Optimizing cardiovascular image segmentation through integrated hierarchical features and attention mechanisms.

BACKGROUND: Cardiovascular diseases are the top cause of death in China. Manual segmentation of cardiovascular images, prone to errors, demands an automated, rapid, and precise solution for clinical diagnosis. OBJECTIVE: The paper highlights deep learning in automatic cardiovascular image segmentation, efficiently identifying pixel regions of interest for auxiliary diagnosis and research in cardiovascular diseases. METHODS: In our study, we introduce innovative Region Weighted Fusion (RWF) and Shape Feature Refinement (SFR) modules, utilizing polarized self-attention for significant performance improvement in multiscale feature integration and shape fine-tuning. The RWF module includes reshaping, weight computation, and feature fusion, enhancing high-resolution attention computation and reducing information loss. Model optimization through loss functions offers a more reliable solution for cardiovascular medical image processing. RESULTS: Our method excels in segmentation accuracy, emphasizing the vital role of the RWF module. It demonstrates outstanding performance in cardiovascular image segmentation, potentially raising clinical practice standards. CONCLUSIONS: Our method ensures reliable medical image processing, guiding cardiovascular segmentation for future advancements in practical healthcare and contributing scientifically to enhanced disease diagnosis and treatment.

Locoregional treatment improves overall survival for liver cancer during second-line regorafenib or immune checkpoint inhibitor.

For advanced hepatocellular carcinoma (HCC), the best second-line treatment after first-line treatment with sorafenib is unclear. This study aimed to compared the efficacy of second-line regorafenib (a tyrosine kinase inhibitor) and immune checkpoint inhibitors (ICIs) in patients with advanced HCC after sorafenib therapy. This retrospective study included 89 patients with HCC treated with sorafenib, and then regorafenib (n = 58) or an ICI (n = 31). Treatment response, overall survival (OS) and progression-free survival (PFS) of the 2 groups were compared, and factors associated with post-treatment mortality or disease progression were evaluated. During follow-up period, compared to regorafenib, treatment with an ICI results in a slight increase in a 20% decrease of AFP (35.7% vs. 31.8%), complete response rate (6.5% vs. 0%), objective response rate (16.1% vs. 6.9%), median overall survival (13.3 vs. 5 months), and median PFS (3.0 vs. 2.6 months). Combined locoregional treatment (LRT) (hazard ratio [HR] = 0.40, 95% confidence interval [CI]: 0.15-0.99) during second-line treatment was associated with a decreased risk of post-treatment mortality. After propensity scoring matching, combined LRT during second-line treatment had longer post-treatment OS than patients without combined LRT. A 20% decrease of AFP (HR = 0.54, 95% CI: 0.31-0.94) was associated with a decreased risk of post-treatment disease progression. In conclusions, second-line treatment with regorafenib or ICI prolongs OS in patients with advanced HCC treated with sorafenib. Combined LRT during second-line treatment is associated with decreased post-treatment mortality. A 20% decrease of AFP level may be predictive of a lower rate of disease progression.

Concurrent Atezolizumab Plus Bevacizumab and High-Dose External Beam Radiotherapy for Highly Advanced Hepatocellular Carcinoma.

BACKGROUND: Atezolizumab plus bevacizumab (atezo-bev) has been recommended for advanced hepatocellular carcinoma (HCC). High-dose external beam radiotherapy (RT) is recognized for its excellent local tumor control. The efficacy and safety of concurrent atezo-bev with RT for highly advanced HCC has been minimally explored. METHODS: In this preliminary retrospective study, we assessed patients with highly advanced HCC, characterized by Vp4 portal vein thrombosis or tumors exceeding 50% of liver volume, who received concurrent atezo-bev and RT (group A). Group A included 13 patients who received proton radiation at a dose of 72.6 GyE in 22 fractions, and one patient who received photon radiation at a dose of 54 Gy in 18 fractions. This group was compared with 34 similar patients treated atezo-bev alone as a control (group B). The primary objectives were to evaluate the objective response rate (ORR), overall survival (OS), and safety. RESULTS: Baseline characteristics were similar between groups, except for a higher incidence of Vp4 portal vein thrombosis in group A (78.6% vs. 21.4%, P = .05). Group A achieved a higher ORR (50.0% vs. 11.8%, P < .01) and a longer OS (not reached vs. 5.5 months, P = .01) after a median follow-up of 5.2 months. Multivariate analysis indicated that concurrent RT independently favored longer OS (hazard ratio: 0.18; 95% CI, 0.05-0.63, P < .01). Group A did not increase any grade adverse events (78.6% vs. 58.8%, P = .19) or severe adverse events of grade ≥ 3 (14.3% vs. 14.7%, P = .97) compared to group B. CONCLUSIONS: The concurrent high-dose external beam radiotherapy appears to safely enhance the effectiveness of atezolizumab plus bevacizumab for highly advanced patients with HCC. Further studies are warranted to confirm these findings.

