Lenvatinib radiofrequency ablation sequential therapy offers survival benefits for patients with unresectable hepatocellular carcinoma at intermediate stage and the liver reserve of Child-Pugh A category: A multicenter study.

AIM: This study aims to evaluate the efficacy and safety of lenvatinib radiofrequency ablation (RFA) sequential therapy for certain hepatocellular carcinoma (HCC) patients. METHODS: One hundred and nineteen patients with unresectable HCC in the intermediate stage with Child-Pugh A were retrospectively recruited in a multicenter setting. Those in the lenvatinib RFA sequential therapy group received lenvatinib initially, followed by RFA and the retreatment with lenvatinib. The study compared overall survival (OS), progression-free survival (PFS), tumor response, and adverse events (AEs) between patients undergoing sequential therapy and lenvatinib monotherapy. RESULTS: After propensity score matching, 25 patients on sequential therapy and 50 on monotherapy were evaluated. Independent factors influencing OS were identified as sequential therapy, modified albumin-bilirubin (mALBI) grade, and relative dose intensity (%) with hazard ratios (HRs) of 0.381 (95% confidence interval [CI], 0.186-0.782), 2.220 (95% CI, 1.410-3.493), and 0.982 (95% CI, 0.966-0.999), respectively. Stratified analysis based on mALBI grades confirmed the independent influence of treatment strategy across all mALBI grades for OS (HR, 0.376; 95% CI, 0.176-0.804). Furthermore, sequential therapy was identified as an independent factor of PFS (HR, 0.382; 95% CI, 0.215-0.678). Sequential therapy significantly outperformed monotherapy on survival benefits (OS: 38.27 vs. 18.96 months for sequential therapy and monotherapy, respectively, p = 0.004; PFS: 13.80 vs. 5.32 months for sequential therapy and monotherapy, respectively, p < 0.001). Sequential therapy was significantly associated with complete response by modified Response Evaluation Criteria in Solid Tumors (odds ratio, 63.089). Ten of 119 patients experienced grade 3 AEs, with no AE beyond grade 3 observed. CONCLUSION: Lenvatinib RFA sequential therapy might offer favorable tolerability and potential prognostic improvement compared to lenvatinib monotherapy.

Clinical significance of circulating biomarkers of immune-checkpoint molecules with atezolizumab plus bevacizumab therapy in unresectable hepatocellular carcinoma.

BACKGROUND: The aims of this study were to identify clinically significant biomarkers of a response to atezolizumab plus bevacizumab (ATZ + BV) therapy and to develop target strategies against unresectable hepatocellular carcinoma (u-HCC). METHOD: We first investigated the potential of circulating tumor DNA (ctDNA) to serve as a biomarker for predicting the therapeutic outcome in 24 u-HCC patients treated with ATZ + BV therapy. Next, we analyzed levels of immune-related cytokines in blood samples from 134 u-HCC patients who received ATZ + BV. For this, serum immune-related molecules or cancer-immune cycle-related molecules that have been reported in HCC patient sera, namely CD274, LAG-3, CCL2, 4, 5, CXCL1, 9, 10, 12, 13, CX3CL1, CCR5, IFNγ and IL-6, 8 were measured using enzyme-linked immunosorbent assay. RESULTS: More than 1% of variant read frequency (VRF) mutations were found in TP53, APC, PIK3CA and VHL, although with no correlation with treatment response. Among the 15 cytokines evaluated, CXCL9 and LAG-3 levels were significantly different between patients with objective response (OR), stable disease (SD), and progressive disease (PD) following ATZ + BV treatment. Receiver-operating characteristic curve analyses of CXCL9 (cut-off value: 419.1 pg/ml) and LAG-3 (cut-off value: 3736.3 pg/ml) indicated areas of 0.779 and 0.697, respectively, for differentiating PD from non-PD and OR from non-OR. In multivariate analysis of progression-free survival (PFS) and overall survival (OS), high serum CXCL9 (hazard ratio (HR) and 95% confidence interval (CI): 0.412 (0.251-0.677) (p = 0.0005) for PFS and 0.252 (0.125-0.508) (p = 0.0001) for OS), and low serum LAG-3 (HR and 95% CI 0.419 (0.249-0.705) (p = 0.0011) for PFS and 0.294 (0.140-0.617) (p = 0.0012) for OS) were independent positive predictive factors. CONCLUSION: Although, as far as we examined, no ctDNA mutations in blood were found to be related to ATZ + BV treatment efficacy, serum CXCL9 and LAG-3 levels, which are related to the cancer-immune cycle, were associated with treatment efficacy and could be predictive markers of the efficacy of ATZ + BV treatment in HCC patients.

