Integrative single-cell transcriptomic analyses reveal the cellular ontological and functional heterogeneities of primary and metastatic liver tumors.

BACKGROUND: The global cellular landscape of the tumor microenvironment (TME) combining primary and metastatic liver tumors has not been comprehensively characterized. METHODS: Based on the scRNA-seq and spatial transcriptomic data of non-tumor liver tissues (NTs), primary liver tumors (PTs) and metastatic liver tumors (MTs), we performed the tissue preference, trajectory reconstruction, transcription factor activity inference, cell-cell interaction and cellular deconvolution analyses to construct a comprehensive cellular landscape of liver tumors. RESULTS: Our analyses depicted the heterogeneous cellular ecosystems in NTs, PTs and MTs. The activated memory B cells and effector T cells were shown to gradually shift to inhibitory B cells, regulatory or exhausted T cells in liver tumors, especially in MTs. Among them, we characterized a unique group of TCF7+ CD8+ memory T cells specifically enriched in MTs that could differentiate into exhausted T cells likely driven by the p38 MAPK signaling. With regard to myeloid cells, the liver-resident macrophages and inflammatory monocyte/macrophages were markedly replaced by tumor-associated macrophages (TAMs), with TREM2+ and UBE2C+ TAMs enriched in PTs, while SPP1+ and WDR45B+ TAMs in MTs. We further showed that the newly identified WDR45B+ TAMs exhibit an M2-like polarization and are associated with adverse prognosis in patients with liver metastases. Additionally, we addressed that endothelial cells display higher immune tolerance and angiogenesis capacity, and provided evidence for the source of the mesenchymal transformation of fibroblasts in tumors. Finally, the malignant hepatocytes and fibroblasts were prioritized as the pivotal cell populations in shaping the microenvironments of PTs and MTs, respectively. Notably, validation analyses by using spatial or bulk transcriptomic data in clinical cohorts concordantly emphasized the clinical significance of these findings. CONCLUSIONS: This study defines the ontological and functional heterogeneities in cellular ecosystems of primary and metastatic liver tumors, providing a foundation for future investigation of the underlying cellular mechanisms.

A comparison of three different microwave systems for laparoscopic liver tumor ablation.

BACKGROUND: Our aim was to perform a comparison of three current microwave ablation (MWA) systems widely used for laparoscopic liver ablations in terms of ablation kinetics and geometry of ablation zones. METHODS: This was a retrospective, institutional review board-approved study comparing Emprint, Emprint HP, and NeuWave systems for laparoscopic liver ablation. Analyses were performed via Mann-Whitney U and χ2 tests. Continuous data are presented as median (interquartile range). RESULTS: For Emprint, Emprint HP, and NeuWave groups, tumor size was 1.16 (0.8), 1.21 (0.7), and 1.27 (0.9) cm (p = 0.54). Ablation time per lesion was 7 (6), 4 (2.8), and 4 (3.3) min (p < 0.0001), yielding similar ablation zone volumes and margins. The time to first ablation bubble was 1 (0.13), 1.5 (0.85), and 0.75 (0.5) min, and total ablation times were 7 (4.4), 4 (2), and 3.5 (2.8) min (p < 0.0001). The roundness index A, B, and transverse were 0.94, 0.98, and 0.79; 0.95, 0.95, and 0.78; and 1.02, 0.95, and 0.96. CONCLUSIONS: Although a saline-cooling system with Emprint system allowed for larger diameter spherical ablation zones to be created, it led to decreased efficiency compared to the CO2-cooled NeuWave system, which exposes the active antenna directly to tissue. Increased power delivered by Emprint HP improved the efficiency of saline-cooled design, as demonstrated by faster ablation times.

Minimally invasive and robotic-assisted approaches applied to pediatric surgical oncology.

The management of pediatric tumors is complex, with surgery, chemotherapy, and radiotherapy being cornerstones in their treatment. Tumor removal is increasingly performed by a minimally invasive approach, which allows for quicker postoperative recovery and less postoperative pain. The goal of this report is to give an overview of minimally invasive surgical approaches for common pediatric tumors, with a focus on technical considerations and postoperative outcomes.