Subsequent locoregional therapy prolongs survival in progressive hepatocellular carcinoma patients under lenvatinib treatment.

BACKGROUND: Locoregional therapy and multi-kinase inhibitor agent have been the backbone of treatment for hepatocellular carcinoma (HCC) patients. However, the effect of combination or sequential use of locoregional therapy on HCC patients receiving multi-kinase inhibitor remain uncertain. Therefore, we aim to explore whether the subsequent locoregional therapy provides better survival in HCC patients under lenvatinib treatment. METHODS: From March 2018 to April 2020, a total of 78 unresectable HCC patients receiving lenvatinib were recruited. Image response was evaluated by dynamic image using the modified RECIST criteria. Among patients with tumor progression under lenvatinib treatment, whether receiving subsequent locoregional therapy or not were documented. Overall survival between two groups and the predictors for tumor progression were also analyzed. RESULTS: Among the 78 patients receiving lenvatinib, the median age was 67.8 years old, and 69.2 % were male. Forty-four patients (56.4 %) experienced tumor progression with time to progression 5.1 months (95 % confidence interval (CI): 4.7-6.8) months. In multivariable Cox regression analysis, albumin-bilirubin (ALBI) grade II (adjusted HR: 2.883, P = 0.0104), and treatment duration less than three months (adjusted HR: 3.801, P = 0.0014) were the independent predictive factors for tumor progression, while patients achieving objective response under lenvatinib treatment within 12 weeks was the independent protective factor for tumor progression (adjusted HR: 0.144, P = 0.0020). Among the 44 patients with tumor progression, twenty-six (59.1 %) patients received subsequent locoregional therapy after tumor progression. Comparing to those with tumor progression without locoregional treatment, patients who received subsequent locoregional therapy had significantly better survival (1st year cumulative survival rate 70 % vs 27 %, log-rank P = 0.003). CONCLUSION: ALBI grade, treatment duration of lenvatinib, and achieving objective image response within twelve weeks were the independent predictive factors for tumor progression. Furthermore, longer overall survival was observed in tumor progression patients with subsequent locoregional therapy and with better liver preserved function.

Electroacupuncture prevents the development or establishment of chronic pain via IL-33/ST2 signaling in hyperalgesic priming model rats.

BACKGROUND: Chronic pain is acomplexhealth issue. Compared to acute pain, which has a protective value, chronic pain is defined as persistent pain after tissue injury. Few clinical advances have been made to prevent the transition from acute to chronic pain. Electroacupuncture (EA), the most common form of acupuncture, is widely used in clinical practice to relieve pain. METHODS: The hyperalgesic priming model, established via a carrageenan injection followed by a prostaglandin E2 injection, was used to investigate the development or establishment of chronic pain. We observed the hyperalgesic effect of EA on rats and investigated the expression p38 mitogen-activated protein kinase, interleukin-33 (IL-33), and its receptor ST2 in astrocytes in the L4-L6 spinal cord dorsal horns (SDHs) after EA. The IL-33/ST2 signaling pathway in SDH is associated with the development of chronic pain. RESULTS: EA can reverse the pain threshold in hyperalgesic priming model rats and regulates the expression of phosphorylated p38, IL-33, and ST2 in astrocytes in the L4-L6 SDHs. We discovered that EA raises the pain threshold. This suggests that EA can prevent the development or establishment of chronic pain by inhibiting IL-33/ST2 signaling in the lower central nervous system. CONCLUSIONS: EA can alleviate the development or establishment of chronic pain by modulating IL-33/ST2 signaling in SDHs. Our findings will help clinicians understand the mechanisms of EA analgesia.

A combination of locoregional treatment with systemic therapy after atezolizumab plus bevacizumab failure for unresectable hepatocellular carcinoma provides survival benefit.

