A Phase 2, Prospective, Multicenter, Single-Arm Trial of Transarterial Chemoembolization Therapy in Combination Strategy with Lenvatinib in Patients with Unresectable Intermediate-Stage Hepatocellular Carcinoma: TACTICS-L Trial.

Introduction: Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC), but recurrence after TACE is common. The present phase 2, prospective, multicenter, single-arm trial, the TACTICS-L trial, investigated the efficacy and safety of TACE plus lenvatinib (LEN), a drug that more strongly promotes vascular normalization and has a better objective response rate (ORR) than sorafenib (jRCTs031180074). Methods: Participants were patients with HCC who had not previously received systemic therapy, hepatic arterial infusion chemotherapy, or immunotherapy and who were ineligible for resection or percutaneous ablation therapy. LEN was to be administered 14-21 days before the first TACE, stopped 2 days before TACE, and resumed 3 days after TACE. Key inclusion criteria were unresectable HCC, Child-Pugh A liver function, 0-2 prior TACE sessions, tumor size ≤10 cm, number of tumors ≤10, and ECOG performance status 0-1. Key exclusion criteria were vascular invasion and extrahepatic spread. The primary endpoint was progression-free survival (PFS) by RECICL, and secondary endpoints were time to untreatable progression, ORR, overall survival (OS), and safety. Results: A total of 62 HCC patients were enrolled in this trial. The median age was 72 years, 77.4% of patients were men, and 95.2% had PS 0. The primary endpoint of median PFS was 28.0 months (90% confidence interval [CI] 25.1-31.0) after a minimum 24 months of follow-up. The secondary endpoint of median OS was not reached (90% CI 35.5 months-NR). LEN-TACE achieved a high response rate and high complete response (CR) rate (4 weeks after the first TACE: ORR 79.0%, CR rate 53.2%; best response: ORR 88.7%, CR rate 67.7%) by RECICL. Exploratory subgroup analyses showed that the characteristics of responders/nonresponders (ORR and CR rate) were similar and that LEN-TACE would be effective in all subgroups, including the population in whom TACE alone would be less likely to be curative (e.g., patients with the non-simple nodular type or a high tumor burden). The relative dose intensity of LEN before the first TACE was important for achieving higher CR rate/ORR by LEN-TACE. No new safety concerns were observed. Conclusion: The results of this trial provide encouraging evidence, supporting the efficacy and favorable safety profile of LEN-TACE in patients who are ineligible for locoregional therapy.

Comparison of Efficacy and Safety of Atezolizumab Plus Bevacizumab and Lenvatinib as First-Line Therapy for Unresectable Hepatocellular Carcinoma: A Propensity Score Matching Analysis.

BACKGROUND: A comparison between atezolizumab plus bevacizumab (ATEZO/BEVA) and lenvatinib (LEN) for the treatment of hepatocellular carcinoma (HCC) remains unclear. OBJECTIVE: This study aimed to compare the therapeutic effects and safety of ATEZO/BEVA and LEN as first-line therapies for HCC. PATIENTS AND METHODS: This study was a retrospective analysis of 810 patients with HCC who underwent ATEZO/BEVA (n = 186) or LEN (n = 624) as first-line systemic therapy between March 2018 to March 2022 at 14 facilities. After propensity score matching, 304 patients (ATEZO/BEVA group: n = 152; LEN group: n = 152) were analyzed. RESULTS: After propensity score matching, although there was no significant difference in objective response rates (ORRs) between the ATEZO/BEVA and LEN groups (ORR 44.8% vs. 46.7%, p = 0.644), the median progression-free survival (PFS) and median overall survival (OS) in the ATEZO/BEVA group were significantly higher than those in the LEN group (median PFS: 8.3 months vs. 6.0 months, p = 0.005; median OS: not reached vs. 20.2 months, p = 0.039). The rates of appetite loss, fatigue, and proteinuria of grade 3 or higher in the ATEZO/BEVA group were lower than those in the LEN group. However, the rate of bleeding of grade 3 or higher in the ATEZO/BEVA group was higher than that in the LEN group. The conversion rate was higher in the ATEZO/BEVA group than that in the LEN group (8.6% vs. 1.9%, p = 0.007). CONCLUSIONS: ATEZO/BEVA showed superiority to LEN in terms of prognosis and conversion rate as first-line therapy. Moreover, ATEZO/BEVA had a lower rate of severe adverse events, except for bleeding, than LEN.