Laparoscopic ablation for liver malignancies: initial experience at a Scandinavian high volume HPB center.

BACKGROUND: Ablation is an effective, parenchymal-sparing treatment for primary liver cancer and liver metastases. The purpose of this study was to report our initial experience with laparoscopic microwave ablation regarding postoperative complications, rate of conversions to open procedure, and technical efficacy. METHODS: This was a quality improvement project carried out at a tertiary care center in Denmark. Patients ≥ 18 years old with liver malignancies, not available for percutaneous ablation, and treated with ultrasound-guided laparoscopic ablation were included. RESULTS: From March 2023 to December 2023, 39 patients were referred for laparoscopic ablation after a multidisciplinary team conference. Of these, two procedures were converted to open procedures due to adhesion and tumor progression. Three patients rejected the sharing of medical information, two procedures were canceled and in one case the strategy was changed perioperatively. Therefore, 32 procedures in 31 patients were available for analysis. Complete ablation was evaluated after 1 month and was achieved in 100% of the procedures. None of the patients died, and no complications were reported in 21 cases (65.6%). Most patients with complications had a grade 1 complication based on the Clavien-Dindo classification, which among others included abdominal and shoulder pain, atrial fibrillation, and subcutaneous hematoma. Two patients had a complication grade 2 (wound infection and decompensated cirrhosis) and one had a grade 4b (sepsis due to pneumonia and urinary tract infection). The median Comprehensive Complication Index was 12.2 (interquartile range 8.7-24.2). Furthermore, univariable logistic regression showed that ≥ 2 tumors treated were associated with a higher risk of complications (odds ratio 6.37, 95% confidence interval [1.20;33.85], p-value = 0.0297). CONCLUSION: Ultrasound-guided laparoscopic microwave ablation of liver malignancies is feasible and safe with little risk for complications, a high technical efficacy, and a low rate of conversions to open procedures.

Assessment of the mode of action of perchloroethylene-induced mouse liver tumors.

Perchloroethylene (PCE) is used as a solvent and chemical intermediate. Following chronic inhalation exposure, PCE selectively induced liver tumors in mice. Understanding the mode of action (MOA) for PCE carcinogenesis in mice is important in defining its possible human cancer risk. The proposed MOA is based on the extensive examination of the peer-reviewed studies that have assessed the mouse liver effects of PCE and its major oxidative metabolite trichloroacetic acid (TCA). Similar to PCE, TCA has also been demonstrated to liver tumors selectively in mice following chronic exposure. The Key Events (KE) of the proposed PCE MOA involve oxidative metabolism of PCE to TCA [KE 1]; activation of the peroxisome proliferator-activated receptor alpha (PPARα) [KE 2]; alteration in hepatic gene expression including cell growth pathways [KE 3]; increase in cell proliferation [KE 4]; selective clonal expansion of hepatic preneoplastic foci [KE 5]; and formation of hepatic neoplasms [KE 6]. The scientific evidence supporting the PPARα MOA for PCE is strong and satisfies the requirements for a MOA analysis. The PPARα liver tumor MOA in rodents has been demonstrated not to occur in humans; thus, human liver cancer risk to PCE is not likely.

Hepatic resections for pediatric hepatoblastoma: analysis of 30-day outcomes using the National Surgical Quality Improvement Program-Pediatric database.

BACKGROUND: Surgical resection remains the cornerstone of treatment for hepatoblastoma in children and offers the best chance of disease-free survival. We aimed to analyze the 30 day outcomes of hepatic resection for hepatoblastoma stratified by extent using the National Surgical Quality Improvement Program-Pediatric (NSQIP-P). METHODS: We queried NSQIP-P for children undergoing resection of Hepatoblastoma from 2012 to 2021. Relevant clinical characteristics and outcomes were extracted for multivariate logistic regression to identify predictors of common adverse outcomes. RESULTS: We included 458 children with a median age of 1.90 years. Overall complications were rare, and perioperative blood transfusion (64.2%) and postoperative ventilation > 48 h (10.0%) were the only adverse events prevalent in more than 5% of patients. Median transfusion volume was 15.7 ml/kg. On multivariate regression, only patients undergoing Trisectionectomy (aOR = 3.387, 95% C.I. = 1.348-8.510) had higher odds of receiving > 75th percentile blood transfusion. Furthermore, only perioperative transfusion and postoperative ventilation > 48 h were statistically more common in patients undergoing extended versus standard resections. CONCLUSIONS: Outcomes following resection of hepatoblastoma are excellent, with low rates of postoperative adverse events. Although children undergoing trisectionectomy likely require greater transfusion volume, extended hepatic resections do not appear to have worse 30 day outcomes despite greater operative complexity and duration.

