[A case of disease-free, long survival in a patient with mixed adenoneuroendocrine carcinoma of the gallbladder treated with induction CDDP/CPT-11 chemotherapy and resection].

A 57-year-old woman with a complaint of a right upper quadrant mass was referred to our hospital. Multimodal studies such as PET-CT revealed large hepatic tumors and swollen para-aortic lymph nodes, the origin of which was unclear. Pathological analysis of a biopsy specimen obtained from the liver tumor led to a diagnosis of neuroendocrine carcinoma. After 4 CDDP/CPT-11 chemotherapy treatment courses, remarkable shrinkage of liver tumors and disappearance of the swollen lymph nodes were achieved. Subsequently, liver tumor and extrahepatic bile duct resection and lymphatic dissection were performed. Pathological analysis of the resected specimens revealed that the liver tumors and metastatic lymph nodes originated from the gallbladder, leading to a diagnosis of mixed adenoneuroendocrine carcinoma. After 5 courses of adjuvant chemotherapy using the same regimen, the patient has remained disease free for 24 months since the initialdiagnosis.

[Effectiveness of systemic chemotherapy of GEM+CBDCA+5-FU/LV and hepatic arterial infusion of CDDP in a case of advanced, combined hepatocellular-cholangiocarcinoma with multiple lung metastases].

This patient is a male in his 30's. He was diagnosed as hepatitis B virus-related huge primary liver cancer, 10cm in diameter, located in segment 4, accompanied with left portal thrombus and multiple lung metastases. Ten months after repeating systemic chemotherapy using gemcitabine (GEM)+carboplatin (CBDCA)+5-FU/leucovorin (LV) and hepatic arterial infusion chemotherapy with cisplatin (CDDP) 4 times, extended left lobectomy with caudate lobe could be successfully performed because of marked reducion of the huge tumor. The pathology revealed almost entirely necrotic changes of the main tumor, and the remaining, viable tumor nests showed combined hepatocellular and cholangiocarcinoma. Systemic chemotherapy was repeatedly given afterwards, which kept the pulmonary metastases stable without growth. The present case suggests that systemic chemotherapy using GEM+CBDCA+5-FU/LV may be useful in the multimodal treatment for the combined hepatocellular and cholangiocarcinoma with distant metastases.

Nitric oxide prevents UV-induced phosphorylation of the p53 tumor-suppressor protein at serine 46: a possible role in inhibition of apoptosis.

Ser-46 of p53 is phosphorylated in response to DNA-damage in vivo, and it plays a pivotal role for apoptotic signaling by p53 through regulating the transcriptional activation of genes involved in apoptosis. We found that the presence of the nitric oxide (NO) donor S-nitroso-N-acetyl-D,L-penicillamine (200-800 microM) during UV-irradiation of MCF-7 cells resulted in a significant reduction in the Ser-46 phosphorylation, compared to the UV-irradiated cells without NO. This reduction occurred independently of cyclic GMP generation and without affecting activities of p53 kinases such as the PI3K family, p38 MAPK, and HIPK2. The presence of NO was found to protect HCT116 human colon tumor cells containing wild-type p53 from UV-induced apoptosis, whereas no apparent inhibitory effect of NO on UV-induced apoptosis was observed in those deficient in p53. Our results suggest that NO-mediated protection of apoptosis is p53-dependent, occurring at least partly through NO-inhibition of phosphorylation of p53 on Ser-46.

Induction of apoptosis by stomach cancer-associated protein-tyrosine phosphatase-1.

Stomach cancer-associated protein-tyrosine phosphatase-1 (SAP-1), a transmembrane-type protein-tyrosine phosphatase, is thought to inhibit integrin signaling by mediating the dephosphorylation of focal adhesion-associated proteins. Adenovirus-mediated overexpression of wild-type SAP-1, but not that of a catalytically inactive mutant of this enzyme, has now been shown to induce apoptosis in NIH 3T3 fibroblasts. This effect of SAP-1 was dependent on cellular caspase activities and was preceded by inactivation of two serine-threonine protein kinases, Akt and integrin-linked kinase (ILK), both of which function downstream of phosphoinositide (PI) 3-kinase to promote cell survival. Coexpression of constitutively active forms of PI 3-kinase or Akt (which fully restored Akt and ILK activities) resulted in partial inhibition of SAP-1-induced cell death. Furthermore, expression of a dominant negative mutant of PI 3-kinase did not induce cell death as efficiently as did SAP-1, although this mutant inhibited Akt and ILK activities more effectively than did SAP-1. Overexpression of SAP-1 had no substantial effect on Ras activity. These results suggest that SAP-1 induces apoptotic cell death by at least two distinct mechanisms: inhibition of cell survival signaling mediated by PI 3-kinase, Akt, and ILK and activation of a caspase-dependent proapoptotic pathway.