Final Results of TACTICS: A Randomized, Prospective Trial Comparing Transarterial Chemoembolization Plus Sorafenib to Transarterial Chemoembolization Alone in Patients with Unresectable Hepatocellular Carcinoma.

Introduction: Several clinical trials comparing the efficacy and safety of transarterial chemoembolization (TACE) plus molecular-targeted agents versus TACE alone revealed no clinical benefits in progression-free survival (PFS) or overall survival (OS). Here, we report the final OS analysis from the TACTICS trial, which previously demonstrated significant improvement in PFS with TACE plus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) (NCT01217034). Methods: Patients with unresectable HCC were randomized to a TACE plus sorafenib group (N = 80) or a TACE alone group (N = 76). Patients in the combination treatment group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable progression. In this trial, TACE-specific PFS was used. TACE-specific PFS is defined as the time from randomization to progressive disease (PD) or death from any cause, and PD was defined as untreatable progression, caused by the inability of a patient to further receive or benefit from TACE for reasons that include intrahepatic tumor progression (25% increase vs. baseline) according to response evaluation criteria in cancer of the liver, the detection of extrahepatic spread, vascular invasion, or transient deterioration of liver function to Child-Pugh C after TACE. Results: At the cut-off date of July 31, 2020, 131 OS events were observed. The median OS was 36.2 months with TACE plus sorafenib and 30.8 months with TACE alone (hazard ratio [HR] = 0.861; 95% confidence interval [CI], 0.607-1.223; p = 0.40, ΔOS, 5.4 months). The updated PFS was 22.8 months with TACE plus sorafenib and 13.5 months with TACE alone (HR = 0.661; 95% CI, 0.466-0.938; p = 0.02). Post-trial treatments with active procedures/agents were received by 47 (58.8%) patients in the TACE plus sorafenib group and 58 (76.3%) in the TACE alone group (p = 0.01). In post hoc analysis, PFS and OS benefit were shown in HCC patients with tumor burden beyond up-to-7 criteria. Conclusions: In TACTICS trial, TACE plus sorafenib did not show significant OS benefit over TACE alone; however, clinical meaningful OS prolongation and significantly improved PFS was observed. Thus, the TACE plus sorafenib can be considered a choice of treatment in intermediate-stage HCC, especially in patients with high tumor burden. Trial Registration: NCT01217034.

Iron Deficiency Anemia Improved by Dental Implantation: A Case Report.

Treatments for improving iron deficiency anemia are generally aimed at increasing oral iron intake and/or administration. Such treatments, however, have been unsuccessful in managing nutritional disorders, including anemia, in patients with masticatory dysfunction caused by impaired occlusion. Nevertheless, few studies have assessed the potential benefits of providing optimal occlusion in such cases. Here, we report a case involving a 53-year-old woman with iron deficiency anemia, wherein we attempted to facilitate efficient mastication by establishing functional occlusion with dental implant placement. The patient was diagnosed with iron deficiency anemia and hospitalized for blood transfusion 2 years before she visited our dental clinic. At the first visit, her hemoglobin (Hb) and mean corpuscular volume values were low; sodium ferrous citrate administration and dietary guidance led to slight improvement. However, blood transfusions and iron supplementation had been ineffective over longer duration. After dental implant placement, her Hb and mean corpuscular volume values were restored and maintained for >4 years without medication. Through this report, we highlight an alternative, non-pharmacological treatment strategy for iron deficiency anemia.

Oncological Outcomes of Operative Microwave Ablation for Intermediate Stage Hepatocellular Carcinoma: Experience in 246 Consecutive Patients.

