Ramucirumab for advanced hepatocellular carcinoma in the current real world: a Japanese single-arm study post-REACH-2 (The R-evolution study).

This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study.

Secondary Budd-Chiari syndrome occurred after adjuvant radiotherapy for perihilar cholangiocarcinoma: a case report.

BACKGROUND: Budd-Chiari syndrome (BCS) is a rare vascular disorder of the liver, and acute and secondary BCS is even rarer. CASE PRESENTATION: A 62-year-old man with perihilar cholangiocarcinoma of Bismuth type IIIa underwent right hemi-hepatectomy with caudate lobectomy and pancreatoduodenectomy. Adjuvant chemoradiotherapy was performed due to a positive hepatic ductal margin. Subsequently, the disease passed without recurrence. The patient visited for acute onset abdominal pain at the 32nd postoperative month. Multidetector-row computed tomography (MDCT) showed stenosis of the left hepatic vein (LHV) root, which was the irradiated field, and thrombotic occlusion of the LHV. The patient was diagnosed with acute BCS caused by adjuvant radiotherapy. Although anticoagulation therapy was performed, the patient complained of sudden upper abdominal pain again. MDCT showed an enlarged LHV thrombus and hepatomegaly. The patient was diagnosed with exacerbated acute BCS, and stenting for the stenotic LHV root was performed with a bare stent. Although stenting for the LHV root was very effective, restenosis occurred twice due to thrombus in the existing stent, so re-stenting was performed twice. The subsequent clinical course was acceptable without recurrence or restenosis of the LHV root as of 6 months after the last stenting using a stent graft. CONCLUSION: Although no case of BCS caused by radiotherapy has yet been reported, the present case showed that late side effect of radiotherapy can cause hepatic vein stenosis and secondary BCS.

Real-world outcomes of molecular targeted agents for patients with hepatocellular carcinoma over 80 years old.

AIM: There is insufficient evidence regarding the safety and efficacy of molecular targeted agents (MTAs) for elderly patients with hepatocellular carcinoma (HCC), who are likely to be vulnerable to adverse events (AEs) of therapy. The aim of this study was to compare sorafenib and lenvatinib use in elderly patients with HCC from the viewpoint of overall survival (OS) and rate of AE-induced MTA discontinuation. METHODS: This retrospective study included patients with HCC over 80 years old who received first-line molecular targeted therapy (MTT) at four hospitals between June 2009 and September 2019. They were divided into three groups according to the era and type of first-line MTA: E1-Sora (sorafenib, between 2009 and 2016), E2-Sora (sorafenib, between 2017 and 2019), and E2-Len (lenvatinib, between 2017 and 2019). RESULTS: The study included 173 patients (E1-Sora, n = 79; E2-Sora, n = 50; E2-Len, n = 44) with a median age of 81.9 years (range, 80-93 years). Median OS was 15.1 months in the entire cohort (E1-Sora, 12.7 months; E2-Sora, 20.5 months; E2-Len, 10.3 months). The rate of treatment discontinuation due to AEs was high in the entire cohort, especially in E1-Sora and E2-Len (49.4% in E1-Sora, 28.0% in E2-Sora, and 54.6% in E2-Len, p = 0.0753). More E2-Sora patients received subsequent MTT than E2-Len patients (E2-Sora, 50%; E2-Len, 28.6%; p = 0.0111). CONCLUSION: Both sorafenib and lenvatinib were effective and feasible for elderly patients with HCC. In terms of discontinuation due to AEs and subsequent MTT, sorafenib might be more desirable for elderly patients with HCC over 80 years.

A randomized, controlled trial of the efficacy of percutaneous transesophageal gastro-tubing (PTEG) as palliative care for patients with malignant bowel obstruction: the JIVROSG0805 trial.