Establishment of nomogram prediction model of contrast-enhanced ultrasound and Gd-EOB-DTPA-enhanced MRI for vessels encapsulating tumor clusters pattern of hepatocellular carcinoma.

To establish clinical prediction models of vessels encapsulating tumor clusters (VETC) pattern using preoperative contrast-enhanced ultrasound (CEUS) and gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging (EOB-MRI) in patients with hepatocellular carcinoma (HCC). A total of 111 resected HCC lesions from 101 patients were included. Preoperative imaging features of CEUS and EOB-MRI, postoperative recurrence, and survival information were collected from medical records. The best subset regression and multivariable Cox regression were used to select variables to establish the prediction model. The VETC-positive group had a statistically lower survival rate than the VETC-negative group. The selected variables were peritumoral enhancement in the arterial phase (AP), hepatobiliary phase (HBP) on EOB-MRI, intratumoral branching enhancement in the AP of CEUS, intratumoral hypoenhancement in the portal phase of CEUS, incomplete capsule, and tumor size. A nomogram was developed. High and low nomogram scores with a cutoff value of 168 points showed different recurrence-free survival rates and overall survival rates. The area under the curve (AUC) and accuracy were 0.804 and 0.820, respectively, indicating good discrimination. Decision curve analysis showed a good clinical net benefit (threshold probability > 5%), while the Hosmer-Lemeshow test yielded excellent calibration (P = 0.6759). The AUC of the nomogram model combining EOB-MRI and CEUS was higher than that of the models with EOB-MRI factors only (0.767) and CEUS factors only (0.7). The nomogram verified by bootstrapping showed AUC and calibration curves similar to those of the nomogram model. The Prediction model based on CEUS and EOB-MRI is effective for preoperative noninvasive diagnosis of VETC.

Multicenter Phase II Trial of Lenvatinib plus Hepatic Intra-Arterial Infusion Chemotherapy with Cisplatin for Advanced Hepatocellular Carcinoma: LEOPARD.

Introduction: Hepatic arterial infusion chemotherapy (HAIC) with cisplatin and lenvatinib exhibits strong antitumor effects against advanced hepatocellular carcinoma (HCC). Higher antitumor activity is expected for the combination treatment. The aim of this trial was to evaluate the efficacy and safety of lenvatinib in combination with HAIC using cisplatin in patients with advanced HCC. Methods: In this multicenter, open-labeled, single-arm, phase II trial, patients with advanced HCC categorized as Child-Pugh class A with no prior history of systemic therapy were enrolled. Patients received lenvatinib plus HAIC with cisplatin (lenvatinib: 12 mg once daily for patients ≥60 kg, 8 mg once daily for patients <60 kg; HAIC with cisplatin: 65 mg/m2, day 1, every 4-6 weeks, maximum of six cycles). The primary endpoint was the objective response rate (ORR) assessed using modified RECIST by the Independent Review Committee. The secondary endpoints were the ORR assessed using RECIST v1.1, progression-free survival, overall survival, and frequency of adverse events associated with the treatment. Results: A total of 36 patients were enrolled between September 2018 and March 2020. In the 34 evaluable patients, the ORR assessed by the Independent Review Committee using modified RECIST and RECIST v1.1 were 64.7% (95% confidence interval [CI]: 46.5-80.3%) and 45.7% (95% CI: 28.8-63.4%), respectively. The median progression-free survival and overall survival were 6.3 months (95% CI: 5.1-7.9 months) and 17.2 months (95% CI: 10.9 - not available, months), respectively. The main grade 3-4 adverse events were increased aspartate aminotransferase (34%), leukopenia (22%), increased alanine aminotransferase (19%), and hypertension (11%). Conclusion: Lenvatinib plus HAIC with cisplatin yielded a favorable ORR and overall survival and was well tolerated in patients with advanced HCC. Further evaluation of this regimen in a phase III trial is warranted.