Atezolizumab plus bevacizumab (A+B) is used to treat unresectable hepatocellular carcinoma (HCC), but the optimal rescue therapy after A+B remains unclear. Combining locoregional therapy (LRT) with systemic treatment has been shown to improve tumor control, but the role in patients who fail A+B is unknown. We retrospectively enrolled patients who experienced radiological progression after A+B. Objective response rate (ORR), disease control rate (DCR), post progression survival (PPS), and secondary progression-free survival (PFS) were evaluated by modified RECIST. Inverse probability weighting (IPW) was used to balance baseline clinical features. A total of 61 patients were enrolled with a median age of 60.7 years, 83.6% male, 88.5% viral hepatitis-related, and 60.7% without prior systemic treatment before A+B. Patients receiving sequential therapies had significantly longer PPS than supportive care (10.5 vs. 2.3 months, P<0.0001). Among 37 patients received sequential systemic treatment, 18 received combined LRT. The median follow-up after post A+B failure was 6.6 months. The combined LRT group had higher ORR (27.8 vs. 0%, P=0.0197) and DCR (72.2 vs. 26.3%, P=0.0052) than systemic alone group. The median PPS and secondary PFS were significantly longer in combined LRT group (PPS: 12.2 vs. 5.8 months, P=0.0070; PFS: 5.0 vs. 2.6 months, P=0.0134) than systemic alone group. After IPW analysis, patients with combined LRT had superior PPS and secondary PFS. The incidence rates of AEs were higher in LRT combination compared to systemic alone (any grade AEs: 94.4 vs. 63.2%, P=0.0422; severe AEs: 33.3 vs. 5.3%, P=0.0422). No significant albumin-bilirubin index changed in the first 3 months in combined LRT group (0.966 [0.647-1.443], P=0.867) though a trend of deterioration in systemic alone group. In conclusion, sequential systemic therapy provides survival benefits after A+B failure. Furthermore, combining LRT with systemic treatment could provide better tumor responses and survival benefits with acceptable toxicity than systemic therapy alone.

The Extended Surgical Concepts for Hepatocellular Carcinoma in the Era of Immune Checkpoint Inhibitors.

Surgical resection remains one of the most effective curative therapies for HCC. However, the majority of patients have advanced unresectable diseases upon presentation. It is of paramount importance to raise the resectability of patients with HCC. The remarkable objective response rate reported by Phase III IMbrave150 trial has led to the concept of "Atezo/Bev followed by curative conversion (ABC conversion)" for initially unresectable HCC. With this revolutionary treatment strategy, the concept of surgical resection for HCC should be amended. The current opinion illustrated three extended surgical concepts, which could be integrated into clinical practice in the era of immune checkpoint inhibitors (ICI).

Adding nutritional status to the original BCLC stage improves mortality prediction for hepatocellular carcinoma patients in HBV-endemic regions.

Hepatocellular carcinoma (HCC) is associated with high mortality, especially in Asian populations where chronic HBV infection is a major cause. Accurate prediction of mortality can assist clinical decision-making. We aim to (i) compare the predicting ability of Barcelona Clinic Liver Cancer classification (BCLC) stage, neutrophil-to-lymphocyte ratio (NLR), and Albumin-Bilirubin (ALBI) score in predicting short-term mortality (one- and two-year) and (ii) develop a novel model with improved accuracy compared to the conventional models. This study enrolled 298 consecutive HCC patients from our hepatology department. The prognostic values for mortality were assessed by area under the receiver operating characteristic curve (AUROC) analysis. A novel model was established and internally validated using 5-fold cross-validation, followed by external validation in a cohort of 100 patients. The primary etiology of cirrhosis was hepatitis B virus (HBV), with 81.2% of HCC patients having preserved liver function. Significant differences were observed in hemoglobin (Hb) and serum albumin levels, which reflect patients' nutrition status, between patients who survived for one year and those who died. BCLC exhibited superior predictive accuracy compared to NLR but had borderline superiority to the ALBI score. Therefore, a novel model incorporating BCLC, Hb, and serum albumin was developed, internally and externally validated, as well as subgroup sensitivity analysis. The model exhibited significantly higher predictive accuracy for one- and two-year mortality than conventional prognostic predictors, with AUROC values of 0.841 and 0.805, respectively. The novel "BCLC-Nutrition Model", which incorporates BCLC, Hb, and serum albumin, may provide improved predictive accuracy for short-term mortality in HCC patients compared to commonly used prognostic scores. This emphasizes the importance of nutrition in the management of HCC patients.

