Antitumor effect of the tyrosine kinase inhibitor nilotinib on gastrointestinal stromal tumor (GIST) and imatinib-resistant GIST cells.

Despite the benefits of imatinib for treating gastrointestinal stromal tumors (GIST), the prognosis for high risk GIST and imatinib-resistant (IR) GIST remains poor. The mechanisms of imatinib resistance have not yet been fully clarified. The aim of the study was to establish imatinib-resistant cell lines and investigate nilotinib, a second generation tyrosine kinase inhibitor (TKI), in preclinical models of GIST and imatinib-resistant GIST. For a model of imatinib-resistant GIST, we generated resistant cells from GK1C and GK3C cell lines by exposing them to imatinib for 6 months. The parent cell lines GK1C and GK3C showed imatinib sensitivity with IC50 of 4.59±0.97 µM and 11.15±1.48 µM, respectively. The imatinib-resistant cell lines GK1C-IR and GK3C-IR showed imatinib resistance with IC50 values of 11.74±0.17 µM (P<0.001) and 41.37±1.07 µM (P<0.001), respectively. The phosphorylation status of key cell signaling pathways, receptor tyrosine kinase KIT (CD117), platelet-derived growth factor receptor alpha (PDGFRA) and downstream signaling kinases: serine-threonine kinase Akt (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) or the non-receptor tyrosine kinase: proto-oncogene tyrosine-protein kinase Src (SRC), was analyzed in established cell lines and ERK1/2 phosphorylation was found to be increased compared to the parental cells. Nilotinib demonstrated significant antitumor efficacy against GIST xenograft lines and imatinib-resistant GIST cell lines. Thus, nilotinib may have clinical potential for patients with GIST or imatinib-resistant GIST.

Advanced endoscopic submucosal dissection with traction.

Endoscopic submucosal dissection (ESD) has been established as a standard treatment for early stage gastric cancer (EGC) in Japan and has spread worldwide. ESD has been used not only for EGC but also for early esophageal and colonic cancers. However, ESD is associated with several adverse events, such as bleeding and perforation, which requires more skill. Adequate tissue tension and clear visibility of the tissue to be dissected are important for effective and safe dissection. Many ESD methods using traction have been developed, such as clip-with-line method, percutaneous traction method, sinker-assisted method, magnetic anchor method, external forceps method, internal-traction method, double-channel-scope method, outerroute method, double-scope method, endoscopic-surgical-platform, and robot-assisted method. Each method has both advantages and disadvantages. Robotic endoscopy, enabling ESD with a traction method, will become more common due to advances in technology. In the near future, simple, noninvasive, and effective ESD using traction is expected to be developed and become established as a worldwide standard treatment for superficial gastrointestinal neoplasias.

Establishment and characterization of novel cell lines and xenografts from patients with gastrointestinal stromal tumors.

At present, no suitable GIST model exists for the analysis of drug resistance or metastasis using established human gastrointestinal stromal tumor (GIST) cell lines or xenografts even though the molecular mechanisms of drug resistance, progression and metastasis require clarification. The aim of this study was to establish and characterize human GIST cell lines and xenografts that can be used for evaluating drug resistance or various new molecularly targeted therapies. GIST tissues from patients were cultured and implanted under the skin of NOG (NOD/Shi-scid, IL-2Rrnu) mice. Two new cell lines (GK1C and GK3C) and three xenografts (GK1X, GK2X and GK3X) were generated from these clinical samples. The established GIST cell lines and xenografts were investigated for tumorigenesis and imatinib sensitivity. These cell lines and xenografts showed characteristic GIST morphology and exhibited KIT expression profiles similar to those of the patient samples. In addition, these GIST cell lines and xenografts were sensitive to imatinib. In conclusion, new human GIST cell lines and xenografts were established and maintained through repeated passages. These models will enable further study of combination therapies and the mechanisms of resistance, and allow testing of novel targeted monotherapies and combination therapies.

[A case of metastatic esophageal cancer - endoscopic resection of the primary site following systemic chemotherapies].

A 64-year-old male presented with discomfort in the chest. His endoscopic examination and CT scan showed esophageal cancer with multiple liver metastases. A total of ten courses of systemic chemotherapy by 5-fluorouracil (5-FU) (800 mg for five days) and cisplatin (CDDP) (80 mg/day on the first day of the week for four weeks) were performed, and liver and lymph node metastases disappeared. The primary lesion was the only site detected positive by PET scan. After a concurrent chemoradiation therapy, salvage endoscopic mucosal resection (EMR) was performed on the remainder of the primary site and the patient gained a complete response (CR). We report this case because, although the mean survival time of advanced esophageal cancer is less than one year, this patient responded to chemotherapy and gained complete response by salvage EMR. This patient has had no recurrence for four years since his initial diagnosis.