Hepatic hemodynamic study: More than just HVPG measurement.

Evaluation and staging of liver disease is essential in the clinical decision-making process of liver tumors. The severity of portal hypertension (PH) is the main prognostic factor in advanced liver disease. Performing an accurate hepatic venous pressure gradient (HVPG) measurement is not always possible, especially when veno-venous communications are present. In those complex cases, a refinement in HVPG measurement with a thorough evaluation of each of the components of PH is mandatory. We aimed at describing how some technical modifications and complementary procedures may contribute to an accurate and complete clinical evaluation to improve therapeutic decisions.

SADSNet: A robust 3D synchronous segmentation network for liver and liver tumors based on spatial attention mechanism and deep supervision.

Highlights: • Introduce a data augmentation strategy to expand the required different morphological data during the training and learning phase, and improve the algorithm's feature learning ability for complex and diverse tumor morphology CT images.• Design attention mechanisms for encoding and decoding paths to extract fine pixel level features, improve feature extraction capabilities, and achieve efficient spatial channel feature fusion.• The deep supervision layer is used to correct and decode the final image data to provide high accuracy of results.• The effectiveness of this method has been affirmed through validation on the LITS, 3DIRCADb, and SLIVER datasets. BACKGROUND: Accurately extracting liver and liver tumors from medical images is an important step in lesion localization and diagnosis, surgical planning, and postoperative monitoring. However, the limited number of radiation therapists and a great number of images make this work time-consuming. OBJECTIVE: This study designs a spatial attention deep supervised network (SADSNet) for simultaneous automatic segmentation of liver and tumors. METHOD: Firstly, self-designed spatial attention modules are introduced at each layer of the encoder and decoder to extract image features at different scales and resolutions, helping the model better capture liver tumors and fine structures. The designed spatial attention module is implemented through two gate signals related to liver and tumors, as well as changing the size of convolutional kernels; Secondly, deep supervision is added behind the three layers of the decoder to assist the backbone network in feature learning and improve gradient propagation, enhancing robustness. RESULTS: The method was testing on LITS, 3DIRCADb, and SLIVER datasets. For the liver, it obtained dice similarity coefficients of 97.03%, 96.11%, and 97.40%, surface dice of 81.98%, 82.53%, and 86.29%, 95% hausdorff distances of 8.96 mm, 8.26 mm, and 3.79 mm, and average surface distances of 1.54 mm, 1.19 mm, and 0.81 mm. Additionally, it also achieved precise tumor segmentation, which with dice scores of 87.81% and 87.50%, surface dice of 89.63% and 84.26%, 95% hausdorff distance of 12.96 mm and 16.55 mm, and average surface distances of 1.11 mm and 3.04 mm on LITS and 3DIRCADb, respectively. CONCLUSION: The experimental results show that the proposed method is effective and superior to some other methods. Therefore, this method can provide technical support for liver and liver tumor segmentation in clinical practice.

Association Between Preoperative Angioembolization and Bleeding Complications in Patients With Benign Liver Tumors: Analysis of a National Database.

