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Most hepatocellular carcinomas (HCCs) occur in cirrhotic livers, but unequivocal diagnosis of early HCC from the fibrotic microenvironment remains a formidable challenge with conventional imaging strategies, mainly because of the massive fibrotic collagen deposition leading to hepatic nodules formation and dysfunction of contrast agent metabolism. Here, we developed a "sweep-and-illuminate" imaging strategy, pre-degrade hepatic fibrotic collagen with collagenase I conjugated human serum albumin (HSA-C) and then targeting visualize HCC lesion with GPC3 targeting nanoparticles (TSI NPs, TJ2 peptide–superparamagnetic iron oxide–indocyanine green) via fluorescence imaging (FLI) and magnetic particle imaging (MPI). TSI NPs delineated a clear boundary of HCC and normal liver, and the tumor-to-background ratios (TBRs) detected by FLI and MPI were 5.43- and 1.34-fold higher than the non-targeted group, respectively. HSA-C could degrade 24.7% fibrotic collagen, followed by 27.2% reduction of nonspecific NPs retention in mice with liver fibrosis. In a pathological state in which HCC occurs in the fibrotic microenvironment, HSA-C-mediated pre-degradation of fibrotic collagen reduced background signal interference in fibrotic tissues and enhanced the intratumoral uptake of TSI NPs, resulting in the clear demarcation between HCC and liver fibrosis, and the TBR was increased 2.61-fold compared to the group without HSA-C pretreatment. We demonstrated the feasibility of combined pre-degradation of fibrotic collagen and application of a GPC3-targeted FLI/MPI contrast agent for early HCC identification, as well as its clinical value in the management of patients with advanced liver fibrosis. Given that liver fibrosis hinders early detection and treatment options of hepatocellular carcinomas (HCCs), we report a "sweep-and-illuminate" imaging strategy to enhance the efficiency of HCC identification by modulating the irreversible liver fibrosis. We first "sweep" nonspecific interference of contrast agent by pre-degrading fibrotic collagen with human serum albumin-carried collagenase I (HSA-C); and then specifically "illuminate" HCC lesions with GPC3-targeted-SPIO-ICG nanoparticles (TSI NPs). HSA-C can degrade 24.7% fibrotic collagen, followed by 27.2% reduction of nonspecific NPs retention in mice with liver fibrosis. Furthermore, in HCC models coexisting with liver fibrosis, the combined application of HSA-C and TSI NPs can clarify the demarcation between HCC and liver fibrosis with a 2.61-fold increase in the tumor-to-background ratio. This study may expand the potential of combinatorial biomaterials for early HCC diagnosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies in China. Most HCC patients are first diagnosed at an advanced stage, and systemic treatments are the mainstay of treatment. Summary: In recent years, immune checkpoint inhibitors have made a breakthrough in the systemic treatment of middle-advanced HCC, breaking the single therapeutic pattern of molecular-targeted agents. To better guide the clinical treatment for effective and safe use of immunotherapeutic drugs, the Chinese Association of Liver Cancer and Chinese Medical Doctor Association has gathered multidisciplinary experts and scholars in relevant fields to formulate the "Chinese Clinical Expert Consensus on Immunotherapy for Hepatocellular Carcinoma (2021)" based on current clinical studies and clinical medication experience for reference in China. Key Messages: The consensus contained 17 recommendations, including the preferred regimen for first- and second-line immunotherapy, evaluation and monitoring before/during/after treatment, management of complications, precautions for special patients, and potential population for immunotherapy. [ABSTRACT FROM AUTHOR]

Early diagnosis and management of hepatocellular carcinoma (HCC) is important for improving the 5-year survival rate. Multimodal imaging is of great significance for obtaining complementary information, improving the efficacy of tumor detection, and monitoring HCC recurrence. The rational development of targeted nanoprobes with excellent performance is of great significance for the accurate diagnosis of HCC and image-guided photothermal therapy (PTT). In the present study, we synthesized a hybrid nanoprobe containing epithelial cell adhesion molecule-functionalized Fe3O4@Au nanoparticles as an HCC-targeted nanoprobe, which served as a dual-modal contrast agent for optoacoustic tomography (OAT) and magnetic resonance imaging (MRI) and as a photothermal sensitizer for PTT. Using this nanoprobe, we evaluated the application of coregistered OAT–MRI for the diagnosis and therapy of HCC to resolve an image alignment problem. Body-position variation in OAT and MRI was minimized using a specially designed 3D-printed dual-modality animal imaging bed constructed from polylactic acid. The registration accuracy of OAT–MRI data was further improved by a robust image registration protocol. Dual-modality coregistered imaging was performed for the early diagnosis of HCC and monitoring of curative effects. To our knowledge, this is the first study to apply a combination of a targeted nanoprobe and coregistration of OAT–MRI for the diagnosis and management of abdominal diseases. [ABSTRACT FROM AUTHOR]

