor (NET) liver metastases.

Stage IV Rectal Cancer and Timing of Surgical Approach.

Liver metastases are seen in at least 60% of patients with colorectal cancer at some point during the course of their disease. The management of both primary and liver disease is uniquely challenging in rectal cancer due to competing treatments and complex sequence of treatments depending on the clinical presentation of disease. Recently, several novel concepts are shaping new treatment paradigms, including changes in timing, sequence, and duration of therapies combined with potential deescalation of treatment components. Overall, the treatment of this clinical scenario mandates multidisciplinary evaluation and personalization of care; however, there is still considerable debate regarding the timing of liver metastasectomy in the context of the overall treatment plan. Herein, we will discuss the current literature on management of rectal cancer with synchronous liver metastasis, current treatment approaches with respect to chemotherapy, and role of hepatic artery infusion therapy.

Significant association of MCP1 rs1024611 and CCR2 rs1799864 polymorphisms with colorectal cancer and liver metastases susceptibility and aggressiveness: A case-control study.

BACKGROUND: The MCP-1/CCR2 axis is one of the major chemokine signaling pathways that play a crucial role in the tumor microenvironment and has been involved in triggering various tumor progression mechanisms, such as increasing the immunosuppressive cells recruitment and promoting tumor cell proliferation and invasiveness. AIM: The current study investigated the association of MCP1 (rs1024611) and CCR2 (rs1799864) genes variants with the risk as well as prognosis of colorectal cancer (CRC) and colorectal liver metastases (CRLM). SUBJECTS AND METHODS: A retrospective cohort study involved 408 patients (284 CRC and 124 CRLM), and 284 healthy control was conducted. Genotyping of selected polymorphisms was performed by PCR-RFLP assays and confirmed by microchip and capillary electrophoresis. RESULTS: The results highlighted a positive association between MCP1 rs1024611 (non-AA) and CCR2 rs1799864 (GA) genotypes with increased CRC and CRLM risk. Correlation between SNPs and clinicopathological characteristics revealed a positive association between MCP1 rs1024611 and CCR2 rs1799864 (dominant model) and CRC poor prognosis features. Kaplan-Meier survival analysis revealed a significant association between MCP1 rs1024611 non-AA carriers and decreased survival rate. Neoadjuvant treatment showed an improvement in CRC and CRLM survival rates among carriers of MCP1 and CCR2 wild-type genotype. FOLFIRI chemotherapy exhibits reduced survival rates for patients who carried mutated genotypes of MCP1 and CCR2 polymorphisms. CONCLUSION: Considering our results, we suggest That both MCP1 and CCR2 polymorphisms may constitute independent factors for CRC and CRLM occurrence and can be helpful targets for an efficient therapeutic approach.

Autotaxin is a novel surrogate marker for oxaliplatin-related sinusoidal obstruction syndrome in patients with colorectal liver metastasis.

BACKGROUND: Chemotherapy for colorectal liver metastasis (CRLM) has improved dramatically over the past few decades. However, sinusoidal obstruction syndrome (SOS) induced by oxaliplatin leads to increased severe morbidity after hepatectomy for CRLM. Autotaxin is a novel liver fibrosis marker known to be taken up and metabolized by sinusoidal endothelial cells. This study aimed to evaluate whether autotaxin levels could be a novel surrogate marker of SOS for CRLM. METHODS: We retrospectively evaluated 73 consecutive patients who underwent hepatectomy for CRLM, and assessed the relationship between their preoperative autotaxin levels and SOS. RESULTS: Median autotaxin level was 0.750 mg/L. Preoperative oxaliplatin-based chemotherapy for CRLM was administered to 51 patients, and SOS was histologically observed in 45 patients. Patients who received the oxaliplatin-based chemotherapy had significantly higher autotaxin levels than those who did not (p = 0.038). Furthermore, autotaxin levels were higher in patients with SOS than in those without (p = 0.011). Univariate and multivariate analyses revealed that autotaxin level can be an independent predictive factor for SOS preoperatively (p = 0.001). CONCLUSIONS: Autotaxin level is a noninvasive and promising surrogate marker for predicting SOS before surgical resection for CRLM.