Differential Diagnosis of Solid Pancreatic Lesions Using Detective Flow Imaging Endoscopic Ultrasonography.

The differential diagnosis of solid pancreatic lesions (SPLs) using B-mode endoscopic ultrasonography (EUS) is challenging. Detective flow imaging (DFI) offers the potential for detecting low-flow vessels in the pancreas, thus enhancing diagnostic accuracy. This retrospective study aimed to investigate DFI-EUS findings of SPLs and analyze their differential diagnostic accuracy for pancreatic cancer. We included 104 patients with pathologically confirmed SPLs who underwent EUS between April 2021 and June 2023. Expert endosonographers, blinded to the patients' clinical data, evaluated images obtained through B-mode, eFLOW, and DFI-EUS. The frame rate and vessel detection sensitivity were compared between eFLOW and DFI, and the diagnostic criteria for pancreatic cancer were established. The visualization rate for vessels in SPLs was significantly higher with DFI-EUS (96%) compared to eFLOW (27%). Additionally, DFI showed a superior frame rate, sensitivity (99%), and accuracy (88%) for detecting pancreatic cancer, although with a modest specificity (43%). On DFI-EUS, characteristics such as hypovascularity, peritumoral vessel distribution, or spotty vessel form were suggestive of pancreatic cancer. DFI-EUS significantly improved the visualization of vascular structures within the SPLs, highlighting its efficacy as a diagnostic modality for pancreatic cancer.

Progression pattern and post-progression survival following atezolizumab and bevacizumab treatment in advanced hepatocellular carcinoma.

BACKGROUND: Although the combination of atezolizumab and bevacizumab (ATZ + BEV) is a standard treatment for advanced hepatocellular carcinoma (HCC), strategies for addressing treatment failure and prognostic factors of post-progression survival (PPS) remain unestablished. METHODS: We conducted a multicentre retrospective study to evaluate PPS following ATZ + BEV treatment in patients with advanced HCC. We classified the patients into three groups: BCLC stage B and BCLC stage C without or with new extrahepatic lesions (BCLCp-C1 and BCLCp-C2, respectively) at the time of progression. RESULTS: Of the 204 patients who started ATZ + BEV treatment between October 2020 and September 2022, 110 showed disease progression, with 33, 55 and 22 showing the BCLCp-B, BCLCp-C1 and BCLCp-C2 stages of the disease, respectively. Specifically, patients with the BCLCp-B stage of the disease showed better overall survival than those with the BCLCp-C1 and BCLCp-C2 stages (hazard ratios: 1.93 [95% confidence interval, CI, 1.06-3.51] and 2.64 [95% CI, 1.32-5.30] for HCC stages BCLCp-C1 and BCLCp-C2, respectively). Via multivariable analysis, we identified the BCLCp-C1 and BCLCp-C2 stages, as well as performance status, Child-Pugh class and alpha-fetoprotein as poor prognostic factors for PPS. CONCLUSIONS: BCLCp-B1 stage was identified as a better prognostic factor for PPS following ATZ + BEV treatment compared with BCLCp-C1 and BCLCp-C2 stages. This may help in making decisions regarding subsequent treatment after ATZ + BEV.

Serum MYCN as a predictive biomarker of prognosis and therapeutic response in the prevention of hepatocellular carcinoma recurrence.

