Lapatinib acts on gastric cancer through both antiproliferative function and augmentation of trastuzumab-mediated antibody-dependent cellular cytotoxicity.

BACKGROUND: Trastuzumab has been recently approved for clinical use to treat HER2-expressing advanced gastric cancer, and anti-HER2-targeting therapy has become a promising option for gastric cancer. Lapatinib is a dual tyrosine kinase inhibitor targeting EGFR and HER2. The aim of the present study was to explore the utility of lapatinib for gastric cancer, with a particular focus on trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC). METHODS: Nine gastric cancer cell lines were evaluated for the effects of lapatinib on the cell-surface accumulation of HER2 and analyzed for their additional effects on trastuzumab-mediated ADCC. Also, HER2 signaling with Western blot, proliferative function with the MTT assay, and apoptosis-inducing activity with 7ADD/Annexin-V were investigated when a panel of gastric cancer cell lines was treated with lapatinib. RESULTS: Lapatinib inhibited HER2 signaling and cell proliferation in the panel of gastric cancer cell lines. Lapatinib also induced the accumulation of HER2 on the cell surface, resulting in the enhancement of trastuzumab-mediated ADCC of gastric cancer. CONCLUSIONS: Lapatinib exhibits inhibitory activity in gastric cancer cells, and the combination of lapatinib with trastuzumab may be a promising treatment strategy for gastric cancer patients.

Lapatinib inhibits receptor phosphorylation and cell growth and enhances antibody-dependent cellular cytotoxicity of EGFR- and HER2-overexpressing esophageal cancer cell lines.

Lapatinib is a dual tyrosine kinase inhibitor of the EGFR and HER2 tyrosine kinase domains. EGFR is expressed in 33.3% and HER2 in 30.3% of esophageal squamous cell carcinomas (ESCCs). To explore the potential utility of Lapatinib for therapy of ESCC patients, we evaluated the effect of Lapatinib on a panel of ESCC cell lines. EGFR and HER2 expression by the cell lines was established, and the effects of Lapatinib on inhibition of the phosphorylation of HER2, antiproliferative effect, apoptosis-inducing activity and accumulation of HER2 and EGFR on cell surface were evaluated. Additionally, the combined effect of Lapatinib together with Herceptin or Cetuximab on cell-mediated cytotoxicity was evaluated. Lapatinib inhibited HER2 phosphorylation in HER2-overexpressing, HER2 gene amplification positive ESCC cell line. Lapatinib also inhibited cell proliferation, induced apoptosis and caused the surface accumulation of HER2 and EGFR in ESCC cell lines. Addition of Lapatinib increased Herceptin-mediated antibody-dependent cell-mediated cytotoxicity by 15-25% with three ESCC target cell lines. Similarly, Cetuximab-mediated antibody-dependent cell-mediated cytotoxicity also increased by 15-30% in two ESCC cell lines on addition of Lapatinib. Cumulatively, the data indicate that Lapatinib has activity in EGFR- and/or HER2-expressing ESCC cells, and the combination therapy of Lapatinib and Cetuximab/Herceptin is a promising strategy in ESCC.

Tumor Vascular Microenvironment of Colorectal Hepatic Metastasis and Chemotherapy Response.

BACKGROUND: The tumor vascular microenvironment has an important role in tumor progression and metastasis. The objective of this study was to assess the significance of metastatic hepatic tumor vascular microenvironment in relation to the response to systemic fluorouracil-based chemotherapy [folinic acid/fluorouracil/oxaliplatin (FOLFOX) or folinic acid/fluorouracil/irinotecan (FOLFIRI)]. PATIENTS AND METHODS: A total of 48 consecutive patients with colorectal cancer (CRC) with hepatic metastasis were retrospectively reviewed, and factors such as metastatic tumor vascular microenvironment, chemotherapy response and hepatic resection, were analyzed. Tumor angiogenesis was microscopically evaluated by microvessel density (MVD) in sections stained immunochemically with antibody to CD34 in patients with hepatic resection. Angiogenesis in the tumor microenvironment in association with ring enhancement (RE) on computed tomography (CT) was also examined. RESULTS: Microscopic examination revealed that peripheral RE on CT of the metastatic tumor was associated with tumor angiogenesis by MVD. The overall response rate after six courses of first-line chemotherapy for liver metastasis with RE on CT was 64% (23/36), whereas the response rate for those without RE was 25% (3/12), which was significantly lower, although the survival of patients with RE-positive and RE-negative tumors did not differ significantly. CONCLUSION: Peripheral RE of metastatic hepatic tumor on CT was associated with angiogenesis in the tumor microenvironment and higher chemotherapy response.

An extremely rare combination of choledochocele and bile duct duplication escalating severe acute pancreatitis and cholangitis: A case report.