BACKGROUND: Few clinical studies concerning the efficacy of microwave ablation for intermediate stage hepatocellular carcinoma have been published. Our purpose was to examine perioperative and long-term outcomes after operative microwave ablation for intermediate stage hepatocellular carcinoma. METHODS: This retrospective study included 246 patients who had undergone operative microwave ablation for intermediate stage hepatocellular carcinoma in our institute between January 2001 and December 2017. We analyzed overall and recurrence-free survival and used the Cox proportional hazard model to evaluate potential prognostic factors. RESULTS: The overall median follow-up time was 51 months. The 1-, 3-, 5-, and 10-year overall survival rates were 98%, 74%, 51%, and 28%, respectively, whereas the 1-, 3-, 5-, and 10-year recurrence-free survival rates were 80%, 32%, 18%, and 10%, respectively. The major complication rate (Clavien-Dindo classification IIIa or above) after operative microwave ablation was 7%, with no procedure-related mortality. Multivariate analysis identified beyond up-to-7 criteria (the sum of the largest tumor's diameter in cm and the total number of tumors), Child-Pugh grade B, and serum alpha-fetoprotein concentration ≥ 100 ng/mL as independent risk factors for overall survival after operative microwave ablation. The overall survival of patients within up-to-7 and Child-Pugh grade A was better than that of the remaining patients, 5-year overall survivals being 67% and 37%, respectively (P < 0.001). CONCLUSIONS: Operative microwave ablation is safe and effective in patients with intermediate stage hepatocellular carcinoma. In particular, patients within up-to-7 and Child-Pugh grade A can be expected to have better long-term outcomes after operative microwave ablation.

Predictive impact of the prognostic nutritional index in early-staged hepatocellular carcinoma after operative microwave ablation.

BACKGROUND: The prognostic nutritional index (PNI) is used to assess immune and nutritional status, and is a prognostic factor for several malignant tumors. However, little evidence exists regarding the predictive impact of prognostic nutritional index (PNI) after local ablation therapy for hepatocellular carcinoma (HCC). The aim of this study was to evaluate the value of PNI to predict recurrence and survival after operative microwave ablation in patients with early-stage HCC. METHODS: This retrospective study included 341 patients who underwent operative microwave ablation for HCC in Barcelona Clinic Liver Cancer (BCLC) stage 0-A at our institute between 2007 and 2015. We analyzed overall survival (OS) and recurrence-free survival (RFS), and evaluated factors related to prognosis in multivariate Cox regression analyses. RESULTS: The OS rates at 1, 3, 5, and 10 years after microwave ablation were 100%, 92.7%, 85.1%, and 57.5% in patients with high-PNI levels, and 96.5%, 78.2%, 59.7%, and 20.7% in patients with low-PNI levels, respectively (P < 0.001). The RFS rates at 1, 3, 5, and 10 years after microwave ablation were 96.3%, 75.2%, 55.4%, and 30.4% in patients with high-PNI levels, and 94.4%, 48.8%, 36.4%, and 13.1% in patients with low-PNI levels, respectively (P < 0.001). In multivariate analyses, preoperative PNI level was an independent prognostic factor for both OS and RFS. CONCLUSION: Our results revealed the preoperative PNI level was a simple and novel predictive marker of survival and recurrence after microwave ablation in patients with early-stage HCC.

Operative Microwave Ablation for Hepatocellular Carcinoma Within 3 cm and 3 Nodules: Experience in 559 Patients.

BACKGROUND: There are few published data regarding long-term outcome survival after microwave ablation (MWA) for hepatocellular carcinoma (HCC) within 3 cm and 3 nodules. The aim of this study was to examine long-term outcomes after operative MWA for HCC within 3 cm and 3 nodules. METHODS: This cohort of this retrospective study comprised 559 patients who underwent operative MWA for HCC within 3 cm and 3 nodules in our institute between 1996 and 2017. We analyzed overall survival (OS) and recurrence-free survival (RFS), and evaluated factors related to prognosis. RESULTS: Median follow-up time was 69 months for the entire cohort. OS rates were 1-year: 98%, 3-year: 87%, 5-year: 73%, and 10-year:39%; RFS rates were 1-year: 91%, 3-year: 60%, 5-year: 42%, and 10-year: 21%. Multivariate analysis revealed that hepatitis C virus (HCV)-positive status, ALBI grade 2 or 3, maximum tumor diameter ≥ 20 mm, and multiple nodules were independent risk factors for both OS and RFS. A prognostic staging model using one point for each risk factor provided a well-categorized predictive model. The 5-year OS rates were 93%, 81%, and 57% for scores of 0, 1 or 2, and 3 or 4, respectively (P < 0.001). The 5-year RFS rates were 70%, 48%, and 28% for scores of 0, 1 or 2, and 3 or 4, respectively (P < 0.001). CONCLUSIONS: Our results revealed good long-term outcomes after operative MWA for HCC within 3 cm and 3 nodules.