The proto-oncogene MYCN expression marked a cancer stem-like cell population in hepatocellular carcinoma (HCC) and served as a therapeutic target of acyclic retinoid (ACR), an orally administered vitamin A derivative that has demonstrated promising efficacy and safety in reducing HCC recurrence. This study investigated the role of MYCN as a predictive biomarker for therapeutic response to ACR and prognosis of HCC. MYCN gene expression in HCC was analyzed in the Cancer Genome Atlas and a Taiwanese cohort (N = 118). Serum MYCN protein levels were assessed in healthy controls (N = 15), patients with HCC (N = 116), pre- and post-surgical patients with HCC (N = 20), and a subset of patients from a phase 3 clinical trial of ACR (N = 68, NCT01640808). The results showed increased MYCN gene expression in HCC tumors, which positively correlated with HCC recurrence in non-cirrhotic or single-tumor patients. Serum MYCN protein levels were higher in patients with HCC, decreased after surgical resection of HCC, and were associated with liver functional reserve and fibrosis markers, as well as long-term HCC prognosis (>4 years). Subgroup analysis of a phase 3 clinical trial of ACR identified serum MYCN as the risk factor most strongly associated with HCC recurrence. Patients with HCC with higher serum MYCN levels after a 4-week treatment of ACR exhibited a significantly higher risk of recurrence (hazard ratio 3.27; p = .022). In conclusion, serum MYCN holds promise for biomarker-based precision medicine for the prevention of HCC, long-term prognosis of early-stage HCC, and identification of high-response subgroups for ACR-based treatment.

Novel peroral cholangioscopy-guided electrohydraulic lithotripsy for difficult stones.

Miwa and colleagues report on their experience with a newly developed peroral cholangioscope that is effective for the removal of difficult stones in the common bile duct and the cystic duct. The scope offers a large working channel and a high mobility bending section, increasing the efficacy of electrohydraulic lithotripsy.

Case Report: The value of contrast-enhanced ultrasound and contrast-enhanced computed tomography in the diagnosis of hepatic angiosarcoma.

Background: Enhanced imaging techniques have the overwhelming advantages of being noninvasive and sensitive enough to evaluate the microcirculation of lesions, thus making them accurate in the diagnosis of hepatic lesions. Unfortunately, there is very little research on and knowledge of the imaging features of a rare cancerous condition: hepatic angiosarcoma (HA). Case summary: In this study, we retrospectively collected the data of six patients who underwent both contrast-enhanced ultrasound (CEUS) and contrast-enhanced computed tomography (CECT), and subsequently obtained a definitive histopathologic diagnosis of HA. We described the imaging appearances of HA by comparing CEUS and CECT images. Furthermore, we analyzed these imaging characteristics from the perspective of histopathology and tumorigenesis. The study included the largest number (six) of histopathologically confirmed HA patients who had received CEUS examinations to date. Conclusion: By offering readers comprehensive knowledge of contrast imaging, especially CEUS, in the diagnosis of HA, our study may reduce misdiagnosis and further improve treatment options.

Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: No adjuvant treatment has been established for patients who remain at high risk for hepatocellular carcinoma recurrence after curative-intent resection or ablation. We aimed to assess the efficacy of adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with high-risk hepatocellular carcinoma. METHODS: In the global, open-label, phase 3 IMbrave050 study, adult patients with high-risk surgically resected or ablated hepatocellular carcinoma were recruited from 134 hospitals and medical centres in 26 countries in four WHO regions (European region, region of the Americas, South-East Asia region, and Western Pacific region). Patients were randomly assigned in a 1:1 ratio via an interactive voice-web response system using permuted blocks, using a block size of 4, to receive intravenous 1200 mg atezolizumab plus 15 mg/kg bevacizumab every 3 weeks for 17 cycles (12 months) or to active surveillance. The primary endpoint was recurrence-free survival by independent review facility assessment in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04102098. FINDINGS: The intention-to-treat population included 668 patients randomly assigned between Dec 31, 2019, and Nov 25, 2021, to either atezolizumab plus bevacizumab (n=334) or to active surveillance (n=334). At the prespecified interim analysis (Oct 21, 2022), median duration of follow-up was 17·4 months (IQR 13·9-22·1). Adjuvant atezolizumab plus bevacizumab was associated with significantly improved recurrence-free survival (median, not evaluable [NE]; [95% CI 22·1-NE]) compared with active surveillance (median, NE [21·4-NE]; hazard ratio, 0·72 [adjusted 95% CI 0·53-0·98]; p=0·012). Grade 3 or 4 adverse events occurred in 136 (41%) of 332 patients who received atezolizumab plus bevacizumab and 44 (13%) of 330 patients in the active surveillance group. Grade 5 adverse events occurred in six patients (2%, two of which were treatment related) in the atezolizumab plus bevacizumab group, and one patient (<1%) in the active surveillance group. Both atezolizumab and bevacizumab were discontinued because of adverse events in 29 patients (9%) who received atezolizumab plus bevacizumab. INTERPRETATION: Among patients at high risk of hepatocellular carcinoma recurrence following curative-intent resection or ablation, recurrence-free survival was improved in those who received atezolizumab plus bevacizumab versus active surveillance. To our knowledge, IMbrave050 is the first phase 3 study of adjuvant treatment for hepatocellular carcinoma to report positive results. However, longer follow-up for both recurrence-free and overall survival is needed to assess the benefit-risk profile more fully. FUNDING: F Hoffmann-La Roche/Genentech.

