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.

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.

Actual 10-Year Survival After Surgical Microwave Ablation for Hepatocellular Carcinoma: A Single-Center Experience in Japan.

BACKGROUND: Little evidence exists regarding long-term survival after microwave ablation for hepatocellular carcinoma (HCC). The aim of this study is to determine actual 10-year survival and clarify the clinicopathological features of patients surviving ≥ 10 years after surgical microwave ablation. PATIENTS AND METHODS: This retrospective study identified 459 patients who underwent surgical microwave ablation for HCC with curative intent between 2001 and 2008. We compared 100 patients who survived ≥ 10 years with 321 patients who died within 10 years. RESULTS: Median overall survival and recurrence-free survival rates were 5.5 and 2.4 years, respectively. The actual 10-year overall survival rate was 23.8%, and the actual 10-year recurrence-free survival rate was 8.1%. Multivariate analysis showed that age > 70 years [odds ratio 1.87, P = 0.029], hepatitis C virus positivity (OR 2.30, P = 0.004), Child-Pugh class B (OR 3.28, P = 0.003), and platelet count < 10 × 104 /µL (OR 1.93, P = 0.033) were independent risk factors for actual 10-year survival. During 10-year follow-up, 66% of the ≥ 10-year survivors developed recurrence, and 91% of these patients underwent further curative treatment, including hepatic resection or local ablation, for HCC recurrence. CONCLUSION: Ten-year survival after surgical microwave ablation for HCC can be expected in approximately 24% of patients, even though nearly 2/3 of our 10-year survival patients experienced recurrence. Close postoperative follow-up and further curative treatment for recurrence are important for improving long-term survival.

Simultaneous microwave coagulo-necrotic therapy (MCN) and laparoscopic splenectomy for the treatment of hepatocellular carcinoma with cirrhotic hypersplenism.

PURPOSE: To establish the efficacy and safety of simultaneous microwave coagulo-necrotic therapy (MCN) and laparoscopic splenectomy (Lap-Sp) for the treatment of hepatocellular carcinoma (HCC) with cirrhotic hypersplenism. METHODS: Seventeen patients with HCC and cirrhotic hypersplenism underwent simultaneous MCN and Lap-Sp at our institution between January, 2010 and July, 2015. Eight and nine patients had Child-Pugh class A and B liver cirrhosis, respectively. The median number of tumors ablated was 1 (range 1-7) and the median largest dimension of the resected lesions was 1.7 cm (range 1.1-3.6 cm). We analyzed postoperative complications and long-term outcomes retrospectively. RESULTS: The median operating time was 283 min (range 197-418 min) and the median blood loss was 125 mL (range 5-1312 mL). Postoperative morbidity and mortality rates were 29 and 0 %, respectively. The median follow-up time after surgery was 22.5 months (range 4.3-70.9 months). The 1-, 3-, and 5-year disease-free survival rates were 68.8, 10.7, and 10.7 %, respectively, and the 1-, 3-, and 5-year overall survival rates were 88.2, 75.6, and 63.0 %, respectively. CONCLUSIONS: The findings of this study suggest that simultaneous MCN and Lap-Sp is safe and effective for treating HCC with cirrhotic hypersplenism.

Identification of the possible new odor-active compounds "12-methyltridecanal and its analogs" responsible for the characteristic aroma of ripe Gouda-type cheese.

The aroma concentrates of the three maturation stages of Gouda-type cheeses were prepared by combining the solvent extraction and the solvent assisted flavor evaporation techniques. The aroma extract dilution analysis applied to the volatile fraction revealed 31 odorants that were identified or tentatively identified from the 38 odor-active peaks with FD factors between 4(3) and 4(8). By comparison with the FD factors in the three maturation stages of the cheeses, 16 odorants, including 12-methyltridecanal, which is a newly identified odorant from the cheese, increased with the increasing maturation stage of the cheese. In addition, many iso- and anteiso-methyl-branched long-chain aliphatic aldehydes could be identified as the analogs of 12-methyltridecanal, which have a unique odor note. It may be then expected that these aldehydes were able to influence the flavor of the highly ripened Gouda cheese, since these compounds also increased with the increasing maturation stage.

Efficacy of Reinforced Stapler for Preventing Postoperative Pancreatic Fistula After Minimally Invasive Distal Pancreatectomy.

BACKGROUND/AIM: Although minimally invasive distal pancreatectomy (MIDP) has become a treatment option for benign and malignant pancreatic tumors, the safety and efficacy of reinforced staplers in MIDP remain controversial. The present study was performed to evaluate the safety of reinforced staplers in MIDP and identify the risk factors for postoperative pancreatic fistula (POPF) after MIDP with reinforced staplers. PATIENTS AND METHODS: In total, 92 consecutive patients who underwent MIDP at NHO Kyushu Medical Center from July 2016 to August 2023 were enrolled in this retrospective study. In all patients, a reinforced black cartridge triple-row stapler (Covidien Japan, Tokyo, Japan) was used during MIDP. The primary endpoint was the incidence of clinically relevant POPF. The risk factors for POPF were evaluated using multivariate analysis. RESULTS: Among the 92 patients, 74 underwent laparoscopic distal pancreatectomy and 18 underwent robot-assisted distal pancreatectomy. Clinically relevant POPF occurred in seven (7.6%) of 92 patients. The rate of severe complications (Clavien-Dindo grade ≥III) was 10.8%, and the mortality rate was 0%. The median postoperative hospital stay was 14 days. Multivariate logistic regression analysis showed that the independent risk factor for clinically relevant POPF after MIDP with a reinforced stapler was a body mass index of ≥22.6 kg/m2 (p=0.050, odds ratio=7.60). CONCLUSION: This study confirmed the safety and efficacy of reinforced staplers for preventing POPF after MIDP. A high body mass index was the only risk factor for clinically relevant POPF after MIDP with a reinforced stapler.