Predictive Factors for Local Recurrence after Intraoperative Microwave Ablation for Colorectal Liver Metastases.

This study aimed to clarify local recurrence (LR) predictive factors following intraoperative microwave ablation (MWA) for colorectal liver metastases. The data from 195 patients with 1392 CRLM lesions, who were preoperatively diagnosed by gadolinium-enhanced MRI with diffusion-weighted imaging and dynamic CT and treated with intraoperative MWA (2450 MHz) with or without hepatectomy, from January 2005 to December 2019, were retrospectively reviewed and analyzed using logistic regression. In addition, the margins were measured on contrast-enhanced CT 6 weeks post-ablation. Overall, 1066 lesions were ablated. The LRs occurred in 44 lesions (4.1%) among 39 patients (20.0%). The multivariate analysis per patient showed that tumor size > 20 mm and ablation margin < 5 mm were significant predictors for LR. Furthermore, multivariate analysis per lesion revealed that segments 1, 7, and 8 and tumor size > 15 mm, ablation margin < 5 mm, tumor size > 20 mm, and proximity to the Glisson were significant LR predictors. Finally, the outcome of this study may help determine indications for MWA.

Avelumab in Combination with Axitinib as First-Line Treatment in Patients with Advanced Hepatocellular Carcinoma: Results from the Phase 1b VEGF Liver 100 Trial.

INTRODUCTION: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for the treatment of advanced/metastatic hepatocellular carcinoma (aHCC). Avelumab is a human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We report the final analysis from VEGF Liver 100 (NCT03289533), a phase 1b study evaluating safety and efficacy of avelumab plus axitinib in treatment-naive patients with aHCC. METHODS: Eligible patients had confirmed aHCC, no prior systemic therapy, ≥1 measurable lesion, Eastern Cooperative Oncology Group performance status ≤1, and Child-Pugh class A disease. Patients received avelumab 10 mg/kg intravenously every 2 weeks plus axitinib 5 mg orally twice daily until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and investigator-assessed objective response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) for HCC. RESULTS: Twenty-two Japanese patients were enrolled and treated with avelumab plus axitinib. The minimum follow-up was 18 months as of October 25, 2019 (data cutoff). Grade 3 treatment-related adverse events (TRAEs) occurred in 16 patients (72.7%); the most common (≥3 patients) were hypertension (n = 11 [50.0%]), palmar-plantar erythrodysesthesia syndrome (n = 5 [22.7%]), and decreased appetite (n = 3 [13.6%]). No grade 4 TRAEs or treatment-related deaths occurred. Ten patients (45.5%) had an immune-related AE (irAE) of any grade; 3 patients (13.6%) had an infusion-related reaction (IRR) of any grade, and no grade ≥3 irAE and IRR were observed. The objective response rate was 13.6% (95% CI: 2.9-34.9%) per RECIST 1.1 and 31.8% (95% CI: 13.9-54.9%) per mRECIST for HCC. CONCLUSION: Treatment with avelumab plus axitinib was associated with a manageable toxicity profile and showed antitumor activity in patients with aHCC.

Combined hepatectomy and microwave ablation for multifocal hepatocellular carcinoma: Long-term outcomes and prognostic factors.