BACKGROUND: A randomized, controlled trial to evaluate the superiority of percutaneous transesophageal gastro-tubing over nasogastric tubing as palliative care for bowel obstruction in patients with terminal malignancy was conducted. SUBJECTS AND METHODS: The subjects were patients with malignant bowel obstruction with no prospect of improvement, for whom surgery was not indicated and with a Palliative Prognostic Index of < 6. They were randomly allocated in a 1:1 ratio to receive either percutaneous transesophageal gastro-tubing (PTEG group) or nasogastric tubing (NGT group). Their symptom scores (the worst 0 to no symptoms 10) were measured for a 2-week period after enrollment, and the areas under the curves for the two groups were compared. The EQ-5D and SF-8 were also used to assess overall quality of life. RESULTS: Forty patients were enrolled between October 2009 and January 2015, with 21 allocated to the PTEG group and 19 to the NGT group. The mean areas under the curves (95% confidence intervals) for the PTEG group and the NGT groups were 149.6 (120.3-178.8) and 44.9 (16.4-73.5), respectively, significantly higher for the NGT group (p < 0.0001). The secondary endpoints of quality of life as assessed by the EQ-5D and SF-8 scores were also significantly higher for patients in the PTEG group (p = 0.0036, p = 0.0020). There was no difference in survival between the groups. No serious adverse events were observed. CONCLUSIONS: In terms of quality of life, percutaneous transesophageal gastro-tubing was superior to nasogastric tubing as palliative care for patients with bowel obstruction due to terminal malignancy.

Prognostic impact of abutment to the branches of the superior mesenteric artery in borderline resectable pancreatic cancer.

PURPOSE: The clinical impact of abutment to an artery and its branch on resectability and prognosis in patients with borderline resectable pancreatic cancer is unclear. METHODS: Patients diagnosed with borderline resectable pancreatic cancer due to artery abutment between April 2012 and December 2018 were enrolled. Contact between arteries and the tumour was assessed by computed tomography (CT). RESULTS: A primary lesion was resected in 63 patients (R group) and unresected in 19 patients (UR group). Overall survival (OS) was worse in the UR group than in the R group (P < 0.001). Multivariate analysis showed that abutment to the superior mesenteric artery (SMA) branches (P = 0.001) was an independent predictor of poor OS after surgery. Regarding the initial recurrence pattern, abutment to the SMA branches was significantly associated with high incidence of distant metastasis (P < 0.001). According to the most distal SMA branch attached on CT, significant differences in RFS were found between absent-J1A (P = 0.017), J2A-J3A (P = 0.0313) and J3A-middle colic artery (MCA, P = 0.0476) but not between J1A-J2A (P = 0.8207). Significant prognostic differences in OS after initiation of the treatment were found between absent-J1A/J2A (P = 0.006) and J1A/J2A-J3A/MCA (P = 0.033) but not between J3A/MCA-UR (P = 0.494). CONCLUSION: Abutment to the SMA branches was associated with high incidence of distant metastasis after resection and a poor survival. Especially, abutment to the J3A or MCA was associated with poor prognosis comparable with that of the UR group.

AS3288802, a highly selective antibody to active plasminogen activator inhibitor-1 (PAI-1), exhibits long efficacy duration in cynomolgus monkeys.

Antibodies have strong affinity to their target molecules, a characteristic that is utilized in antibody drugs. For antibody drugs, target molecule specificity and long duration pharmacokinetics, along with strong affinity to the target molecule are important characteristics. Plasminogen activator inhibitor-1 (PAI-1) is one of the key regulators of the fibrinolysis system, and the benefits of PAI-1 activity inhibition have been widely reported for multiple thrombosis and fibrosis-related diseases. Here, we generated a novel antibody, AS3288802, with high selectivity for active PAI-1. AS3288802 exhibited prolonged and strong inhibition of PAI-1 activity in cynomolgus monkey blood in vivo. Given that AS3288802 showed prolonged antigen inhibition activity due to its high target molecule selectivity, we propose that increasing target molecule selectivity may be a key strategy for lengthening the efficacy duration of antibody drugs. AS3288802 may be a promising anti-PAI-1 antibody drug with multiple clinical applications including thrombosis and fibrosis-related diseases.

Evaluation of stent placement for vena cava syndrome: phase II trial and phase III randomized controlled trial.