Impact of body composition for patients with hepatocellular carcinoma who received atezolizumab plus bevacizumab therapy.

OBJECTIVE: To investigate the association between body composition and prognosis in patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab. METHODS: This cohort study analysed 119 patients who received atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. We investigated the association between body composition and progression-free survival and overall survival. Body composition was quantified by the visceral fat index, subcutaneous fat index, and skeletal muscle index. A high or low index score was defined as that above or below the median of these indices. RESULTS: Poor prognosis was observed in the low visceral fat index and low subcutaneous fat index groups. The mean progression-free survival in the low visceral fat index and low subcutaneous fat index groups vs. the other groups were 194 and 270 days, respectively [95% confidence interval (CI), 153-236 and 230-311 days, respectively; P = 0.015], while the mean overall survival was 349 vs. 422 days, respectively (95% CI, 302-396 and 387-458 days, respectively; P = 0.027). In the multivariate analysis, both a low subcutaneous fat index and low visceral fat index were statistically associated with lower progression-free and overall survival rates [hazard ratio (HR) 1.721; 95% CI, 1.101-2.688; P = 0.017; and HR 2.214; 95% CI, 1.207-4.184; P = 0.011, respectively]. CONCLUSION: Low visceral fat index and subcutaneous fat index scores were independent predictors of poor prognosis in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

Loop technique for guidewire manipulation during endoscopic ultrasound-guided hepaticogastrostomy.

Background and Aim: Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) is widely used in the management of biliary obstructions; however, literature on guidewire manipulation is lacking. This study aimed to assess the utility and optimal conditions of the loop technique for guidewire manipulation during EUS-HGS. Methods: Consecutive patients who underwent EUS-HGS between April 2015 and January 2022 were included in this study. Patient characteristics and procedural details were retrospectively analyzed. Guidewire manipulations were classified as conventional technique or loop technique, based on the shape of the guidewire tip. Results: A total of 52 patients (Median age: 73 years, 38 male and 14 female) underwent EUS-HGS. The median guidewire insertion time was 49 s and the median overall procedure time was 20.5 min. The initial guidewire direction was toward the peripheral side in 23 patients (44%). Technical success rate of the EUS-HGS was 100%. Twenty patients (38%) underwent the procedure using the loop technique and 32 (62%) with the conventional technique. In the logistic regression analysis, an angle between the bile duct and needle of >70° was independently associated with use of the loop technique (OR 9.84; 95% CI: 2.24-43.13; P <0.01). Conclusion: This study revealed the utility of the loop technique in EUS-HGS. This technique is recommended if the bile duct is punctured at an angle >70°.

Study on method of organ section retention and tracking through deep learning in automated diagnostic and therapeutic robotics.