BACKGROUND: It remains to be clarified whether combined hepatectomy and microwave ablation for multifocal hepatocellular carcinoma (HCC) is feasible. This aim of this study was to examine the perioperative and oncological outcomes after combined hepatectomy and microwave ablation for multifocal HCC. METHODS: This retrospective study included 81 patients who underwent combined hepatectomy and microwave ablation for multifocal HCC in our institute between June 1998 and December 2017. We analyzed overall survival (OS) and recurrence-free survival (RFS), and evaluated factors related to prognosis. RESULTS: Median follow-up time was 45.6 months for the entire cohort. OS rates were 1-year: 96%, 3-year: 72%, and 5-year: 54%; RFS rates were 1-year: 77%, 3-year: 37%, and 5-year: 22%. The major complication rate (Clavien-Dindo classification IIIa or above) after surgery was 10%, with one patient of in-hospital mortality. Multivariate analysis revealed that des-γ-carboxy prothrombin level >200 mAU/mL and >5 tumors were independent risk factors for OS, and des-γ-carboxy prothrombin level >200 mAU/mL, > 5 tumors, and maximum tumor size >5 cm were independent risk factors for RFS. CONCLUSIONS: Our results indicate that combined hepatectomy and microwave ablation is safe and feasible for selected patients with multifocal HCC.

Glomus tumor of the duodenum: a rare case report.

BACKGROUND: Glomus tumors (GTs) are mesenchymal neoplastic lesions arising from the glomus bodies and generally occur in the fingers and toes. Gastrointestinal GTs are rare, and most of them originate from the stomach; however, GT arising from the duodenum is exceedingly rare. CASE PRESENTATION: A 68-year-old man was admitted due to abdominal pain. Endoscopy showed a round, smooth, elevated mass in the second portion of the duodenum with central ulceration. Abdominal contrast computed tomography showed a hypervascular tumor measuring 26 mm in diameter in the second portion of the duodenum, and pancreatic invasion was suspected. Endoscopic ultrasonography of the lesion confirmed a hypoechoic mass arising from the fourth layer of the duodenal wall. A biopsy was performed for central ulceration, and immunochemical studies showed positive results for smooth muscle actin (SMA) and negative results for S100, C-Kit, and CD34. Leiomyoma or gastrointestinal stromal tumor was suspected and pancreatoduodenectomy was performed. The specimen exhibited a vascular-rich tumor, 24 × 24 × 19 mm in size, with deep ulceration in the duodenum. Histological examination showed uniform small round cells with central nuclei and a pale cytoplasm (glomus cell) with perivascular proliferation. Immunochemical studies showed that the tumor was positive for SMA and collagen type IV, and negative for C-Kit, CD34, desmin, and S100. We diagnosed the tumor as a GT of the duodenum. CONCLUSION: GTs of the duodenum are exceedingly rare, but should be considered in the differential diagnoses of duodenal submucosal lesions.

Feasibility and safety of surgical microwave ablation for hepatocellular carcinoma in elderly patients: a single center analysis in Japan.

The feasibility and safety of microwave ablation in elderly hepatocellular carcinoma (HCC) patients remains unknown. The aim of this study was to evaluate the feasibility and safety of surgical microwave ablation for HCC in patients older than 80 years of age. This retrospective study enrolled consecutive 114 patients older than 80 years of age who underwent surgical microwave ablation for HCC between July 1994 and December 2017. We analyzed perioperative outcomes and long-term outcomes to clarify the prognostic factors. The 1-, 3-, 5-year overall survival and recurrence-free survival rates were 97.3%, 76.0%, 49.2% and 84.2%, 44.7%, and 32.5%, respectively. The overall major morbidity rates (Clavien-Dindo grade IIIA or above) were 2.6%. There were no cases of mortality. Multivariate analysis showed that hepatitis C virus antibody (HCV-Ab) positivity and the presence of multiple tumors were independent prognostic factors for long-term outcomes. The overall survival rate of patients with HCV-Ab negative and single tumor was better than that of other patients (p = 0.026). Surgical microwave ablation was feasible and safe for elderly patients with HCC. Elderly patients with HCV-Ab negative and single tumor would be expected to have better long-term outcomes after surgical microwave ablation.

A case of small cell neuroendocrine carcinoma of the ampulla of Vater.