PURPOSE: Vena cava syndrome (VCS) from stenosis of the superior vena cava or inferior vena cava caused by compression from a malignant tumor is one of the typical clinical conditions in patients with advanced stage malignant disease. VCS is difficult to manage and painful, reducing patients' quality of life. Although several reports have investigated stent placement for VCS, this treatment has never been established as the standard because of the lack of evidence of the safety and efficacy. We conducted a phase II trial and a phase III randomized controlled trial to clarify the role of stent placement in managing patients with VCS. METHODS: In the phase II trial, 28 eligible patients were treated with stent placement. The efficacy of stent placement for VCS was evaluated based on the reduction of patients' symptom scores during 14 days following treatment. Technical success, technical feasibility, overall survival, recurrence of symptoms, and adverse events were evaluated. In the phase III trial, 32 patients were enrolled and randomly assigned to the test (n = 16) and control groups (n = 16). The area under the symptom score curve was compared between the groups. The EQ-5D, SF-8, and adverse events were evaluated until discontinuation of the protocol treatment or 28 days after enrollment. RESULTS: In the phase II trial, the median patients' symptom scores significantly decreased from 10.50 before the procedure to 3.00 after the procedure. Technical success and technical feasibility rates were 96.4% and 100%, respectively. The incidence of treatment-related grade 3 or higher adverse events was 14.3%. In the phase III trial, significant superiority of stent placement was observed in the test, compared to that in the control, group. There was no significant difference in most other evaluations between the groups. CONCLUSIONS: Stent placement significantly improved the symptoms of VCS; thus, it might be accepted as the standard treatment to manage the symptoms of VCS. TRIAL REGISTRATION: JIVROSG-0402, JIVROSG-0807.

Corticosteroid and progesterone transactivation of mineralocorticoid receptors from Amur sturgeon and tropical gar.

The response to a panel of steroids by the mineralocorticoid receptor (MR) from Amur sturgeon and tropical gar, two basal ray-finned fish, expressed in HEK293 cells was investigated. Half-maximal responses (EC50s) for transcriptional activation of sturgeon MR by 11-deoxycorticosterone, corticosterone, 11-deoxycortisol, cortisol and aldosterone, and progesterone (Prog) were between 13 and 150 pM. For gar MR, EC50s were between 8 and 55 pM. Such low EC50s support physiological regulation by these steroids of the MR in sturgeon and gar. Companion studies with human and zebrafish MRs found higher EC50s compared with EC50s for sturgeon and gar MRs, with EC50s for zebrafish MR closer to gar and sturgeon MRs than was human MR. For zebrafish MR, EC50s were between 75 and 740 pM; for human MR, EC50s were between 65 pM and 2 nM. In addition to Prog, spironolactone (spiron) and 19nor-progesterone (19norP) were agonists for all three fish MRs, in contrast with their antagonist activity for human MR, which is hypothesized to involve serine-810 in human MR because all three steroids are agonists for a mutant human Ser810Leu-MR. Paradoxically, sturgeon, gar, and zebrafish MRs contain a serine corresponding to serine-810 in human MR. Our data suggest alternative mechanism(s) for Prog, spiron, and 19norP as MR agonists in these three ray-finned fishes and the need for caution in applying data for Prog signaling in zebrafish to human physiology.

A second estrogen receptor from Japanese lamprey (Lethenteron japonicum) does not have activities for estrogen binding and transcription.

Estrogens regulate many physiological responses in vertebrates by binding to the estrogen receptor (ER), a ligand-activated transcription factor. To understand the evolution of vertebrate ERs and to investigate how estrogen acts in a jawless vertebrate, we used degenerate primer sets and PCR to isolate DNA fragments encoding two distinct ER subtypes, Esr1a and Esr1b from the Japanese lamprey, Lethenteron japonicum. Phylogenetic analysis indicates that these two ERs are the result of lineage-specific gene duplication within the jawless fishes, different from the previous duplication event of Esr1 (ERα) and Esr2 (ERß) within the jawed vertebrates. Reporter gene assays show that lamprey Esr1a displays both constitutive and estrogen-dependent activation of gene transcription. Domain swapping experiments indicate that constitutive activity resides in the A/B domain of lamprey Esr1a. Unexpectedly, lamprey Esr1b does not bind estradiol and is not stimulated by other estrogens, androgens or corticosteroids. A 3D model of lamprey Esr1b suggests that although estradiol fits into the steroid binding site, some stabilizing contacts between the ligand and side chains that are found in human Esr1 and Esr2 are missing in lamprey Esr1b.

Large-bore Chest Tube Insertion: Seldinger Technique over Two Guidewires.