PURPOSE: In high-intensity focused ultrasound (HIFU) treatment of the kidney and liver, tracking the organs is essential because respiratory motions make continuous cauterization of the affected area difficult and may cause damage to other parts of the body. In this study, we propose a tracking system for rotational scanning, and propose and evaluate a method for estimating the angles of organs in ultrasound images. METHODS: We proposed AEMA, AEMAD, and AEMAD++ as methods for estimating the angles of organs in ultrasound images, using RUDS and a phantom to acquire 90-degree images of a kidney from the long-axis image to the short-axis image as a data set. Six datasets were used, with five for preliminary preparation and one for testing, while the initial position was shifted by 2 mm in the contralateral axis direction. The test data set was evaluated by estimating the angle using each method. RESULTS: The accuracy and processing speed of angle estimation for AEMA, AEMAD, and AEMAD++ were 23.8% and 0.33 FPS for AEMAD, 32.0% and 0.56 FPS for AEMAD, and 29.5% and 3.20 FPS for AEMAD++, with tolerance of ± 2.5 degrees. AEMAD++ offered the best speed and accuracy. CONCLUSION: In the phantom experiment, AEMAD++ showed the effectiveness of tracking the long-axis image of the kidney in rotational scanning. In the future, we will add either the area of surrounding organs or the internal structure of the kidney as a new feature to validate the results.

Multicenter retrospective study of stereotactic body radiotherapy for patients with previously untreated initial small hepatocellular carcinoma.

AIM: We aimed to verify the therapeutic efficacy and safety of stereotactic body radiotherapy (SBRT) for previously untreated initial small hepatocellular carcinoma (HCC) in a multicenter, retrospective study. METHODS: Patients who underwent SBRT for HCC at the Japanese Society of Clinical Oncology (JCOG) member hospitals in Japan between July 2013 and December 2017 and met the following eligibility criteria were included: (1) initial HCC; (2) ≤3 nodules, ≤5 cm in diameter; (3) Child-Pugh score of A or B; and (4) unsuitability for or refusal of standard treatment. We analyzed the overall survival, recurrence-free survival, and cumulative incidence of local recurrence rate, and adverse events directly related to SBRT. RESULTS: Seventy-three patients with 79 lesions from 14 hospitals were analyzed. The median age was 77 years (range: 50-89 years), and the median tumor size was 23 mm (range: 6-50 mm). The median radiation dose was 40 Gy (range: 35-60 Gy) in five fractions (range: 4-8). The median follow-up period was 45 months (range: 0-103 months). The 3-year overall survival, recurrence-free survival, and cumulative incidence of local recurrence rates were 69.9% (95% CI: 58.7%-81%), 57.9% (95% CI: 45.2%-70.5%), and 20.0% (95% CI: 11.2%-30.5%), respectively. Four cases (5.5%) of adverse events of grade 3 or higher were reported: three cases of grade 3 and one case of grade 4 (duodenal ulcer). No grade 5 toxicities were observed. CONCLUSION: SBRT is a promising treatment modality, particularly for small HCCs, as they are not suitable for standard treatment.

Association Between Immune-Related Adverse Events and Survival in Patients with Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are effective for advanced hepatocellular carcinoma (HCC). However, there are few reports on the correlation between the clinical efficacy of ICIs and the development of immune-related adverse events (irAEs) in patients with HCC. The aim of this study was to investigate the association between irAE development and survival in patients with HCC treated with atezolizumab plus bevacizumab. PATIENTS AND METHODS: We enrolled 150 patients with advanced HCC treated with atezolizumab plus bevacizumab between October 2020 and October 2021 at 5 territorial institutions. We compared the efficacy of atezolizumab plus bevacizumab between patients who experienced irAEs (irAE group) and those who did not (non-irAE group). RESULTS: Thirty-two patients (21.3%) developed irAEs of any grade. Grade 3/4 irAEs were observed in 9 patients (6.0%). The median progression-free survivals (PFS) in the irAE and non-irAE groups were 273 and 189 days, respectively (P = .055). The median overall survivals (OS) in the irAE and non-irAE groups were not reached and 458 days, respectively (P = .036). Grade 1/2 irAEs significantly prolonged PFS (P = .014) and OS (P = .003). Grade 1/2 irAEs were significantly associated with PFS (hazard ratio [HR], 0.339; 95% confidence interval [CI], 0.166-0.691; P = .003) and OS (HR, 0.086; 95% CI, 0.012-0.641; P = .017) on multivariate analysis. CONCLUSION: The development of irAEs was associated with increased survival in a real-world population of patients with advanced HCC treated with atezolizumab plus bevacizumab. Grade 1/2 irAEs were strongly correlated with PFS and OS.

Cabozantinib in Japanese patients with advanced hepatocellular carcinoma: Final results of a multicenter phase II study.