INTRODUCTION: The role of angioembolization (AE) in patients with benign liver diseases is an area of active research. This study aims to assess any difference in liver resection outcomes in patients with benign tumors dependent on utilization of preoperative AE. METHODS: A retrospective cohort study of patients undergoing elective liver resections for benign liver tumors was performed using the National Surgical Quality Improvement Program database (2014-2019). Only tumors of 5 cm in size or more were included in the analysis. We categorized the patients based on preoperative AE (AE + versus AE -). The primary outcome measured included bleeding complications within 72 h. The secondary outcomes were to determine predictors of bleeding. RESULTS: After propensity score matching, there were 103 patients in both groups. There was no difference in intraoperative or postoperative blood transfusions within 72 h of surgery (14.6% versus 12.6%; P = 0.68), reoperation (1.9% versus 1.9%; P = 1), or mortality (1.0% versus 0.0%; P = 1) between the two groups. Multivariate regression analysis revealed an open surgical approach (odds ratio [OR]: 4.59 confidence interval [CI]: 2.94-7.16), use of Pringle maneuver (OR: 1.7, CI: 1.26-2.310), preoperative anemia (OR: 2.79, CI: 2.05-3.80), and preoperative hypoalbuminemia (OR: 1.53 [1.14-2.05]) were associated with the need for intraoperative or postoperative blood transfusions within 72 h of surgery. CONCLUSIONS: Preoperative AE was not associated with reducing intraoperative or postoperative bleeding complications or blood transfusions within 72 h after surgery.

Consensus classification of pediatric hepatocellular tumors: A report from the Children's Hepatic tumors International Collaboration (CHIC).

BACKGROUND: Liver tumors are rare in children with histologic heterogeneity that makes diagnosis challenging. Systematic histopathological review, performed as part of collaborative therapeutic protocols, identified relevant histologic subtypes that are important to distinguish. The Children's Hepatic tumors International Collaboration (CHIC) was established to study pediatric liver tumors on a global scale and led to establishment of a provisional consensus classification for use in international clinical trials. The current study is the validation of this initial classification and first large-scale application by international expert reviewers. PROCEDURE: The CHIC initiative includes data from 1605 children treated on eight multicenter hepatoblastoma (HB) trials. Review of 605 available tumors was performed by seven expert pathologists from three consortia (US, EU, Japan). Cases with discordant diagnoses were collectively reviewed to reach a final consensus diagnosis. RESULTS: Of 599 cases with sufficient material for review, 570 (95.2%) were classified as HB by all consortia, and 29 (4.8%) as non-HB, which included "hepatocellular neoplasm, NOS" and malignant rhabdoid tumors. 453 of 570 HBs were classified as epithelial by final consensus. Some patterns (i.e., small cell undifferentiated, macrotrabecular, cholangioblastic) were selectively identified by reviewers from different consortia. All consortia identified a similar number of mixed epithelial-mesenchymal HB. CONCLUSIONS: This study represents the first large-scale application and validation of the pediatric malignant hepatocellular tumors consensus classification. It is a valuable resource to train future generations of investigators on accurate diagnosis of these rare tumors and provides a framework for further international collaborative studies and refinement of the current classification of pediatric liver tumors.

Introduction to interventional oncology: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Interventional radiology (IR) is a valuable resource when caring for pediatric solid tumor patients. As minimally invasive, image-guided procedures become more relied upon to answer challenging diagnostic questions and provide alternative therapeutic options, IR is poised to become a contributing member of the multidisciplinary oncology team. Improved imaging techniques allow for better visualization during biopsy procedures, transarterial locoregional treatments have the potential to deliver targeted cytotoxic therapy while limiting systemic side effects, and percutaneous thermal ablation can be used to treat chemo-resistant tumors of various solid organs. Additionally, interventional radiologists are able to perform routine, supportive procedures for oncology patients that include central venous access placement, lumbar punctures, and enteric feeding tube placements with high levels of technical success and excellent safety profiles.

A study on prevention of bleeding complications using lusutrombopag for safe RFA in patients with hepatocellular carcinoma with low platelet counts: prospective observational study.