Purpose: Large-bore chest tube insertion is commonly performed using the trocar technique and blunt dissection; however, large-bore chest tube can cause severe visceral injury due to penetration, which is a life-threatening complication. Conversely, small-bore chest tubes can be safely inserted using the Seldinger technique; however, small-bore chest tubes are prone to blockage, especially in empyema cases. Therefore, this study aimed to demonstrate large-bore chest tube insertion using the Seldinger technique over two guidewires following image-guided puncture. Material and Methods: We started performing large-bore chest tube insertion using the Seldinger technique over two guidewires following image-guided puncture in February 2022. Demographic data and procedural details, such as chest tube size, dilator size, procedure time, and type of image-guided puncture, of patients who underwent this procedure between February 2022 and March 2023 were retrospectively reviewed. Technical success was defined as the successful drainage of the pleural cavity. Results: This method was used for performing ten procedures in nine patients who presented with empyema, pneumothorax, and pulmonary fistula. The insertion of a large-bore chest tube with a size ranging from 18- to 24-French was successfully performed in all cases without any complications. The median procedure time was 17.5 (first quartile-third quartile, 13.5-28.0) min. Conclusions: Large-bore chest tube insertion using the Seldinger technique over two guidewires may be used as an alternative to conventional methods.

No lipiodol, no beads-another transcatheter arterial chemoembolization (TACE) with fine cisplatin powder and porous gelatin particles for TACE-naïve, multifocal, up-to-seven out hepatocellular carcinoma.

AIM: The Japanese Interventional oncology group (JIVROSG) showed the efficacy and safety of nonselective transarterial chemoembolization (TACE) with fine cisplatin powder (diamminedichloroplatinum; DDP-H) (65 mg/m2) and porous gelatin particles (DDP-H TACE) without lipiodol for extensive multifocal hepatocellular carcinoma (HCC). However, there are no studies on this method following the JIVROSG study. Therefore, we aimed to evaluate the efficacy of this new DDP-H TACE and its effect on liver function. METHODS: We retrospectively reviewed the medical records of TACE-naïve patients with multifocal HCC (Child-Pugh class A, up-to-seven out, no prior history of systemic therapy) who underwent whole-liver DDP-H TACE between January 2006 and December 2019. RESULTS: Sixty patients were included in this study. The median age of the patients was 71 (range, 35-88) years. The median maximum size of tumors was 26 (range, 8-184) mm; 86.7% of patients met the up-to-11 criteria out. The overall survival duration was 30.3 months. At the time of initial evaluation (median, 45 days), the overall response rate was 65.0%; the disease control rate was 86.7% based on the modified response evaluation criteria in solid tumors guideline. Although nine patients' liver function had deteriorated to Child-Pugh class B at initial evaluation, six of them recovered to Child-Pugh class A. Only three patients (5%) showed permanently impaired liver function. CONCLUSIONS: Whole-liver DDP-H TACE without lipiodol or beads effectively reduced tumors and preserved liver function.

Ectopic localization of auxin and cytokinin in tobacco seedlings by the plant-oncogenic AK-6b gene of Agrobacterium tumefaciens AKE10.

The oncogenic 6b gene of Agrobacterium tumefaciens induces a number of morphological and metabolic alterations in plants. Although molecular functions associated with the 6b genes have been proposed, including auxin transport, sugar transport, transcriptional regulation, and miRNA metabolism, so far an unequivocal conclusion has not been obtained. We investigated the association between auxin accumulation and tumor development of the tobacco seedlings expressing the AK-6b gene under the control of the dexamethasone-inducible promoter. Indole-3-acetic acid (IAA) localization was examined by immunochemical staining with monoclonal antibody against IAA and by histochemical analysis using the IAA-specific induced construct, DR5::GUS (ß-glucuronidase). Both procedures indicated that IAA preferentially accumulated in the tumorous protrusions as well as in newly developing vascular bundles in the tumors. Furthermore, true leaves also showed abaxial IAA localization, leading to altered leaves in which the adaxial and abaxial identities were no longer evident. Co-localization of cytokinin and auxin in the abaxial tumors was verified by immunochemical staining with an antibody against cytokinin. Treatment of AK-6b-seedlings with N-1-naphthylphthalamic acid, an inhibitor of polar auxin transport, promoted the morphological severity of phenotypes, whereas 1-naphthoxyacetic acid, a specific auxin influx carrier inhibitor, induced tumor regression on cotyledons and new tumorous proliferations on hypocotyls. Prominent accumulation of both auxin and cytokinin was observed in both regressed and newly developing tumors. We suggest from these results that modulation of auxin/cytokinin localization as a result of AK-6b gene expression is responsible for the tumorous proliferation.