BACKGROUND: Gastroenteric neuroendocrine carcinomas (NECs) account for 6.2% of gastroenteric neuroendocrine tumors (NETs), and only 1% or less of gastroenteric NETs occur in the ampulla of Vater (AoV). Clinical features of NEC of the AoV remain obscure. CASE PRESENTATION: A 65-year-old man visited a general practitioner because of jaundice, and an abdominal contrast-enhanced computed tomography scan revealed a tumor of 11 mm in diameter, which was enhanced in the arterial phase at the duodenal papilla, with dilation of the upstream bile duct. Gastrointestinal scope revealed an unexposed tumor of the AoV. Based on a biopsy of the site, a moderately differentiated tubular adenocarcinoma was suspected, and pancreatoduodenectomy was performed. Histopathological examination revealed dysplasia and highly proliferative small tumor cells, with solid and nodular formation at the AoV. Histological analysis showed a high mitotic count, and immunohistochemical staining revealed a Ki-67 index of 40-50% and cells positive for synaptophysin, chromogranin A, and p53. Small cell-type NEC was finally diagnosed. Four months post pancreatoduodenectomy, multiple liver metastases developed, and systemic chemotherapy was administered. Salvage liver resection for liver metastases was performed 14 months after the pancreatoduodenectomy. Unfortunately, multiple liver metastases developed 2 months after liver resection, and the patient died 18 months after the pancreatoduodenectomy. CONCLUSIONS: Neuroendocrine carcinoma originating from the bile duct is very rare; therefore, in this article, we provide a review of the literature and a case report.

A Case of Advanced Hepatocellular Carcinoma with Partial Response after Continuous Ramucirumab Treatment beyond Radiological Progression.

A 73-year-old male was initially treated with sorafenib for advanced stage HCC. However, the disease progressed 2 months after starting sorafenib. Progressive disease (PD) was confirmed by radiological examination, which revealed mediastinal and abdominal lymph node metastasis, pulmonary metastasis, and intrahepatic recurrence. The patient was enrolled in the REACH-2 (NCT02435433) trial and randomized to receive ramucirumab (8 mg/kg div. every 2 weeks). The patient had a Child-Pugh score of 6A and his AFP level was found to be 1,256.8 ng/mL at initiation. Radiological examination revealed PD, 5 months after starting ramucirumab. Ramucirumab treatment was continued after the confirmation of radiological PD, not but clinical progression, as allowed by the study protocol. His AFP level increased after continuous ramucirumab treatment, however, it suddenly decreased from 7,653 ng/mL to within normal limits 10 months after initiation of ramucirumab treatment. Radiological evaluation revealed a significant decrease in the size of the tumors, which constituted a partial response (PR). We reported a rare case of advanced HCC with PR to a continuous ramucirumab treatment after radiological PD.

Ramucirumab after prior sorafenib in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein: Japanese subgroup analysis of the REACH-2 trial.

BACKGROUND: The global, randomized, phase 3 REACH-2 study (ClinicalTrials.gov identifier: NCT02435433) found significantly longer overall survival (OS) for second-line ramucirumab versus placebo (hazard ratio [HR]: 0.710, 95% confidence interval [CI] 0.531-0.949, P = 0.0199) in patients with advanced hepatocellular carcinoma (HCC) and alpha-fetoprotein (AFP) ≥ 400 ng/mL. This prespecified subgroup analysis evaluated the efficacy and safety of ramucirumab in the Japanese patients enrolled in the study. METHODS: Patients with advanced HCC and AFP ≥ 400 ng/mL after first-line sorafenib were randomized 2:1 to ramucirumab (8 mg/kg intravenously) or placebo every 2 weeks. Hazard ratios for progression-free survival (PFS) and OS (primary endpoint of the overall study) were estimated using the stratified Cox regression model. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with AFP ≥ 400 ng/mL. RESULTS: In the Japanese REACH-2 subpopulation, there were improvements for ramucirumab (n = 41) versus placebo (n = 18) in PFS (HR 0.282, 95% CI 0.144-0.553) and OS was numerically prolonged (HR 0.599, 95% CI 0.303-1.187), consistent with the significant benefit seen in the overall REACH-2 study population. In the ramucirumab and placebo arms, respectively, the objective response rate was 7.3% and 0%, and the disease control rate was 70.7% and 33.3%. The most frequently reported grade ≥ 3 treatment-emergent adverse event was hypertension (ramucirumab: 15%; placebo: 11%). CONCLUSIONS: Ramucirumab after prior sorafenib improved PFS and OS compared with placebo, with a manageable safety profile, in the Japanese REACH-2 subpopulation, consistent with the overall REACH-2 study results. Ramucirumab is the first agent to demonstrate clinical benefit for Japanese patients with HCC in the second-line setting.