Combination of systemic immune-inflammation index and albumin-bilirubin grade predict prognosis of regorafenib in unresectable hepatocellular carcinoma.

Regorafenib improved prognosis for unresectable hepatocellular carcinoma (uHCC) after sorafenib treatment failure. We aimed to investigate prognostic value of combining systemic inflammatory markers with liver function evaluation in patients receiving sorafenib-regorafenib sequential therapy. A total of 122 uHCC patients who received sorafenib-regorafenib sequential therapy were retrospectively enrolled for analysis. The pre-treatment preserving liver function and six inflammatory indexes were collected. The Cox regression model was used to identify independent predictors of progression-free survival (PFS) and overall survival (OS). Baseline ALBI grade I (hazard ratio (HR) = 0.725, P = 0.040 for PFS; HR = 0.382, P = 0.012 for OS) and systemic inflammatory index (SII) ≤ 330 (HR = 0.341, P = 0.017 for OS; HR = 0.485, P = 0.037 for OS) were identified as independent prognostic factors in multivariable analysis and were used to develop the scoring system. Patients who fulfilled both criteria (2 points; score-high) had the longest median PFS (not-reached) and OS (not-reached), followed by fulfilling 1 criterion (1 point; score-intermediate; PFS: 3.7 months and OS: 17.9 months), and patients fulfilled no criterion (0 point; score-low; PFS: 2.9 months, overall log-rank P = 0.001 and OS: 7.5 months, overall log-rank P = 0.003). Additionally, best radiological response was significantly higher in patients with score-high (complete response/partial response/stable disease/progressive disease: score-high: 5.9%/5.9%/58.8%/29.4% vs. score-intermediate: 0%/14.0%/44.2%/41.9% vs. score-low: 0%/0%/25.0%/75.0%; P = 0.011). In conclusion, a combination of baseline ALBI grade and SII index can be used as a simple and powerful parameter to predict prognosis of uHCC patients receiving regorafenib after sorafenib-refractory treatment. The score may help with patient counseling but requires prospective validation.

Factors predictive of clinical outcome in advanced hepatocellular carcinoma patients receiving ramucirumab treatment: A real-world experience.

PURPOSE: The aim of this study was to investigate the factors predictive of clinical outcome in advanced hepatocellular carcinoma patients receiving ramucirumab treatment. METHODS: We conducted a retrospective study using a multi-institutional electronic medical records database in Taiwan. We included advanced HCC patients newly receiving ramucirumab as second-line or beyond systemic therapy between January 2016 and February 2022. The clinical outcomes were median progression-free survival (PFS) based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST), overall survival (OS) and adverse events. We applied Kaplan-Meier methods to estimate median PFS and OS. Uni-variable and multi-variable Cox regression models were applied to identify the prognostic factors. RESULTS: We included 39 ramucirumab naive users with a median age of 65.5 (IQR: 57.0-71.0) years and treatment time of 5.0 (3.0-7.0) cycles, of whom 82.1% were male and 84.6% were Barcelona Clinic Liver Cancer (BCLC) stage C. After median follow-up time of 6.0 months, 33.3% of patients' AFP level had decreased more than 20% within 12 weeks. The median PFS and OS were 4.1 months and non-reach, respectively. Moreover, tumor burden beyond the up-to-11 criteria (HR: 2.95, 95% CI: 1.04-8.38) and a decrease in estimated glomerular filtration rate of more than 10% within 12 weeks (HR: 0.31, 0.11-0.88) were significantly related to PFS in the multi-variable analysis. No patient discontinued ramucirumab during the treatment on account of side effects. CONCLUSION: Ramucirumab was an effective treatment option with good AFP response for advanced HCC patients in real-world experience. Tumor burden beyond the up-to-11 criteria and a decrease in estimated glomerular filtration rate were independent predictive factors for progression-free survival.

Similar efficacy and safety between lenvatinib versus atezolizumab plus bevacizumab as the first-line treatment for unresectable hepatocellular carcinoma.