AIM: Cabozantinib showed a favorable benefit-risk profile in Japanese patients with advanced hepatocellular carcinoma (HCC) in an open-label, phase II study (NCT03586973). This analysis presents cumulative data to final database lock. METHODS: Patients with previously treated, advanced HCC received cabozantinib 60 mg/day. Progression-free survival (PFS) and tumor response rates in prior-sorafenib and sorafenib-naïve cohorts were assessed by independent radiology committee (IRC) and an investigator. Liver function was evaluated by albumin-bilirubin (ALBI) score. RESULTS: Median cabozantinib exposure was 5.6 months. In the prior-sorafenib cohort (n = 20), median PFS was 7.4 months per IRC assessment and 5.6 months per investigator assessment. In the sorafenib-naïve cohort (n = 14), median PFS was 3.6 and 4.4 months per IRC and investigator assessment, respectively. Six-month PFS rate per IRC and investigator assessment in the prior-sorafenib cohort was 59.8% and 49.5%, respectively, and in the sorafenib-naïve cohort was 16.7% and 35.7%, respectively. Disease control rate by both IRC and investigator assessment was 85.0% in the prior-sorafenib cohort and 64.3% in the sorafenib-naïve cohort. Median overall survival (Kaplan-Meier estimate) was 19.3 and 9.9 months in the prior-sorafenib and sorafenib-naïve cohort, respectively. Mean ALBI score remained relatively constant in patients able to continue treatment. The most frequent adverse events were palmar-plantar erythrodysesthesia syndrome, diarrhea, hypertension, and decreased appetite. No new safety concerns were identified. CONCLUSIONS: Cabozantinib showed efficacy and a manageable safety profile in Japanese patients with advanced HCC.

A VS ultrasound diagnostic system with kidney image evaluation functions.

PURPOSE: An inevitable feature of ultrasound-based diagnoses is that the quality of the ultrasound images produced depends directly on the skill of the physician operating the probe. This is because physicians have to constantly adjust the probe position to obtain a cross section of the target organ, which is constantly shifting due to patient respiratory motions. Therefore, we developed an ultrasound diagnostic robot that works in cooperation with a visual servo system based on deep learning that will help alleviate the burdens imposed on physicians. METHODS: Our newly developed robotic ultrasound diagnostic system consists of three robots: an organ tracking robot (OTR), a robotic bed, and a robotic supporting arm. Additionally, we used different image processing methods (YOLOv5s and BiSeNet V2) to detect the target kidney location, as well as to evaluate the appropriateness of the obtained ultrasound images (ResNet 50). Ultimately, the image processing results are transmitted to the OTR for use as motion commands. RESULTS: In our experiments, the highest effective tracking rate (0.749) was obtained by YOLOv5s with Kalman filtering, while the effective tracking rate was improved by about 37% in comparison with cases without such filtering. Additionally, the appropriateness probability of the ultrasound images obtained during the tracking process was also the highest and most stable. The second highest tracking efficiency value (0.694) was obtained by BiSeNet V2 with Kalman filtering and was a 75% improvement over the case without such filtering. CONCLUSION: While the most efficient tracking achieved is based on the combination of YOLOv5s and Kalman filtering, the combination of BiSeNet V2 and Kalman filtering was capable of detecting the kidney center of gravity closer to the kidney's actual motion state. Furthermore, this model could also measure the cross-sectional area, maximum diameter, and other detailed information of the target kidney, which meant it is more practical for use in actual diagnoses.

Fib-4 index predicts prognosis after achievement of sustained virologic response following direct-acting antiviral treatment in patients with hepatitis C virus infection.

