Hirofumi Toi

Endoglin-Targeted Cancer Therapy

Vascular-targeting antiangiogenic therapy (VTAT) of cancer can be advantageous over conventional tumor cell targeted cancer therapy if an appropriate target is found. Our hypothesis is that endoglin (ENG; CD105) is an excellent target in VTAT. ENG is selectively expressed on vascular and lymphatic endothelium in tumors. This allows us to target both tumor-associated vasculature and lymphatic vessels to suppress tumor growth and metastasis. ENG is essential for angiogenesis/vascular development and a co-receptor of TGF-β. Our studies of selected anti-ENG monoclonal antibodies (mAbs) in several animal models and in vitro studies support our hypothesis. These mAbs and/or their immunoconjugates (immunotoxins and radioimmunoconjugates) induced regression of preformed tumors as well as inhibited formation of new tumors. In addition, they suppressed metastasis. Several mechanisms were involved in the suppressive activity of the naked (unconjugated) anti-ENG mAbs. These include direct growth suppression of proliferating endothelial cells, induction of apoptosis, ADCC (antibody-dependent cell-mediated cytotoxicity) and induction of T cell immunity. To facilitate clinical application, we generated a human/mouse chimeric anti-ENG mAb termed c-SN6j and performed studies of pharmacokinetics, toxicology and immunogenicity of c-SN6j in nonhuman primates. No significant toxicity was detected by several criteria and minimal immune response to the murine part of c-SN6j was detected after multiple i.v. injections. The results support our hypothesis that c-SN6j can be safely administered in cancer patients. This hypothesis is supported by the ongoing phase 1 clinical trial of c-SN6j (also known as TRC105) in patients with advanced or metastatic solid cancer in collaboration with Tracon Pharma and several oncologists (NCT00582985).

The upstream regulator, Rsr1p, and downstream effectors, Gic1p and Gic2p, of the Cdc42p small GTPase coordinately regulate initiation of budding in Saccharomyces cerevisiae

Background: Cdc42p, a Rho family small GTPase, is essential for budding initiation in the yeast Saccharomyces cerevisiae. The homologous proteins Gic1p and Gic2p (Gic1/2p) are effectors of Cdc42p, but their precise functions remain unknown. Rsr1p/Bud1p is a Ras family small GTPase that controls the selection of the budding site. Previous observations suggested that Rsr1p‐GTP recruits Cdc24p, a GDP/GTP exchange factor for Cdc42p, at the incipient bud site. However, this model only addresses how Rsr1p determines the budding site, because the rsr1 mutant normally initiates budding.

Preoperative evaluation of hepatic functional reserve by converted ICGR15 calculated from 99mTc‐GSA scintigraphy

Background and Aim:  Conversion of data from technetium 99 m diethylenetriaminepentaacetic acid galactosyl human serum albumin (99mTc‐GSA) scintigraphy to ICGR15 (indocyanin green retention at 15 min) is an easy and convenient method for obtaining parameters to determine the appropriate and safe extent of liver resection. We investigated a conversion method which also accounts for LHL15 (receptor index: uptake ratio of the liver to the liver plus heart at 15 min) and HH15 (blood clearance index: uptake ratio of the heart at 15 min to that at 3 min) characteristics.

Percutaneous transhepatic gallbladder drainage followed by elective laparoscopic cholecystectomy in patients with moderate acute cholecystitis under antithrombotic therapy.

Standard treatment for acute cholecystitis (AC) in patients receiving antithrombotic drugs has not been established. We evaluated the safety of percutaneous transhepatic gallbladder drainage (PTGBD) followed by elective laparoscopic cholecystectomy (LC) in patients with moderate AC who were receiving antithrombotics.

Hepatic sinusoidal obstruction associated with S-1 plus cisplatin chemotherapy for highly advanced gastric cancer with paraaortic lymph node metastases: report of a case

A 56-year-old man who was diagnosed with gastric cancer with multiple paraaortic lymph node metastases was treated with S-1 plus cisplatin. The spleen gradually enlarged during the therapeutic courses. After the 6th course of therapy, the primary gastric lesion and paraaortic lymphadenopathies disappeared. He underwent a curative resection, including a distal gastrectomy with regional and paraaortic lymph node dissections. Irregularly distributed congestion of the liver was noted during the surgery. Histological examinations revealed residual cancer cells in 3 regional lymph nodes and no cancer cells in the primary site and paraaortic lymph nodes. Hepatic sinusoidal obstruction syndrome (SOS) was also confirmed histologically. This is the first report of a case with SOS after S-1 plus cisplatin therapy. S-1 plus cisplatin therapy can cause SOS, although it is a promising preoperative chemotherapy for highly advanced gastric cancer.