Facile Hydrogenative Deprotection of N-Benzyl Groups Using a Mixed Catalyst of Palladium and Niobic Acid-on-Carbon.

The palladium-on-carbon (Pd/C)-catalyzed hydrogenative deprotection of the N-benzyl-protecting group was effectively facilitated by the combined use of niobic acid-on-carbon (Nb2O5/C). Nb2O5/C is an acidic heterogeneous catalyst prepared from NbCl5 and activated carbon. The catalysts were easily removed from the reaction mixture and reusable. Deprotected amines were obtained in excellent yields without an additional neutralization process. The facilitating effect of Nb2O5/C was also observed during the Pd/C-catalyzed hydrogenative deprotection of the N-benzyloxycarbonyl (Cbz) and O-benzyl groups.

Efficacy of surgical microwave ablation for recurrent hepatocellular carcinoma after curative hepatectomy.

BACKGROUND: Little evidence exists regarding postrecurrence survival after microwave ablation for recurrent hepatocellular carcinoma (HCC) after curative hepatectomy; we aimed to evaluate the feasibility of surgical microwave ablation. METHODS: In this retrospective review, we enrolled patients who underwent curative hepatectomy for primary HCC in our department and had intrahepatic recurrence. We analyzed overall survival according to treatment modality to clarify the prognostic factors for survival. RESULTS: Of 257 patients, 119 had intrahepatic recurrence. Three patients underwent repeat hepatectomy; 75 patients underwent surgical microwave ablation, and 34 patients underwent transcatheter arterial chemoembolization or hepatic arterial infusion chemotherapy. The median postrecurrence survival time and 5-year postrecurrence survival after surgical microwave ablation were 37.4 months and 55.4%, respectively. The major complication rate (Clavien-Dindo classification IIIa or above) after surgical microwave ablation was 5.3% with no mortality. Multivariate analysis showed that microvascular invasion at primary tumors, and recurrent tumors within 3 cm and 3 nodules were independent prognostic factors for overall survival after surgical microwave ablation for recurrent HCC. CONCLUSION: Our results suggested that surgical microwave ablation is safe and feasible for recurrent intrahepatic HCC after curative hepatectomy. Close follow-up and further curative treatment could be important for improving postrecurrence survival.

REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset.

BACKGROUND: A phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority [OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79-1.06], and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported. METHODS: The intent-to-treat population enrolled in Japan was analyzed. RESULTS: Of 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm (N = 81) or the SOR arm (N = 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62-1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm. CONCLUSIONS: The efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC. TRIAL REGISTRATION ID: ClinicalTrials.gov. No. NCT01761266.

Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial.

OBJECTIVE: This trial compared the efficacy and safety of transarterial chemoembolisation (TACE) plus sorafenib with TACE alone using a newly established TACE-specific endpoint and pre-treatment of sorafenib before initial TACE. DESIGN: Patients with unresectable hepatocellular carcinoma (HCC) were randomised to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable (unTACEable) progression (TTUP), defined as untreatable tumour progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is not a conventional one but defined as TTUP, or time to any cause of death plus overall survival (OS). Multiplicity was adjusted by gatekeeping hierarchical testing. RESULTS: Median PFS was significantly longer in the TACE plus sorafenib than in the TACE alone group (25.2 vs 13.5 months; p=0.006). OS was not analysed because only 73.6% of OS events were reached. Median TTUP (26.7 vs 20.6 months; p=0.02) was also significantly longer in the TACE plus sorafenib group. OS at 1 year and 2 years in TACE plus sorafenib group and TACE alone group were 96.2% and 82.7% and 77.2% and 64.6%, respectively. There were no unexpected toxicities. CONCLUSION: TACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with those of previous TACE combination trials. TRIAL REGISTRATION NUMBER: NCT01217034.