Portal vein tumor thrombus (PVTT) is very common and it plays a major role in the prognosis and clinical staging of hepatocellular carcinoma (HCC). We have published the first version of the guideline in 2016 and revised in 2018. Over the past several years, many new evidences for the treatment of PVTT become available, especially for the advent of new targeted drugs and immune checkpoint inhibitors which have further improved the prognosis of PVTT. So, the Chinese Association of Liver Cancer and Chinese Medical Doctor Association revised the 2018 version of the guideline to adapt to the development of PVTT treatment. Future treatment strategies for HCC with PVTT in China would depend on new evidences from more future clinical trials. [ABSTRACT FROM AUTHOR]

Despite advancements in diagnostic methods and therapeutic strategies, the mortality rate of hepatocellular carcinoma (HCC) remains as high as its incidence rate. Most liver cancers are detected in the advanced stages, when treatment options are limited. Small HCC is difficult to diagnose and is often overlooked by current imaging methods because of the complexity of the liver environment, especially in cirrhotic livers. In the present study, we developed a tumor "cruise missile", mesoporous Fe3O4-containing glucose oxidase-conjugated GPC3 peptide nanoparticles (FGP NPs). It was designed to enhance the accuracy of small HCC visualization to 85.7% using combined ultrasound/photoacoustic imaging in complex liver environment, which facilitated sequential catalytic targeted therapy for small HCC. In a carcinogen-induced mouse HCC model, FGP NPs could be used to accurately diagnose HCC in a liver cirrhosis background as well as distinguish HCC nodules from other abnormal liver nodules, such as cirrhosis nodules and necrotic nodules, by dynamic contrast-enhanced photoacoustic imaging. In a mouse xenograft HCC model, highly reactive oxygen species were formed by sequential catalytic reactions, which promoted HCC cell apoptosis, significantly increasing the survival of the model mice. The present study provides a basis for the precise detection and elimination of small HCCs in the complex liver environment. [ABSTRACT FROM AUTHOR]

Effective and noninvasive diagnosis and prompt treatment of early-stage hepatocellular carcinoma (HCC) are urgently needed to reduce its mortality rate. Herein, the integration of high-resolution diagnostic second near-infrared (NIR-II) photoacoustic computed tomography (PACT) and imaging-guided targeted photothermal ablation of orthotopic small HCC (SHCC) is presented for the first time, which was enabled by a plasmonic platinum (Pt)-doped polydopamine melanin-mimic nanoagent. As designed, an antibody-modified nanoagent (designated Pt@PDA-c) with a plasmonic blackbody-like NIR absorption and superior photothermal conversion efficiency (71.3%) selectively targeted and killed CXCR4-overexpressing HCC (HepG2) cells, which was validated in in vitro experiments. The targeted accumulation properties of Pt@PDA-c in vivo were previously recognized by demonstrating effective NIR-II PA imaging and photothermal ablation in a subcutaneous HCC mouse model. Subsequently, with real-time quantitative guidance by PACT for the accurate diagnosis of intraabdominal SHCC (approximately 4 mm depth), the effective and noninvasive photothermal ablation of SHCCs was successfully demonstrated in an orthotopic tumor-bearing mouse model without damaging adjacent liver tissues. These results show a great potential of NIR-II PACT-guided noninvasive photothermal therapy as an innovative phototheranostic approach and expand the biomedical applications of melanin-mimic materials. In this paper, we report the first diagnostic NIR-II photoacoustic computed tomography (PACT)-guided noninvasive photothermal ablation of small hepatocellular carcinoma (SHCC) located in deep tissues in orthotopic tumor-bearing mice; this process is empowered by a polydopamine-based melanin-mimic tumor-targeting