[Prehepatectomy Chemotherapy Using Circadian Chrono-HAI for Liver Metastases from Colorectal Cancer].

We investigated the safety and efficacy of circadian chronotherapy via the hepatic artery(chrono-HAI)as a prehepatectomy chemotherapy for initially unresectable colorectal liver metastases. Five-day course of chrono-HAI using 5-FU, l-LV, and L-OHP plus systemic panitumumab with 9-day interval were administered to 24 patients with failure for previous chemotherapy. Response rate and Grade 3 adverse effect(AE) were 63% and 54%, respectively. Among 22 patients( excluding 2 CR patients), conversion surgery could be performed in 10(45%). Two-year overall survival of patients with surgery (58%)was longer in those without(20%, p=0.057). Although incidence of AE was a bit high, chrono-HAI plus systemic panitumumab is an effective prehepatectomy chemotherapy for patients with aggressive colorectal liver metastases.

TAS0728, A Covalent-binding, HER2-selective Kinase Inhibitor Shows Potent Antitumor Activity in Preclinical Models.

Activated HER2 is a promising therapeutic target for various cancers. Although several reports have described HER2 inhibitors in development, no covalent-binding inhibitor selective for HER2 has been reported. Here, we report a novel compound TAS0728 that covalently binds to HER2 at C805 and selectively inhibits its kinase activity. Once TAS0728 bound to HER2 kinase, the inhibitory activity was not affected by a high ATP concentration. A kinome-wide biochemical panel and cellular assays established that TAS0728 possesses high specificity for HER2 over wild-type EGFR. Cellular pharmacodynamics assays using MCF10A cells engineered to express various mutated HER2 genes revealed that TAS0728 potently inhibited the phosphorylation of mutated HER2 and wild-type HER2. Furthermore, TAS0728 exhibited robust and sustained inhibition of the phosphorylation of HER2, HER3, and downstream effectors, thereby inducing apoptosis of HER2-amplified breast cancer cells and in tumor tissues of a xenograft model. TAS0728 induced tumor regression in mouse xenograft models bearing HER2 signal-dependent tumors and exhibited a survival benefit without any evident toxicity in a peritoneal dissemination mouse model bearing HER2-driven cancer cells. Taken together, our results demonstrated that TAS0728 may offer a promising therapeutic option with improved efficacy as compared with current HER2 inhibitors for HER2-activated cancers. Assessment of TAS0728 in ongoing clinical trials is awaited (NCT03410927).

Adjuvant hepatic arterial infusion chemotherapy with 5-Fluorouracil and interferon after curative resection of hepatocellular carcinoma: a preliminary report.

BACKGROUND AND AIM: Advanced hepatocellular carcinoma (HCC) with portal vein invasion or intrahepatic metastases has an unfavorable prognosis, even after curative hepatic resection. The aim of the present study was to evaluate the efficacy of adjuvant hepatic arterial infusion chemotherapy with 5-fluorouracil (5-FU) and systemic interferon (IFN). PATIENTS AND METHODS: Patients who were diagnosed as having HCC with portal vein invasion or intrahepatic metastases were included in the study (n=33). Out of these patients, 16 were treated with adjuvant therapy consisting of continuous arterial infusion of 5-FU and subcutaneous injection of IFN-α. Another 17 patients who underwent hepatic resection without adjuvant chemotherapy served as controls. RESULTS: The five-year cumulative survival rate was significantly higher in the adjuvant treatment group (71.1%) than in the control group (44.0%; p=0.023). The rate of patients with multiple (≥4) recurrent intrahepatic nodules was significantly lower in the adjuvant group (44.4%) than in the control group (100%; p=0.040). The development of intrahepatic recurrence within 12 months was significantly lower in the adjuvant group (33.3%) than in the control group (80.0%; p=0.040). CONCLUSION: Our data suggest that this adjuvant chemotherapy can improve postoperative prognosis by reducing intrahepatic recurrence.

Usefulness of prophylactic transcatheter arterial infusion of anticancer agents with lipiodol to prevent recurrence of hepatocellular carcinoma after hepatic resection.

To improve the prognosis after hepatectomy for HCC, repeated postoperative transcatheter arterial infusions of anticancer drugs and lipiodol (TAI) were given. TAI may be effective as an adjuvant therapy for prevention of residual liver recurrence after hepatectomy, probably by suppression of the development of intrahepatic micrometastases rather than of multicentric carcinogenesis.

[Efficacy of circadian chronotherapy via hepatic arterial infusion].

For hepatectomy after neoadjuvant chemotherapy (NAC), we applied circadian chronotherapy via the hepatic artery for multiple bilobar liver metastases from colorectal cancer. Four patients underwent chronotherapy and 16 patients underwent flat infusion therapy (5 day q 2 weeks, 4 or more courses). We used 2 drugs, (5-fluorouracil (5-FU) and l-leucovorin (l-LV)), and partially added cisplatin (CDDP) in the flat infusion group. The result was a higher response rate (75% vs 37.5%) and lower toxicity (0% vs 31.3%) in the chronotherapy group. Hepatectomy was performed on 12 of the 20 patients. The 5 responders to NAC showed better overall survival (p < 0.05) and lower remnant liver recurrence (p = 0.052) than the 7 non-responders. We therefore conclude that chronotherapy via the hepatic artery prior to hepatectomy may improve the survival of patients with multiple bilobar liver metastases.