Glucose use in fasted rats under sevoflurane anesthesia and propofol anesthesia.

BACKGROUND: We previously reported the marked differences in the effects of sevoflurane anesthesia and propofol anesthesia on glucose use in fed rats; however, we could not elucidate mechanisms underlying the differences. METHODS: We used fasted rats in this study. After surgical preparation under sevoflurane anesthesia, rats were divided into 3 groups: awake rats, rats under sevoflurane anesthesia, and rats under propofol anesthesia. All rats underwent the IV glucose tolerance test (IVGTT); 0.5 g/kg glucose was administered IV to rats. Just before IVGTT, some rats were pretreated with glibenclamide or diazoxide. We measured glucose, insulin, tumor necrosis factor-α (TNF-α), and high molecular weight adiponectin levels during IVGTT and calculated the quantitative insulin sensitivity check index (QUICKI) using glucose and insulin levels before glucose administration in each rat. RESULTS: Before glucose administration, rats under sevoflurane anesthesia showed similar glucose and insulin levels with significantly higher QUICKI compared with awake rats, while rats under propofol anesthesia showed similar glucose levels and significantly higher insulin levels with significantly lower QUICKI compared with awake rats. After glucose administration, rats under sevoflurane anesthesia showed significantly higher glucose levels and similar insulin levels compared with awake rats, while rats under propofol anesthesia showed similar glucose levels and significantly higher insulin levels compared with awake rats. Before glucose administration, TNF-α levels in rats under sevoflurane anesthesia and rats under propofol anesthesia were similar to those in awake rats. After glucose administration, TNF-α was undetectable in all awake rats and all rats under sevoflurane anesthesia, whereas TNF-α was detectable in all rats under propofol anesthesia; TNF-α levels in rats under propofol anesthesia were significantly higher than those in awake rats. High molecular weight adiponectin levels in rats under sevoflurane anesthesia and rats under propofol anesthesia were similar to those in awake rats throughout the experimental period. In rats under sevoflurane anesthesia, glibenclamide significantly decreased glucose levels and significantly increased insulin levels; however, diazoxide produced no significant effects on glucose and insulin levels. In rats under propofol anesthesia, glibenclamide significantly decreased glucose levels and significantly increased insulin levels, while diazoxide significantly decreased glucose levels without changing insulin levels. CONCLUSIONS: Sevoflurane anesthesia attenuates glucose-induced insulin secretion without affecting basic insulin secretion, while propofol anesthesia enhances insulin secretion. Propofol anesthesia exaggerates insulin-resistive conditions, whereas sevoflurane anesthesia dose not impair insulin sensitivity; there may be a possible association of TNF-α with insulin-resistive conditions under propofol anesthesia.

A Case of Bilateral Internal Mammary Arterial Infusion Chemotherapy Using Implantable Port-catheter Systems for Anterior Chest Wall Metastasis of Breast Cancer.

The patient was a 53-year-old woman who presented with a metastatic tumor of the anterior chest wall after chemotherapy for right accessory breast cancer and radiation therapy for right axillary lymphadenopathy. She had already received standard treatment, but the metastatic tumor was uncontrollable and exacerbated. Palliative treatment by arterial infusion chemotherapy with an implantable catheter-port system was planned. We indwelled a port system through the arteries because the bilateral internal mammary arteries presented a dominant blood supply. The metastatic tumor almost disappeared by arterial infusion chemotherapy after 3 months. This method may be effective in selected cases of arterial infusion chemotherapy for breast cancer.

Embolization of pseudoaneurysms in the ureteral branch of the renal artery.