BACKGROUND: Platelet (PLT) transfusion was the most practical way to increase patients' PLT counts before invasive hepatic procedures such as radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). A novel drug that raises the PLT count by acting on the thrombopoietin receptor has recently become available. METHODS: Lusutrombopag 3 mg was administered daily for 7 days to patients who underwent RFA for liver tumors with low PLT counts (< 50,000 PLT µL- 1). We collected demographic data concerning the patients' liver function and PLT counts. RESULTS: Lusutrombopag was administered to 91 patients, with a median age of 71 years (range 51-86). Forty-two patients had hepatitis C, 12 had hepatitis B, 21 had alcoholic liver disease, 11 had nonalcoholic steatohepatitis, and five had other diseases. The median Child-Pugh score was 7 (range 5-11). Thirty-seven patients had stage I tumors, 41 had Stage II, 12 had stage III, and one had stage IV. PLT count was elevated from 4.4 × 104 ± 1.4 × 104 to 8.6 × 104 ± 2.5 × 104 PLT µL- 1. Lusutrombopag administration prevented PLT transfusions in 84/91 patients (92%). No patient had bleeding complications after RFA. One had portal thrombosis after lusutrombopag administration. Patients who achieved PLT counts of > 50,000 PLT µL- 1 had higher PLT counts before lusutrombopag administration. The degree of splenomegaly did not affect the rate of PLT count elevation. There was no specific adverse effect by administrating lusutrombopag for patients with PLT counts of around 50,000 µL- 1 but > 50,000 µL- 1. CONCLUSIONS: Lusutrombopag administration before RFA was effective and seemed to be relatively safe for hepatocellular carcinoma patients with low PLT counts. TRIAL REGISTRATION: This study was approved by Japanese Red Cross Medical Center Institutional Reseach Comittie (#862, 07/03/2016), and was registered in a publically accessible primary register (#UMIN000046629, registered date: 14/01/2022).

Evaluation of the carcinogenicity of carbon tetrachloride.

Carbon tetrachloride (CCl4) has been extensively used and reported to produce toxicity, most notably involving the liver. Carbon tetrachloride metabolism involves CYP450-mediated bioactivation to trichloromethyl and trichloromethyl peroxy radicals, which are capable of macromolecular interaction with cell components including lipids and proteins. Radical interaction with lipids produces lipid peroxidation which can mediate cellular damage leading to cell death. Chronic exposure with CCl4 a rodent hepatic carcinogen with a mode of action (MOA) exhibits the following key events: 1) metabolic activation; 2) hepatocellular toxicity and cell death; 3) consequent regenerative increased cell proliferation; and 4) hepatocellular proliferative lesions (foci, adenomas, carcinomas). The induction of rodent hepatic tumors is dependent upon the dose (concentration and exposure duration) of CCl4, with tumors only occurring at cytotoxic exposure levels. Adrenal benign pheochromocytomas were also increased in mice at high CCl4 exposures; however, these tumors are not of relevant importance to human cancer risk. Few epidemiology studies that have been performed on CCl4, do not provide credible evidence of enhanced risk of occurrence of liver or adrenal cancers, but these studies have serious flaws limiting their usefulness for risk assessment. This manuscript summarizes the toxicity and carcinogenicity attributed to CCl4, specifically addressing MOA, dose-response, and human relevance.

Circulating microRNA Panels for Detection of Liver Cancers and Liver-Metastasizing Primary Cancers.

Malignant liver tumors, including primary malignant liver tumors and liver metastases, are among the most frequent malignancies worldwide. The disease carries a poor prognosis and poor overall survival, particularly in cases involving liver metastases. Consequently, the early detection and precise differentiation of malignant liver tumors are of paramount importance for making informed decisions regarding patient treatment. Significant research efforts are currently directed towards the development of diagnostic tools for different types of cancer using minimally invasive techniques. A prominent area of focus within this research is the evaluation of circulating microRNA, for which dysregulated expression is well documented in different cancers. Combining microRNAs in panels using serum or plasma samples derived from blood holds great promise for better sensitivity and specificity for detection of certain types of cancer.

Improved survival and higher rates of surgical resection associated with hepatocellular carcinoma in children as compared to young adults.