BACKGROUND: Combination of choledochocele and extra-hepatic duct duplication is an extremely rare congenital abnormality. CASE PRESENTATION: The patient was an 81-year-old Japanese man. He visited the emergency room for severe abdominal colic pain. He was diagnosed with severe pancreatitis with cholelithiasis and treated conservatively by percutaneous trans-hepatic gallbladder drainage (PTGBD) for 4 months. Thereafter, he was transferred to our institute and cholangiography was performed via the PTGBD tube, revealing cholecysto- and choledocho-lithiasis. The cystic-duct joined the right hepatic duct with extra-hepatic bile duct duplication and the terminal bile duct flowed into the cystic papilla of Vater. The main pancreatic duct also joined into the cystic papilla. These observations confirmed choledochocele with extra-hepatic bile duct duplication. Surgical exploration was performed, and hepatico-jejunostomy with hepatic-ductplasty and cholecystectomy with choledocholithotomy were carried out. He was discharged and his course was uneventful. CONCLUSION: A very rare combined case of choledochocele with bile duct duplication, which would escalate the pancreatitis and cholangitis, was successfully treated. Their pathogeneses in relation to pancreaticobiliary maljunction is discussed.

Expression of MHC Class I on breast cancer cells correlates inversely with HER2 expression.

HER2 is a promising target for immunotherapeutic interventions with T cell-based approaches since it is amplified and overexpressed in 20-30% of breast cancers. However, several previous studies including ours showed that HER2-overexpressing tumors may escape cytotoxic T lymphocyte-mediated lysis by downregulating MHC Class I and components of the antigen-processing machinery. The aims of the present study were to analyze the relationship between HER2 and MHC Class I expression and to elucidate the mechanisms underlying MHC Class I downregulation in breast cancer. We explored expression of HER2, MHC Class I, PTEN, Ki67, estrogen and progesterone expression in 70 breast cancer patients by immunohistochemistry (IHC) and analyzed their correlation. We also explored the components of the signal transduction pathway that are involved in the regulation of MHC Class I expression using small-interfering RNAs targeting HER2 as well as an inhibitor of HER2 signaling. HER2 expression in breast cancers correlated inversely with MHC Class I expression analyzed by IHC. HER2 depletion by small-interfering RNAs resulted in MHC Class I upregulation. Moreover, MHC Class I expression on breast cancer cell lines was upregulated by PD98059, an inhibitor of mitogen-associated protein kinases, in a dose-dependent manner. Thus, agents that target the MAPK signaling pathway may increase MHC Class I expression in breast cancer cells.

Immunonutritional diet modulates natural killer cell activation and Th17 cell distribution in patients with gastric and esophageal cancer.

OBJECTIVE: Although randomized clinical trials have shown that immunonutrition results in the improvement of postoperative complications, the detailed mechanisms of its immunomodulation are still unclear. In the present study, we investigated if such immunonutrition could affect T-cell and natural killer (NK) cell functions, with particular focus on type 17 helper T (Th17) cells and NK cell-activating markers, in patients with esophageal and gastric cancer and in healthy volunteers. METHODS: Patients (n = 22) and healthy volunteers (n = 10) were orally administered an immunonutritional diet (Impact, 750 mL/d) in addition to a conventional diet for 5 d. The expression of NK cell-activation markers (NKG2D, CD16, CD107a, NKp30, NKp44, and NKp46), frequency of CD56(dim) NK, Th17, and regulatory T cells, and trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity were analyzed before and after immunonutrition. RESULTS: Immunonutrition significantly enhanced antibody-dependent cell-mediated cytotoxic activity as an NK cell function, paralleling the upregulated expression of NKG2D and CD16 and increased frequency of CD56(dim) NK cells. Furthermore, the immunonutrition significantly increased the frequency of Th17 cells. CONCLUSION: Immunonutrition modulates NK and T-cell-mediated immunity.

Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression.

BACKGROUND: Although it was previously reported that lapatinib combined with Herceptin improved the progression-free survival rate compared with lapatinib alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. MATERIALS AND METHODS: We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). RESULTS: In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. CONCLUSION: Lapatinib may have the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2.

Complete remission of multiple recurrent hepatocellular carcinomas by oral administration of enteric-coated tegafur/uracil in a patient with huge hepatocellular carcinoma extending to the inferior vena cava after hepatic resection: analysis of mRNA expression of fluoropyrimidine metabolism enzymes in the primary tumor.

We herein report the complete remission of multiple recurrent hepatocellular carcinomas (HCCs) by the oral administration of tegafur/uracil (UFT) alone. A 56-year-old Japanese man with two huge HCCs was admitted and underwent hepatic resection. Intraoperative ultrasonography revealed that the tumor thrombus extended to the inferior vena cava (IVC) with a small tumor in the left hepatic lobe. Right trisectionectomy of the liver, removal of the tumor thrombus in the IVC, and partial resection of the left lobe were performed. Microscopic examination revealed that the larger tumor was moderately to poorly differentiated HCC and the smaller tumor was well-differentiated HCC. The small tumor in the left lobe was diagnosed as an intrahepatic metastasis of the larger tumor. Two months after the surgery, computed tomography (CT) revealed multiple HCC recurrences in the remnant liver, but complete remission was achieved by the administration of UFT alone. To clarify the reason for the good response of the recurrent HCC to UFT, the mRNA expression level of several fluoropyrimidine metabolism enzymes was measured in resected specimens. A lower expression of thymidine phosphorylase (TP) might explain the good response to UFT. The patient is alive without intra- or extrahepatic recurrence more than 6 years after the hepatic resection.