nanoagent doped with plasmonic platinum that provides superior NIR-II (1064 nm) absorption and photothermal conversion efficiency of 71.3%. Following surface modification with anti-CXCR4 antibodies, the nanoagent (namely Pt@PDA-c) can selectively target CXCR4-overexpressed HepG2 carcinoma cells and tumor lesions, and serve as the theranostic agent for both NIR-II PACT-based diagnosis of orthotopic SHCC (diameter less than 5 mm) and efficient NIR-II PTT in vivo. This study may also extend the potential of melanin-derived blackbody materials for optical-biomedical and water distillation applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose: To establish a valid prediction model to prognose the occurrence of microvascular invasion (MVI), and to compare the efficacy of anatomic resection (AR) or non-anatomic resection (NAR) for hepatocellular carcinoma (HCC). Methods: Two hundred twenty-eight patients with HCC who underwent surgical treatment were enrolled. Their hematological indicators, MRI imaging features, and outcome data were acquired. Result: In the multivariable analysis, alpha-fetoprotein >15 ng/mL, neutrophil to lymphocyte ratio >3.8, corona enhancement, and peritumoral hypointensity on hepatobiliary phase were associated with MVI. According on these factors, the AUROC of the predictive model in the primary and validation cohorts was 0.884 (95% CI: 0.829, 0.938) and 0.899 (95% CI: 0.821, 0.967), respectively. Patients with high risk of MVI or those with low risk of MVI but tumor size >5 cm in the AR group were associated with a lower rate of recurrence and death than patients in the NAR group; however, when patients are in the state of low-risk MVI with tumor size >5 cm, there is no difference in the rate of recurrence and death between AR and NAR. Conclusion: Our predictive model for HCC with MVI is convenient and accurate. Patients with high-risk of MVI or low-risk of MVI but tumor size >5 cm executing AR is of great necessity. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to build and evaluate a radiomics feature-based model for the preoperative prediction of microvascular invasion (MVI) in patients with hepatocellular carcinoma. Methods: A total of 145 patients were retrospectively included in the study pool, and the patients were divided randomly into two independent cohorts with a ratio of 7:3 (training cohort: n = 101, validation cohort: n = 44). For a pilot study of this predictive model another 18 patients were recruited into this study. A total of 1,231 computed tomography (CT) image features of the liver parenchyma without tumors were extracted from portal-phase CT images. A least absolute shrinkage and selection operator (LASSO) logistic regression was applied to build a radiomics score (Rad-score) model. Afterwards, a nomogram, including Rad-score as well as other clinicopathological risk factors, was established with a multivariate logistic regression model. The discrimination efficacy, calibration efficacy, and clinical utility value of the nomogram were evaluated. Results: The Rad-score scoring model could predict MVI with the area under the curve (AUC) of 0.637 (95% CI, 0.516–0.758) in the training cohort as well as of 0.583 (95% CI, 0.395–0.770) in the validation cohort; however, the aforementioned discriminative approach could not completely outperform those existing predictors (alpha fetoprotein, neutrophilic granulocyte, and preoperative hemoglobin). The individual predictive nomogram which included the Rad-score, alpha fetoprotein, neutrophilic granulocyte, and preoperative hemoglobin showed a better discrimination efficacy with AUC of 0.865 (95% CI, 0.786–0.944), which was higher than the conventional methods' AUCs (nomogram vs Rad-score, alpha fetoprotein, neutrophilic granulocyte, and preoperative hemoglobin at P < 0.001, P = 0.025, P < 0.001, and P = 0.001, respectively). When applied to the validation cohort, the nomogram discrimination efficacy was still outbalanced those above mentioned three remaining methods (AUC: 0.705; 95% CI, 0.537–0.874). The calibration curves of this proposed method showed a satisfying consistency in both cohorts. A prospective pilot analysis showed that the nomogram could predict MVI with an AUC of 0.844 (95% CI, 0.628–1.000). Conclusions: The radiomics feature-based predictive model improved the preoperative prediction of MVI in HCC patients significantly. It could be a potentially valuable clinical utility. [ABSTRACT FROM AUTHOR]