BACKGROUND: Although transcatheter arterial embolization for pseudoaneurysms is already well-established, ureteral artery pseudoaneurysm embolization is extremely rare. The present case shows a successful transcatheter arterial embolization for pseudoaneurysms in the ureteral branch of the renal artery due to ureteral invasion from gastric cancer. CASE PRESENTATION: A 57-year-old female presented with gross hematuria after treatments for poorly differentiated gastric adenocarcinoma. A contrast-enhanced computed tomography revealed pseudoaneurysms around the right ureter with a massive hematoma in the right ureter and bladder. The diagnosis was ureteral branch pseudoaneurysms resulting from possible retroperitoneal invasion due to pelvic lymph node metastasis of gastric cancer. Transcatheter arterial embolization was performed using gelatin particles, successfully controlling her hematuria without complications. CONCLUSIONS: Ureteral branch artery embolization, although extremely rare, may be an effective and safe treatment option.

Cortical signature related to psychometric properties of pain vigilance in healthy individuals: A voxel-based morphometric study.

The Pain Vigilance and Awareness Questionnaire (PVAQ) is a questionnaire for non-clinical and clinical cases of patients, such as those suffering from chronic pain. Moreover, it is used for evaluation of two aspects of habitual attention to pain: attention to pain and attention to changes in pain. As the PVAQ assesses two different aspects of attention function, different neural basis may present. However, it remains unclear which brain regions are involved. Here, we performed voxel-based morphometry (VBM) in 30 healthy participants to determine the regional morphology associated with the two attention states. Multiple regression analysis was conducted between each score and the regional grey matter (GM) volume, which revealed that a decreased GM volume in the left anterior insular cortex (AIC) was associated with a higher attention to pain score. In contrast, no brain region was correlated with the attention to changes in pain score. Our VBM results demonstrate that attention to pain scores assessed by PVAQ are associated with morphological features of the left AIC. Moreover, they may contribute to the elucidation of the complex psychological and neurophysiological characteristics of patients with chronic pain.

Computed tomographic pulmonary angiography: Three cases of low-tube-voltage acquisition with a slow injection of contrast medium.

Acute pulmonary thromboembolism occurring during cancer treatment has been increasing with the number of cancer patients and chemotherapy cases. Computed tomographic pulmonary angiography (CTPA) for evaluating the pulmonary artery is generally performed using rapid injection of contrast medium. However, intravenous catheters for contrast medium injection might cause extravasation due to rapid injection. This case series describes three patients who underwent contrast-enhanced computed tomography combined with low-tube-voltage imaging and slow injection. Low-tube-voltage slow-injection CTPA can be an effective technique for obtaining high contrast enhancement while accommodating fragile veins and low injection rates.

Hepatitis C virus eradication prolongs overall survival in hepatocellular carcinoma patients receiving molecular-targeted agents.

BACKGROUND: The aim of this multicenter retrospective study was to evaluate the impact of the eradication of hepatitis C virus (HCV) on the clinical outcomes of patients with hepatocellular carcinoma (HCC) treated with molecular-targeted agents (MTAs). METHODS: Among 877 patients who received any MTA as first-line systemic therapy for HCC between June 2009 and March 2019, 569 patients with HCV-related HCC were enrolled in this retrospective study. Of these, 109 patients achieved sustained virological response (SVR) before starting MTA. After propensity score matching, the clinical outcomes of 109 patients in the SVR group and 109 patients in the non-SVR group were compared. RESULTS: The median time to progression in the SVR group (7.8 months) was similar to that in the non-SVR group (5.6 months) (p = 0.212). The median time to treatment failure in the SVR group (5.3 months) was longer than that in the non-SVR group (2.8 months) (p = 0.059), and post-progression survival and overall survival in the SVR group were significantly longer than those in the non-SVR group (12.0 months vs 7.2 months; p = 0.039, and 18.1 months vs 11.3 months; p = 0.019). At the end of first-line MTA therapy, the albumin-bilirubin (ALBI) score in the SVR group ( - 2.25) was significantly lower than that in the non-SVR group ( - 2.10) (p = 0.008). CONCLUSIONS: The eradication of HCV before MTA therapy maintained liver function and led to a prolonged treatment period and improved overall survival of HCV-related HCC patients. We should not overlook the benefits of HCV eradication in HCC patients.

Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma.

BACKGROUND AND AIMS: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet. APPROACH AND RESULTS: We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009-2012, n = 267; period 2: 2013-2016, n = 352; period 3: 2017-2019, n = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, p < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively (p = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; p < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC. CONCLUSIONS: The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.