Hepatocellular adenocarcinoma (HCC) is the second most common primary hepatic malignancy in children with a 5-year overall survival of 30%. Few studies have examined the similarities and differences between pediatric and adult HCC. This article aims to examine the relationship between tumor characteristics, treatments and outcomes in pediatric and adult patients with HCC. The 2019 National Cancer Database was queried for patients with HCC. Patients were stratified by age: pediatric <21 years (n = 214) and young adults 21 to 40 (n = 1102). Descriptive statistics and chi square were performed. The mean age at diagnosis was 15.5 years (SD 5.6) in the pediatric and 33 years (5.3) in the adult group. Children had a comparable rate of metastasis (30% vs 28%, P = .47) and increased fibrolamellar histology (32% vs 9%). Surgical resection was more common in children compared to adults (74% vs 62%, P < .001), children also had more lymph nodes examined (39% vs 19%, P < .001), positive lymph nodes (35% vs 17%, P = .02) and surgical resection when metastasis were present at diagnosis (46% vs 18%, P < .001). The 1-, 3- and 5-year overall survival was higher for pediatric patients than adults (81%, 65%, 55%, vs 70%, 54%, 48%). Despite higher prevalence of fibrolamellar histology, greater number of positive lymph nodes and comparable rates of metastasis at diagnosis, children with HCC have improved overall survival compared to adults. Age did not significantly contribute to survivorship, so it is likely that the more aggressive surgical approach contributed to the improved overall survival in pediatric patients.

Advances in the treatment of pediatric solid tumors: A 50-year perspective.

In the United States, more than 10 000 cancers occur annually in children aged 0-14 years, and more than 5000 in adolescents aged 15-19. In the last 50 years, significant advances have been made in imaging, molecular pathology, stage and risk assessment, surgical approach, multidisciplinary treatment, and survival for pediatric solid tumors (particularly neuroblastoma, Wilms tumor, rhabdomyosarcoma, and hepatoblastoma). Moreover, the molecular driver for fibrolamellar hepatocellular carcinoma, which occurs in adolescence and young adulthood, has been identified.

Assessment of a new 150 W single-antenna microwave ablation system in the treatment of malignant liver tumors: The first worldwide experience.

BACKGROUND AND OBJECTIVES: Data in literature regarding liver microwave ablation pertain to systems delivering 100 W of maximum power. Our aim is to assess a new 150 W microwave system for liver tumor ablation. METHODS: This was an institutional review board-approved study of patients undergoing ablation of malignant liver tumors using a 150 W microwave system. Feasibility, safety, ablation algorithm, perioperative outcomes, and efficacy were analyzed. Comparison was made to historical patients undergoing ablation using a 100 W microwave system. RESULTS: There were 33 patients with 76 malignant liver lesions who underwent ablation with the 150 W system. Using a step-wise algorithm, ablations without intraoperative complications were performed for tumors ranging in size from 0.3 to 6.7 cm. Ninety-day morbidity was 5%, with no mortality. Compared to the 100 W system, the 150 W system shortened ablation time and created larger ablation zones with a single stick. CONCLUSION: This first worldwide experience showed that surgical ablations could be safely created at 150 W using a step-wise algorithm with complete tumor destruction achieved at short-term follow-up. Advantages versus 100 W systems include reduction in ablation time and creation of larger ablation zones with a single stick.

The usefulness of three-dimensional ultrasound fusion imaging for precise needle placement in liver thermal ablation: a phantom and an in vivo simulation study.