BACKGROUND: Lenvatinib and atezolizumab plus bevacizumab(A + B) have been used for unresectable hepatocellular carcinoma (HCC) as first-line therapy. Real-world studies comparison of efficacy and safety in these two regimens are limited, we therefore conduct this study to investigate these issues. METHODS: We retrospectively reviewed patients received lenvatinib (n = 46) and A + B (n = 46) as first-line systemic therapy for unresectable HCC in a tertiary medical center. Objective response rate (ORR), progression free survival (PFS), and overall survival (OS) were evaluated according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Inverse probability weighting (IPW) was performed for baseline clinical features balance. RESULTS: A total of 92 patients with median age of 63.8 year-old, 78.3% male, 85.9% viral hepatitis infected, 67.4% BCLC stage C were enrolled. The median treatment and follow-up duration were 4.7 months and 9.4 months, respectively. There was no significant difference in ORR (26.1% vs. 41.3%, p = 0.1226), PFS (5.9 vs. 5.3 months, p = 0.4066), and OS (not reached vs. not reached, p = 0.7128) between the lenvatinib and A + B groups. After IPW, the results of survival and response rate were also compared. Subgroup analysis suggested that using lenvatinib was not inferior to A + B in regards of PFS, including those with elder, Child-Pugh class B, beyond up-to-seven, or portal vein invasion VP4 patients. Among the lenvatinib treated patients, multivariate analysis showed patients elder than 65-year-old was an independent predictor associated with shorter PFS (adjust HR: 2.085[0.914-4.753], p = 0.0213). The incidence rates of adverse events were similar between two groups (76 vs. 63%, p = 0.1740). Both of two regimens had similarly few impact on liver function by comparison of baseline, third month, and sixth month albumin-bilirubin index and Child-Pugh score. CONCLUSIONS: The efficacy and safety of lenvatinib are similar to A + B as a first-line systemic therapy for unresectable HCC.

Systemic Treatment of Advanced Unresectable Hepatocellular Carcinoma after First-Line Therapy: Expert Recommendations from Hong Kong, Singapore, and Taiwan.

Background: Asia has a high burden of hepatocellular carcinoma (HCC) due to the high rates of chronic hepatitis B infection and accounts for 70% of HCC cases globally. In the past 20 years, the systemic treatment landscape of advanced HCC has evolved substantially - from tyrosine kinase inhibitors to immune-oncology agents plus anti-vascular endothelial growth factor agents. The appropriate sequence of therapies has become critical in optimizing patient outcomes given the increase in systemic therapeutic options. This article evaluates the evidence and provides expert recommendations for the use of systemic therapies after first-line treatment in patients with advanced HCC. Summary: Based on three virtual meetings held in early 2021, a team of 17 experts comprising oncologists, a hepatologist, and a hepatobiliary surgeon from Hong Kong, Singapore, and Taiwan reviewed available data about systemic treatments for HCC after first line and formulated 28 statements. These statements aimed to provide expert guidance on selecting first and subsequent lines of therapies as well as recommending therapies in special circumstances, such as poor liver function, posttransplantation, recent gastrointestinal bleeding, or autoimmune diseases. Data supporting the statements were drawn from clinical trials and real-world studies. The 28 statements were then evaluated anonymously using a 5-point Likert scale, and 24 reached consensus, predefined as achieving 75% agreement. Statements generated covered the selection of first-line systemic therapy, considerations and goals of second-line systemic therapies, treatment selection following first-line therapy, and treatment recommendations following first-line tyrosine kinase inhibitors, immune-oncology monotherapy, or immune-oncology combination therapy. The authors also shared expert opinion on the use of second-line systemic therapy in patients with liver dysfunction, liver transplantation, and recent gastrointestinal or autoimmune disease. Key Messages: These expert statements summarize the latest data and expert opinion on selecting systemic treatment following first-line therapy in patients with unresectable advanced or metastatic HCC.

Combination of CRAFITY score with Alpha-fetoprotein response predicts a favorable outcome of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma.