Clinically relevant model of oxaliplatin-induced sinusoidal obstruction syndrome.

AIM: Sinusoidal obstruction syndrome (SOS) induced by oxaliplatin-including chemotherapies (OXCx) is associated with impaired hepatic reserve and higher morbidity after hepatic resection. However, in the absence of an appropriate animal experimental model, little is known about its pathophysiology. This study aimed to establish a clinically relevant reproducible model of FOLFOX-induced SOS and to compare the clinical/histopathological features between the clinical and animal SOS settings. METHODS: We performed clinical/pathological analyses of colorectal liver metastasis (CRLM) patients who underwent hepatectomy with/without preoperative treatment of FOLFOX (n = 22/18). Male micro-minipigs were treated with 50% of the standard human dosage of the FOLFOX regimen. RESULTS: In contrast to the monocrotaline-induced SOS model in rats, hepatomegaly, ascites, congestion, and coagulative necrosis of hepatocytes were absent in patients with CRLM with OXCx pretreatment and OXCx-treated micro-minipigs. In parallel to CRLM cases with OXCx pretreatment, OXCx-challenged micro-minipigs exhibited deteriorated indocyanine green clearance, morphological alteration of liver sinusoidal endothelial cells, and upregulated matrix metalloproteinase-9. Using our novel porcine SOS model, we identified the hepatoprotective influence of recombinant human soluble thrombomodulin in OXCx-SOS. CONCLUSIONS: With distinct differences between monocrotaline-induced rat SOS and human/pig OXCx-SOS, our pig OXCx-SOS model serves as a preclinical platform for future investigations to dissect the pathophysiology of OXCx-SOS and seek preventive strategies.

Microwave ablation for hepatic malignancies: a systematic review of the technology and differences in devices.

BACKGROUND: Microwave ablation (MWA) has become the standard thermal-based treatment for hepatic malignancies in patients who have unresectable disease based on the biology of the tumor, the patients' comorbidities, and certain disease sites. The technical effectiveness, ablation success, local recurrence rates of hepatic malignancies treated with the various commercial microwave ablation devices has not been previously published in the peer reviewed literature. The aim of this systematic review is to summarize the clinical outcomes for the various MWA devices in the use of a hepatic malignancies to best educate hepatic surgeons as well as interventional radiologists. METHODS: A comprehensive review of the literature and instructions for use of each device that was published from 1/2013 to 12/2020 was performed. The main outcomes extracted were technical success, ablation success, major complications, local and new recurrence rates, recurrence-free survival, ablation volumes, time, and the number of antennas required. A qualitative review of the literature was performed. RESULTS: In total, 29 studies reporting data on 3250 patients and 4500 tumors were included in this review. Median patient age was 60.5 years (range 3-91). 76.3% (2420 M/753 F) of patients were male. Hepatocellular carcinoma (55%) was the most common tumor pathology followed by colorectal liver metastasis (10%) and cholangiocarcinoma (4%). A majority of studies reported technical success (range, 91.6-100%) and ablation success (range, 73.1-100%), as well as major complications (range, 0-9.1%). Local recurrence (range, 0-50%) was reported by 21 of the studies; however, new recurrence (range, 12.2-64%) was reported less frequently (6 studies) and were further specified in 12, six, and four studies as intrahepatic distant recurrence (11.3-54.2%), extrahepatic distant recurrence (3.6-20%), and metastasis (1.1-36%). A total of three, six, and five studies report disease, progression, and recurrence-free survival rates, respectively. CONCLUSION: Microwave ablation is frequently used for the treatment of hepatic malignancies. A thorough understanding of the clinical outcomes associated with different pathologies and MWA devices can improve surgeon awareness and help prepare for operative planning and patient management. More consistent reporting of key outcomes in the literature is needed to achieve such an understanding.