Aim: The diagnosis and treatment of hepatocarcinoma (HCC) is believed to be improved due to the development of specific targeting probes by molecular imaging methods. GPC3, which is a hepatocellular carcinoma (HCC)-specific tumor marker, anchors at most HCC cells. To target this cell membrane protein, we developed a novel nanoparticle by conjugating WS2-Ga3+-PEG and a short peptide with favorable specificity and affinity to the GPC3 protein. Materials & methods: In in vitro assay, several physical properties of the novel probe were evaluated. In in vivo assay, MRI, photoacoustic imaging and photothermal therapy were performed in the subcutaneous HepG2-bearing mice with the novel probe. Results & conclusion: The effect of imaging and photothermal therapy was significant. We revealed that the novel nanosheet WS2-Ga3+-PEG-peptide is promising to detect and treat HCC-expressing GPC3. [ABSTRACT FROM AUTHOR]

BACKGROUND: Laparoscopic hepatectomy for centrally located hepatocellular carcinoma is challenging to perform. Augmented reality navigation (ARN) and fluorescence imaging are currently safe and reproducible techniques for hepatectomy, but the efficacy results for centrally located hepatocellular carcinoma have not been reported. This study aimed to evaluate the efficacy of an ARN system combined with fluorescence imaging (ARN-FI) in laparoscopic hepatectomy for centrally located hepatocellular carcinoma. STUDY DESIGN: This was a post hoc analysis of an original nonrandomized clinical trial that was designed to evaluate the feasibility and efficacy of ARN-FI for laparoscopic liver resection. A total of 76 patients were consecutively enrolled from June 2018 to June 2021, of which 42 underwent laparoscopic hepatectomy using ARN-FI (ARN-FI group), and the other 34 who did not use ARN-FI guidance (non–ARN-FI group). Perioperative outcomes and disease-free survival were compared between the 2 groups. RESULTS: Compared with the non–ARN-FI group, the ARN-FI group had less intraoperative blood loss (median 275 vs 300 mL, p = 0.013), lower intraoperative transfusion rate (14.3% vs 64.7%, p < 0.01), shorter postoperative hospital stay (median 8 vs 9 days, p = 0.005), and lower postoperative complication rate (35.7% vs 61.8%, p = 0.024). There was no death in the perioperative period and follow-up period. There was no significant difference in overall disease-free survival between the 2 groups (p = 0.16). CONCLUSIONs: The ARN system and fluorescence imaging may be of value in improving the success rate of surgery, reducing postoperative complications, accelerating postoperative recovery, and shortening postoperative hospital stay. This study found that augmented reality navigation and fluorescence imaging showed favorable results in the perioperative period. In addition, although no significant differences in disease-free survival (DFS) were found between the 2 groups overall, the cohort with both techniques showed higher DFS in subgroup analysis of type IV centrally located hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Nanoparticle-based photothermal ablation (PTA) has been intensively investigated recently. However, the poor biocompatibility of most PTA agents and potential long-term toxicity obstruct their clinical translation. Meanwhile, previous PTA studies are limited to surface tumors because of insufficient light penetration depth of near-infrared (NIR) light for deep abdominal tumors. Therefore, minimally invasive PTA combined with biocompatible agents may pave a promising way to treat deep orthotopic hepatocellular carcinoma (HCC). Herein, a multifunctional agent based on superparamagnetic iron oxide (SPIO) and new indocyanine green (IR820) was constructed with good biocompatibility. Outstanding fluorescence, photoacoustic and magnetic resonance imaging capabilities were observed in vitro. Additionally, in vivo results indicated that early-stage HCC (diameter less than 2 mm) could be effectively detected by this agent. Furthermore, for the first time, we developed minimally invasive laparoscopic-assisted photothermal ablation (L-A PTA) method coupled with this agent to completely ablate orthotopic HCC in nude mice model, neither recurrences nor obvious side effects were observed during the experiments. Remarkable shrinkage of primary tumor and disappearance of intrahepatic metastasis were also observed. In summary, minimally invasive L-A PTA is an effective preoperative neoadjuvant treatment for HCC. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel polydopamine-based drug platform was synthesized that can be used for multi-modal imaging and targeted drug delivery. • The nanoprobe can respond to high GSH/low PH tumor environment and complete drug delivery in response to tumor cell hypoxia. • The nanoprobe reduces Sorafenib resistance in hepatocellular carcinoma. • The nanoprobe reduces tumor hypoxia and tumor microvessel formation, effectively inhibiting tumor growth. Hepatocellular carcinoma is a common and highly malignant disease. As a currently designated systemic chemotherapeutic agent for advanced Hepatocellular carcinoma, sorafenib has been confronted with dilemma of drug-resistance caused by tumor hypoxia, which hinders the therapeutic efficacy of the drug. Based on this, a multifunctional mesoporous polydopamine nanoprobe 2Me-SPIO-CY5.5@AAZ-MPDA with a mesoporous frame loaded 2-Methoxyestradiol, Superparamagnetic Iron Oxide Nanoparticles and the near-infrared dye cyanine 5.5, conjugated with hypoxia Hepatocellular carcinoma-specific targeting molecule of sulfonamides acetazolamide, is fabricated for hypoxic region targeting, sorafenib resistance reversion and photothermal therapy of Hepatocellular carcinoma. In addition, the magnetic resonance imaging/fluorescence/photoacoustic tri-modal imaging ability enables the tracing of the nanoprobes and monitoring the treatment procedure in vivo, providing a new methods of imaging-guided Hepatocellular carcinoma synergic treatment which improves the long-term therapeutic effects of sorafenib. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC), the fifth most common cancer worldwide, is increasing nowadays and poses a serious threat to human health. However, if treated effectively and timely, it is clinically manageable or curable. Therefore, accurate detection and complete surgical resection remain priorities for HCC with a high potential of improving both survival and quality of life. Lacking of real-time guide technology, traditional surgery are usually relied on the subjective experience of surgeon, which have the limitation of high sensitivity detection tumor. Here, we developed a contrast agent, ZnGa 2 O 4 Cr 0.00 4 (ZGC), used for guided surgery during operation to accurate delineation of HCC. ZGC showed excellent long-lasting afterglow properties that lasted for hours, which can aid in real-time guided surgery. Meanwhile, ZGC display high spatial resolution and deep penetration during pre-operation for diagnostic computed tomography (CT). Interestingly, we observed reverse imaging in the tumor region, known as a “dark hole”, which further improves the contrast for surgery. This new multi-modality nanoparticle has great potential for accurate liver cancer imaging and resection guidance. [ABSTRACT FROM AUTHOR]

Highlights from the article: Keywords: fluorescence-guided surgery; hepatocellular carcinoma; intraoperative photothermal therapy; triple-modality imaging In article number 1900085, Chihua Fang, Jie Tian, and co-workers develop a multifunctional epithelial cell adhesion molecule (EpCAM)-targeting nanoparticle with triple-modality visualization, uniting magnetic resonance, photoacoustic, and fluorescence imaging for the high precision diagnosis of hepacellular carnicoma (HCC) and intraoperative imaging guidance for accurate hepatectomy. Hepatocellular carcinoma, fluorescence-guided surgery, intraoperative photothermal therapy, triple-modality imaging.

Hepatectomy is one of the main treatments for hepatocellular carcinoma (HCC). However, because microscopic tumor residues are often present after surgery, the recurrence rate of HCC remains extremely high. A multimodality imaging‐guided multifunctional nanoparticle, indocyanine‐green–gadolinium–copper sulfide@bovine‐serum‐albumin–epithelial‐cell‐adhesion molecule (EpCAM), is developed for HCC treatment based on a novel theranostic strategy. After intravenous injection of these nanoparticles into HCC‐bearing mice, remarkably selective accumulation and highly efficient retention of the nanoparticles in tumor sites are observed. This is due to the EpCAM's specific targeting ability, which also results in enhanced HCC contrast in a tri‐modal visualization, which unites magnetic resonance, photoacoustic, and fluorescence imaging. Moreover, nanoparticle uptake into the HCC allows photothermal therapy (PTT) as an interoperative adjuvant strategy for further eliminating possible microscopic residues and boosting HCC surgery outcomes. This theranostic strategy not only helps with precise diagnosis of HCC but enables intraoperatively imaging guidance for accurate tumor resection. Moreover, postoperation longitudinal observation demonstrates that intraoperative imaging‐guided resection alongside a PTT‐integrated treatment strategy can result in a significant improvement of overall survival rate. These multifunctional EpCAM‐targeting nanoparticles may respresent a novel theranostic strategy to improve postsurgical HCC treatment. [ABSTRACT FROM AUTHOR]