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.

Expression of Porphyromonas gingivalis gingipain antigen Hgp44 domain on surface of Lactococcus lactis.

Porphyromonas gingivalis, a pathogen involved in the development of chronic periodontitis, has a number of major virulence factors, among which are its surface cysteine protease gingipains. The purpose of this study was to investigate the feasibility of inducing protective antibodies against P. gingivalis by means of immunization with recombinant Lactococcus lactis expressing the 44-kDa gingipain adhesion/hemagglutinin domain (Hgp44). Part of the Hgp44 sequence encoding the first 314 amino acid residues, residues 188-251, and residues 354-393 was amplified and inserted into shuttle plasmid pSGANC332, with the resulting chimeric plasmids designated as pISTY210, pCOL, and pSHGRP44A, respectively. After confirming the clone sequences, expression of recombinant proteins was investigated by immunoblot. The results revealed that while pISTY210 and pCOL both expressed the Hgp44 antigen on the surface of L. lactis, the level of expression was quite low. To enhance expression of the protein on the surface of the cells, cysteine residues were changed to serine residues by site-directed mutagenesis. Replacement of 3 out of 5 cysteine residues (pISTY213) significantly increased expression of the recombinant protein on the surface of the bacteria. Interestingly, replacement of the 4th cysteine residue (pISTY215) reduced antigenicity of the recombinant protein. These results indicate that expression of Hgp44 on the surface of L. lactis cells requires the replacement of several key cysteine residues, and that L. lactis expressing this antigen could be a promising candidate for immunization against P. gingivalis-induced periodontitis.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Rapamycin enhances chemotherapy-induced cytotoxicity by inhibiting the expressions of TS and ERK in gastric cancer cells.

We have previously reported the synergistic cytotoxic effects of Docetaxel (TXT) and S-1 in gastric cancer in vitro and in vivo, and the combination regimen is now under phase III clinical trail. In this study, to elucidate whether the rapamycin, the inhibitor of the mTOR (mammalian target of rapamaycin), can enhance the potentiation of TXT and 5-fluorouracil (5-Fu) in gastric carcinoma cells. Rapamycin inhibited the growth of TMK-1, MKN-28, MKN-45 and MKN-74 cell lines by MTT assay, and it demonstrated the cytostatic effects as G1 arrest shown by flowcytometry. However, the cytotoxic effects of 5-Fu, TXT and cisplatin were enhanced by 2 to 4 times with the concomitant administration of rapamycin. To clarify the mechanism of the potentiation, the expression changes of the enzymes relating DNA metabolism and cell growth signal transduction pathways were examined by western blot analysis. Interestingly, the expression of thymidilate synthase was markedly decreased by the administration of rapamycin in TMK-1 cells in a time- and dose-dependent manner. Moreover, rapamycin decreased the phosphorylation of 4E-BP1, the phosphorylation of ERK1/2 and enhanced the phosphorylation of c-Jun NH2-terminal kinase, and the activation of caspase of apoptotic pathways in combination with TXT. These results strongly indicate that the mTOR inhibitor can enhance the potentiation of TXT and 5-Fu or S-1 and can serve as a new therapeutic tool for advanced and recurrent gastric cancer patients.

Identification and formation of volatile components responsible for the characteristic aroma of mat rush (igusa).

An aroma concentrate of the mat rush (igusa) was prepared by combining solvent extraction with the solvent-assisted flavor evaporation (SAFE) technique. An aroma extract dilution analysis (AEDA) applied to the volatile fraction revealed 51 odor-active peaks with FD factors between 4(3) and 4(7). Among the perceived odorants, twelve peaks with the higher FD factors (>or=4(6)) were proved to be the most important components of the characteristic aroma in mat rush. Eleven odorants were identified or tentatively identified from the twelve peaks as methional, (E,Z)-2,6-nonadienal, (E)-2-nonenal, (E,E)-2,4-nonadienal, (E,E,Z)-2,4,6-nonatrienal, trans-4,5-epoxy-(E)-2-decenal, 4-hydroxy-2,5-dimethyl-3(2H)-furanone, 3-hydroxy-4,5-dimethyl-2(5H)-furanone, isovaleric acid, methyl anthranirate, and vanillin. The FD factors of the odor-active peaks in dried mat rush were observed to be much higher than those in raw mat rush. This finding suggests that the drying process during manufacturing of the mat rush is one of the most important factors for the formation of the characteristic mat rush aroma.

[A case of small cell lung cancer (extensive disease) with liver metastasis acquiring stable disease by hepatic arterial infusion chemotherapy].

The patient was a 58-year-old male with small cell lung cancer [T2N1M1 (HEP) ED case] who was treated systemic chemotherapy with 2 courses of CDDP+CPT-11 and 3 courses of CBDCA+PTX. After 5 courses of chemotherapy, the total response was stable disease (SD). Because the primary lesion had achieved a minor response, however, liver metastasis evidenced no change. Because of his good performance status, he was immediately treated by hepatic arterial infusion chemotherapy ( HAI) using CPT-11 to control the liver metastasis. After the HAI of weekly CPT-11 during eleven months until progression of primary lung lesion, no change in size of the liver metastasis was recognized with decreasing ProGRP (18,400 -->5,800). HAI is considered very useful for disease control without progression and for good quality of life.