Immune checkpoint inhibitors (ICIs) with atezolizumab plus bevacizumab are promising agents for unresectable hepatocellular carcinoma (HCC). We tried to guide the treatment based on recent developed CRAFITY score combining with on-treatment AFP response. Eighty-nine patients who received atezolizumab plus bevacizumab regardless of as a first-line therapy or not for unresectable HCC were enrolled for analyses. Radiologic evaluation was based on modified Response Evaluation Criteria in Solid Tumors (mRECIST). The objective response rate (ORR) and disease control rate (DCR) were 25.0% and 65.5%, respectively. Multivariate analysis showed that low CRAFITY score (AFP<100 ng/ml or CRP<10 mg/l) and satisfactory AFP response at 6 weeks (≥75% decrease or ≤10% increase from baseline) were independent factors determining good overall survival (OS) (hazard ratio [HR]=0.143, P=0.002 & HR=0.337, P=0.031), progression-free survival (PFS) (HR=0.419, P=0.022 & HR=0.429, P=0.025) and good responder (odds ratio [OR]=1.763, P=0.044 & OR=3.881, P=0.011). Patients were further divided into three classes by combination of CRAFITY score and AFP response at 6 weeks [The CAR (CRAFITY score and AFP-Response) classification)]: low CRAFITY score with satisfactory AFP response at 6 weeks (class I), either high CRAFITY score or unsatisfactory AFP response at 6 weeks (class II) and high CRAFITY score together with unsatisfactory AFP response at 6 weeks (class III). ORR was 35.0%, 18.2%, and 0% in class I, II and III patients, respectively (overall P=0.034). Patients in the class I had the best OS and PFS, followed by class II and class III (median OS: not reached vs. 11.1 vs. 4.3 months, log-rank P<0.001; median PFS: 7.9 vs. 6.6 vs. 2.6 months, log-rank P=0.001). Combination CRAFITY score and AFP response at 6 weeks with AUROC predicts OS and tumor response to be 0.809 and 0.798, respectively, better than either CRAFITY score (0.771 & 0.750) or AFP response at 6 weeks (0.725 & 0.680) alone. In conclusions, the CAR classification which combining CRAFITY score and AFP response at 6 weeks provides a practical guidance for atezolizumab plus bevacizumab therapy in unresectable HCC patients.

Proton beam radiotherapy combined with anti-PD1/PDL1 immune checkpoint inhibitors for advanced hepatocellular carcinoma.

Anti-Programmed cell Death protein 1 (Anti-PD1) or Programmed Death-Ligand 1 (PDL1) immune checkpoint inhibitors provide treatment options for advanced HCC patients with low response rates. Combination therapy is becoming a major issue to improve the unmet need. Proton beam radiotherapy (PBT) could effectively control the local tumor with a low-risk injury to peripheral liver parenchyma. We retrospectively reviewed the patients who have received PBT combined with anti-PD1/PDL1 to evaluate the efficacy and safety of the advanced HCC patients. This study reviewed 29 advanced HCC patients who have received PBT and anti-PD1/PDL1 during 2016 and 2019. All were Child-Pugh A and performance status 0-1. Seventeen patients (58.6%) had extrahepatic spreading. Concurrent PBT started during anti-PD1/PDL1 with a median of 96.6 grays equivalent dose. The PBT field covered all tumors in 13 (44.8%) patients under curative intent. Other patients (55.2%) received palliative PBT that covered only the principal tumors. All patients have completed the concurrent PBT protocol. The median anti-PD1/PDL1 duration was 3.9 months. After a median follow-up of 13.2 months, the rates of 1-year PBT infield tumor control, 1-year outfield tumor control, and overall response were 90.5%, 90.9%, and 61.5%, and 70.8%, 69.2%, and 43.8%, respectively for curative-intent and palliative-control PBT. Complete response was found in 4 (30.8%) curative-intent and 1 (6.3%) palliative-control patients. The median overall progression-free survival was 27.2 months for curative-intent patients and 15.9 months for palliative-control patients. The overall survival was non-reached for both groups. The ALBI grade and Child-Pugh score change at 3-month and 6-month after PBT initiation were nonsignificant. No unexpected adverse event occurred except nine patients (31.0%) had treatment-related adverse events higher than or equal to Grade 3, including 2 (6.9%) had a radiation-induced liver injury. PBT combined with anti-PD1/PDL1 was safe without unexpected adverse events. The concurrent therapy could effectively treat advanced HCC through sustained local tumor necrosis and effective systemic tumor control for the patients who received curative-intent or palliative-control PBT combined with anti-PD1/PDL1.

AXL and MET in Hepatocellular Carcinoma: A Systematic Literature Review.