OBJECTIVES: Toinvestigate liver carcinogenesis and other causes of death by collecting clinical data, including the Fib-4 index, from patients with successfully eradicated hepatitis C virus (HCV) by direct-acting antivirals (DAA) treatment. METHODS: Patients ( n = 690), who achieved a sustained virologic response (SVR) between 2014 and 2021, were identified and followed up for approximately 6.8 years; 71 incident hepatocellular carcinoma (HCC) cases were identified. The Fib-4 index was calculated at DAA-treatment initiation and HCV eradication, and its relationship with carcinogenesis and prognosis was analyzed. RESULTS: The Fib-4 index was initially calculated and divided into three groups: Fib-4<1.45, 1.45 ≤ Fib-4<3.25, and 3.25 ≤ Fib-4 to develop HCC over time. On analysis, no carcinogenic cases were observed at Fib-4<1.45. In patients with a Fib-4 index ≥3.25, the initial HCC carcinogenic rate was higher than that in patients with Fib-4=1.45-3.25, and a significant difference was obtained between the two groups [ P = 0.0057 (<1.45 vs. >3.25); P = 0.0004 (<1.45-3.25 vs. >3.25)]. Regarding all 18 death and Fib-4 at treatment initiation, a significant difference was observed after stratification into two groups [Fib-4 < 3.25 and 3.25 ≤ Fib-4; P = 0.0136 (<3.25 vs. ≥3.25)]. Significant differences were obtained in another analysis of 13 deaths, not due to HCC. CONCLUSIONS: The high Fib-4 index calculated at baseline and SVR12 significantly correlated not only with liver carcinogenesis but also with all mortality rates, including those due to causes other than liver cancer. Our findings suggest that improving liver fibrosis by eradicating HCV improves prognosis related to all etiologies.

Added Value of Ultrasound-Based Multimodal Imaging to Diagnose Hepatic Sclerosed Hemangioma before Biopsy and Resection.

Imaging methods have the overwhelming advantage of being non-invasive in the diagnosis of hepatic lesions and, thanks to technical developments in the field of ultrasound (US), radiation exposure can also be avoided in many clinical situations. In particular, contrast-enhanced US (CEUS) outperforms other radiological methods in regard to real-time images, repeatability, and prompt reporting and demonstrates relatively few contraindications and adverse reactions. In this study, we reported in detail a rare benign tumor: hepatic sclerosed hemangioma (HSH). We described US-based multimodal imaging (B-flow imaging, US elastography, and Sonazoid CEUS) features of this HSH case. Furthermore, by summarizing the recently published literature on the imaging diagnosis of HSH, we offered readers comprehensive knowledge of conventional imaging methods (CT, MRI) and CEUS in the diagnosis of HSH and preliminarily discussed their mechanism of pathology-based diagnosis. Our multimodal imaging approach may provide a diagnostic strategy for HSH, thus avoiding unnecessary biopsy or resection.

The change rate in serum nitric oxide may affect lenvatinib therapy in hepatocellular carcinoma.

BACKGROUND: Lenvatinib is appropriate for reducing the production of nitric oxide (NO) and facilitating as block angiogenesis. However, to our knowledge, there are no data that support the correlation between NO and clinical response in patients who received lenvatinib therapy for HCC. Therefore, we investigated the correlation between the change rate of NO levels and clinical responses including adverse events (AEs) after lenvatinib therapy for unresectable hepatocellular carcinoma (HCC). METHODS: This study was conducted using previously collected data from another study. We enrolled 70 patients who received lenvatinib for advanced or unresectable HCC. NO was measured by converting nitrate (NO3-) to nitrite (NO2-) with nitrate reductase, followed by quantitation of NO2- based on Griess reagent. To determine whether lenvatinib influences NO in unresectable HCC, we evaluated the influence of the change rate of NO from baseline after administration of lenvatinib on maximal therapeutic response and SAE. RESULTS: After lenvatinib administration, a change rate in the NO from 0.27 to 4.16 was observed. There was no difference between the clinical response to lenvatinib and the change rate of NO (p = 0.632). However, the change rate of NO was significantly lower in patients with AEs than in those without AEs (p = 0.030). When a reduction in NO rate of < 0.8 was defined as a clinically significant reduction of NO (CSRN), the CSRN group had significantly worse progression-free survival (PFS) and overall survival (OS) than the non-CSRN group (p = 0.029 and p = 0.005, respectively). CONCLUSION: Decreased NO levels were associated with the occurrence of AEs and worse prognosis after lenvatinib administration. Change rate in serum NO can be used as predictive markers in patients receiving lenvatinib therapy for HCC.