PURPOSE: To investigate the value of three-dimensional ultrasound fusion imaging (3DUS-FI) in real-time guiding needle placement by phantom models and in vivo simulations. MATERIALS AND METHODS: Two radiologists (beginner and expert) performed needle placement using two-dimensional ultrasound (2DUS) and 3DUS-FI, respectively. In the phantom study, single-needle placement was performed by puncturing the center point of each ball and assessed based on the specimen length. Multiple-needles placement was performed by placing three needles in each ball, and their locations were confirmed by computed tomography, and assessed based on the distance deviation between needles. In the in vivo simulation study, simulated-needle placement was performed by placing a virtual ablation needle in each liver tumor and assessed by the simulated ablative cover rate and margin. RESULTS: Specimen length was significantly longer with 3DUS-FI in the beginner, whereas no significant difference was observed in the expert (2DUS vs. 3DUS-FI: beginner, 14.60 ± 2.60 mm vs. 16.25 ± 1.38 mm, p = .017; expert, 16.78 ± 1.40 mm vs. 16.95 ± 1.15 mm, p = .668). Distance deviation between needles was significantly smaller with 3DUS-FI (2DUS vs. 3DUS-FI: beginner, 25.06 ± 16.07 mm vs. 3.72 ± 1.99 mm, p < .001; expert, 11.70 ± 7.79 mm vs. 2.89 ± 1.52 mm, p < .001). The simulated ablative cover rate and margin were significantly larger with 3DUS-FI for the beginner, whereas only the latter was significantly larger for the expert (2DUS vs. 3DUS-FI: beginner, 73.55 ± 8.73% vs. 81.38 ± 11.84%, p = .001, 0.82 ± 0.97 mm vs. 2.65 ± 1.23 mm, p < .001; expert, 78.60 ± 9.91% vs. 83.24 ± 11.69%, p = .059; 1.65 ± 1.15 mm vs. 2.95 ± 1.13 mm, p < .001). CONCLUSIONS: 3DUS-FI is useful for real-time guiding precise needle placement and may be further use to improve the efficacy of liver thermal ablation.

Evaluation of the mode of action and human relevance of liver tumors in male mice treated with epyrifenacil.

Epyrifenacil (trademark name: Rapidicil®), a novel protoporphyrinogen oxidase (PPO)-inhibiting herbicide, induces hepatocellular adenomas and carcinomas in male CD-1 mice after 78 weeks treatment. The mode of action (MOA) of these mouse liver tumors and their relevance to humans was assessed based on the 2006 International Programme on Chemical Safety (IPCS) Human Relevance Framework. Epyrifenacil is not genotoxic and induced liver tumors via the postulated porphyria-mediated cytotoxicity MOA with the following key events: (#1) PPO inhibition; (#2) porphyrin accumulation; (#3) hepatocellular injury; with (#4) subsequent regenerative cell proliferation; and ultimately (#5) development of liver tumors. This article evaluates the weight of evidence for this MOA based on the modified Bradford Hill criteria. The MOA data were aligned with the dose and temporal concordance, biological plausibility, coherence, strength, consistency, and specificity for a porphyria-mediated cytotoxicity MOA while excluding other alternative MOAs. Although the postulated MOA could qualitatively potentially occur in humans, we demonstrate that it is unlikely to occur in humans because of quantitative toxicodynamic and toxicokinetic differences between mice and humans. Therefore, this MOA is considered not relevant to humans, utilizing the IPCS Human Relevance Framework; consequently, a nonlinear, threshold dose response would be appropriate for human risk assessment.

Modeling of Respiratory Motion to Support the Minimally Invasive Destruction of Liver Tumors.

OBJECTIVE: Respiratory movements are a significant factor that may hinder the use of image navigation systems during minimally invasive procedures used to destroy focal lesions in the liver. This article aims to present a method of estimating the displacement of the target point due to respiratory movements during the procedure, working in real time. METHOD: The real-time method using skin markers and non-rigid registration algorithms has been implemented and tested for various classes of transformation. The method was validated using clinical data from 21 patients diagnosed with liver tumors. For each patient, each marker was treated as a target and the remaining markers as target position predictors, resulting in 162 configurations and 1095 respiratory cycles analyzed. In addition, the possibility of estimating the respiratory phase signal directly from intraoperative US images and the possibility of synchronization with the 4D CT respiratory sequence are also presented, based on ten patients. RESULTS: The median value of the target registration error (TRE) was 3.47 for the non-rigid registration method using the combination of rigid transformation and elastic body spline curves, and an adaptation of the assessing quality using image registration circuits (AQUIRC) method. The average maximum distance was 3.4 (minimum: 1.6, maximum 6.8) mm. CONCLUSIONS: The proposed method obtained promising real-time TRE values. It also allowed for the estimation of the TRE at a given geometric margin level to determine the estimated target position. Directions for further quantitative research and the practical possibility of combining both methods are also presented.