Background: Multikinase inhibitors (MKIs) have been shown to improve survival in patients with hepatocellular carcinoma (HCC) compared with placebo. Distinct from other MKIs, cabozantinib has inhibitory activity for both AXL and MET. This review considers the literature elucidating the role of AXL and MET in HCC progression, treatment resistance, and immunomodulation. A systematic search of the PubMed database was conducted on November 16, 2020, and identified a total of 174 search results. A further 36 potentially relevant articles were identified based on the authors' knowledge. After initial screening by title/abstract, 159 underwent full-text screening and we identified 69 original research articles reporting empirical data from in vitro or in vivo models of HCC evaluating the effects of manipulating AXL or MET signaling on tumorigenic behavior. Summary: AXL expression is highly correlated with HCC progression and outcomes and has been reported to be involved in transforming growth factor-ß and the regulation of PI3K/AKT, ERK/MAPK, and CCN proteins. MET protein expression is increased in HCC with the highest histological grade and has been reported to be involved in the regulation of PI3K/AKT, PLCγ/DAG/PKC, and MAPK/ERK signaling. Both AXL and MET are key regulators of sorafenib resistance in HCC. In terms of immunomodulation, there are data to indicate that AXL and MET interact with the immune components of the tumor microenvironment and promote tumorigenesis and treatment resistance. In addition, AXL was found to play a potential role in the development of a protumorigenic neutrophil phenotype in HCC. Combined inhibition of MET and programmed cell death protein resulted in additive reduction of HCC cell growth. Key Messages: AXL and MET play key roles in HCC progression, treatment resistance, and immunomodulation. Continued development of drugs that target these receptor tyrosine kinases appears likely to represent a useful strategy to improve outcomes for patients with HCC.

A Primary Extraskeletal Osteosarcoma of the Spleen: Rare Case Report.

Extraskeletal osteosarcoma is a rare malignant soft-tissue sarcoma that is difficult to diagnose. Surgery is a common treatment, although chemotherapy and radiotherapy are also used. Patients at risk of bleeding can undergo embolization combined with resection. The occurrence of primary splenic extraskeletal osteosarcoma in humans does not seem to have been reported in the literature. A 50-year-old woman who complained of pain in the left upper abdomen for 1 day was initially diagnosed with "splenic hemangioma with a high possibility of rupture and bleeding" and urgently underwent digital subtraction angiography, combined with splenic arteriography and embolization. Abdominal pain worsened 2 days postoperatively, with a hemoglobin level of 106.0 g/L. Consequently, emergency laparotomy combined with splenectomy was performed. The clinical and imaging features, pathological diagnosis, and embolization treatment of this case were analyzed retrospectively. CT of the upper abdomen revealed splenomegaly, an irregular low-density shadow in the spleen, and a flake-like calcification in the lateral margin of the left kidney. Nuclear MRI of the upper abdomen showed splenomegaly and a mass (approximately 8.4 cm × 5.7 cm × 6.3 cm) below the spleen with clear boundaries-this exhibited an uneven signal, which was slightly low in T1-weighted imaging (T1WI) and slightly high in T2-weighted imaging (T2WI). Several small cystic lesions or cystic cavities were observed in the mass, which exhibited a longer T2 signal. During the enhanced scan, the signal of the lesion showed progressive enhancement, and the enhancement range increased in the delayed phase scan, as well as a hematoma below the spleen capsule and calcification below the lesion (nodular T1WI/T2WI hypointense, approximately 3.3 cm × 3.6 cm). Postoperative biopsy pathology showed splenic soft tissue tumor: at low magnification, the multinucleated giant cells were scattered; at medium magnification, osteoclast-like multinucleated giant cells were observed; and at high magnification, lace- or grid-like tumor osteogenesis was detected. Immunohistochemistry showed that the expression of CD31, CD34, F8, s-100, desmin, SMA, and CD99 was negative, whereas the expression of ß-catenin, BCL-2, SATB-2, and P16 was positive. CD68 and MDM-2 showed low expression, while 50% of the cells were positive for Ki-67 expression. No abnormal concentration of radioactivity was found on the bone scan with 99mTc-MDP after the operation, further ruling out the occurrence of other bone tumors. The patient was diagnosed with primary extraskeletal osteosarcoma. It is necessary for multidisciplinary teams to diagnose malignant extraskeletal osteosarcomas.

Soluble form of CTLA-4 is a good predictor for tumor recurrence after radiofrequency ablation in hepatocellular carcinoma patients.

BACKGROUND: A soluble form of cytotoxic-T-lymphocyte-antigen-4 (sCTLA-4) is a prognostic biomarker for several cancers but remains unclear in HCC patients. The aim of study is to evaluate the predictive role of serum sCTLA-4 levels for tumor recurrence of chronic hepatis C (CHC)-HCC patients receiving radiofrequency ablation (RFA). MATERIAL AND METHOD: A prospective study recruiting 88 CHC-HCC patients was done between 2013 and 2019. Cox regression analysis was used to determine the predictors of early recurrence. All tests were two-tailed, and the level of statistical significance was set as p < 0.05. RESULTS: During a median follow-up of 44.4 months, 53 of the 88 (60.2%) CHC-HCC patients encountered early recurrence within 2 years. The predictability of sCTLA-4 for local recurrence (LR) and intrahepatic metastasis (IHM) by 2-years using AUROC curve analysis were 0.740 and 0.715, respectively. Patients with high sCTLA-4 levels (>9 ng/ml) encountered shorter recurrence-free survival (RFS) for LR (log-rank p = 0.017) but paradoxically longer RFS for IHM (log-rank p = 0.007) compared to those with low levels (≤9 ng/ml). By multivariate Cox regression analysis, sCTLA-4 levels and antiviral therapy were independent prognostic factor of early recurrence both in LR and IHM. A combination of baseline sCTLA-4 and AFP level could improve the predictability of early LR and IHM with specificity of 80.0% and 79.7% and positive predictive value of 63.3% and 67.3%, respectively. CONCLUSIONS: sCTLA-4 level is a good predictor for early HCC recurrence with higher levels indicating susceptibility to early LR, but protecting from early IHM.

Proton Beam Therapy in Managing Unresectable Hepatocellular Carcinoma with Bile Duct Invasion.

Hepatocellular carcinoma (HCC) with bile duct invasion is a rare and notorious subtype of HCC. This study included patients that had unresectable HCC with bile duct invasion and proton beam therapy between November 2015 and February 2021. Twenty patients fit the inclusion criteria. The median tumor size was 6.3 cm. Nine patients (45.0%) had major vascular invasions. All included patients received the radiation dose of 72.6 gray relative biological effectiveness due to the proximity of porta hepatis and tumor. The median follow-up time was 19.9 months. The median overall survival was 19.9 months among deceased patients. The 1-year cumulative local recurrence rates were 5.3%, with only two patients developing in-field failure. The 1-year and 2-year overall survival rates were 79.4% and 53.3%. The 1-year progression-free survival was 58.9%. Four patients developed radiation-induced liver disease. The 1-year cholangitis-free survival was 55.0%. Skin toxicity was the most common acute toxicity and rarely severe. Eight patients developed ≤ grade 3 gastrointestinal ulcers. Proton beam therapy offers desirable survival outcomes for unresectable HCC patients with bile duct invasion. Optimal local tumor control could also be obtained within acceptable toxicities.

Dynamic Change of Albumin-Bilirubin Score Is Good Predictive Parameter for Prognosis in Chronic Hepatitis C-hepatocellular Carcinoma Patients Receiving Transarterial Chemoembolization.

Background and Aims: The Albumin-Bilirubin (ALBI) grade is a good index for liver function evaluation and is also associated with the outcomes of hepatocellular carcinoma patients receiving TACE. However, the correlation between the dynamic change to the ALBI score and clinical outcome is seldom discussed. Therefore, this study aimed to investigate the application of ALBI grade and dynamic change of ALBI grade (delta ALBI grade) after first TACE for prognosis prediction in HCC patients with chronic hepatitis C infection. Method: From January 2005 to December 2015, newly diagnosed naive chronic hepatitis C-hepatocellular carcinoma (CHC-HCC) patients who were treated with TACE as the initial treatment at the Chang Gung Memorial Hospital, Linkou Medical Center, were retrospectively recruited. The pre-treatment host factors, tumor status and noninvasive markers were collected. The Cox regression model was used to identify independent predictors of overall survival and tumor recurrence. Results: Among 613 treatment-naive CHC-HCC patients, 430 patients died after repeated TACE during a median follow-up of 26.9 months. Complete remission after repeated TACE occurred in 46.2% patients, and 208 patients (33.9%) had tumor recurrence, with a median recurrence-free interval of 8.5 months. In Cox regression analysis, ALBI grade II/III (aHR: 1.088, p = 0.035) and increased delta ALBI grade (aHR: 1.456, p = 0.029) were independent predictive factors for tumor recurrence. Furthermore, ALBI grade II/III (aHR: 1.451, p = 0.005) and increased delta ALBI grade during treatment (aHR: 1.436, p = 0.006) were predictive factors for mortality, while achieving complete response after repeated TACE (aHR: 0.373, p < 0.001) and anti-viral therapy (aHR: 0.580, p = 0.002) were protective factors for mortality. Conclusion: Both ALBI and delta ALBI grade are independent parameters to predict survival and tumor recurrence of CHC-HCC patients receiving TACE treatment.