[A case of pathological complete response of advanced rectal cancer with liver metastasis accompanied by tumor thrombus following treatment with bevacizumab/FOLFOX4 chemotherapy].

A 58-year-old man underwent low anterior resection for type 2 rectal cancer with liver metastasis. An abdominal computed tomography (CT) scan showed multiple hepatic tumors (in S2, S3, S4, and S6) and a filling defect in the left portal vein. Pathological examination revealed a moderately differentiated adenocarcinoma, pSS, pN0, ly0, v3, with a tumor thrombus in the portal vein. After surgery, the patient was treated with combined chemotherapy of bevacizumab/Leucovorin and fluorouracil with oxaliplatin (FOLFOX4). After 11 courses of chemotherapy, tumor marker levels normalized, and the sizes of the liver metastases and thrombus in the left portal vein remarkably decreased. Resection of the left hepatic lobe and a partial resection of S6 were performed. Pathological examination revealed no residual cancer cells and indicated that the histological classification due to the chemotherapy regimen was Grade 3. The patient was alive for 5 years after the initial surgery, without recurrence.

Weekly paclitaxel in combination with doxifluridine for peritoneally disseminated gastric cancer with malignant ascites.

BACKGROUND: The efficacy of systemic chemotherapy for peritoneal dissemination of gastric cancer remains unclear. The efficacy of weekly paclitaxel in combination with doxifluridine (5'-DFUR) in gastric cancer patients with malignant ascites was evaluated. PATIENTS AND METHODS: Patients with histologically confirmed gastric cancer with ascites were eligible. The treatment consisted of paclitaxel intravenously (i.v.) administered at 80 mg/m(2) on days 1, 8 and 15 every 4 weeks, and doxifluridine administered orally at 533 mg/m(2) on days 1-5 every week. The response rate for patients with ascites was determined based on the Japanese Classification of Gastric Carcinoma. Also, the concentration of paclitaxel in the ascites was measured. RESULTS: Twenty-four patients were investigated. The response rate (RR) was 41.7%, including complete remission (CR) and partial remission (PR) in 4 and 6 patients, respectively. The concentration of paclitaxel in the ascites was maintained between 0.01 µM and 0.05 µM until 72 hours. The median overall survival (OS) was 215 days, and 1-year survival rate was 29.2%. No severe toxicity was noted. CONCLUSION: Weekly paclitaxel in combination with doxifluridine is effective for gastric cancer patients with malignant ascites with an acceptable toxicity profile.

[A case of complete response for advanced gastric cancer with liver metastasis treated with combination chemotherapy of weekly paclitaxel and doxifluridine].

A 68-year-old man underwent total gastrectomy for Type 3 gastric cancer with liver metastasis. The final finding was T3(SE), N1, H1, P0, CY0(class IV), Stage IV, Cur C. After surgery, he was treated with combination chemotherapy of weekly paclitaxel(PTX)/doxifluridine(5'-DFUR). Paclitaxel was administered at a dose of 80 mg/m(2) on day 1, 8 and 15, and doxifluridine was orally administered at a dose of 533 mg/m(2) day for five days followed by withdrawal for two days. This regimen was repeated every four weeks. After 2 courses, the tumor marker level normalized, and the size of the liver metastasis was remarkably decreased. After 5 courses, a CT scan revealed the liver metastasis had disappeared, and he has now survived without recurrence after the disappearance of the liver metastasis. No severe adverse reactions were observed, and the man can be treated as an outpatient. This therapy may thus be effective in the treatment of advanced gastric cancer following non-curative operation.

PX-RICS mediates ER-to-Golgi transport of the N-cadherin/beta-catenin complex.

Cadherins mediate Ca2+-dependent cell-cell adhesion. Efficient export of cadherins from the endoplasmic reticulum (ER) is known to require complex formation with beta-catenin. However, the molecular mechanisms underlying this requirement remain elusive. Here we show that PX-RICS, a beta-catenin-interacting GTPase-activating protein (GAP) for Cdc42, mediates ER-to-Golgi transport of the N-cadherin/beta-catenin complex. Knockdown of PX-RICS expression induced the accumulation of the N-cadherin/beta-catenin complex in the ER and ER exit site, resulting in a decrease in cell-cell adhesion. PX-RICS was also required for ER-to-Golgi transport of the fibroblast growth factor-receptor 4 (FGFR4) associated with N-cadherin. PX-RICS-mediated ER-to-Golgi transport was dependent on its interaction with beta-catenin, phosphatidylinositol-4-phosphate (PI4P), Cdc42, and its novel binding partner gamma-aminobutyric acid type A receptor-associated protein (GABARAP). These results suggest that PX-RICS ensures the efficient entry of the N-cadherin/beta-catenin complex into the secretory pathway, and thereby regulates the amount of N-cadherin available for cell adhesion and FGFR4-mediated signaling.

PX-RICS, a novel splicing variant of RICS, is a main isoform expressed during neural development.

In our previous study, we identified RICS, a novel beta-catenin-interacting protein with the GAP activity toward Cdc42 and Rac1, and found that RICS plays an important role in the regulation of neural functions, including postsynaptic NMDA signaling and neurite outgrowth. Here we report the characterization of an N-terminal splicing variant of RICS, termed PX-RICS, which has additional phox homology (PX) and src homology 3 (SH3) domains in its N-terminal region. The PX domain of PX-RICS interacted specifically with phosphatidylinositol 3-phosphate [PtdIns(3)P], PtdIns(4)P and PtdIns(5)P. Consistent with this binding affinity, PX-RICS was found to be localized at the endoplasmic reticulum (ER), Golgi and endosomes. We also found that wild-type PX-RICS possessed much lower GAP activity than RICS, whereas a mutant form of PX-RICS whose PX domain lacks the binding ability to phosphoinositides (PIs) exhibited the GAP activity comparable to that of RICS. However, PX-RICS and RICS exhibited similar inhibitory effects on neurite elongation of Neuro-2a cells. Furthermore, we demonstrate that PX-RICS is a main isoform expressed during neural development. Our results suggest that PX-RICS is involved in early brain development including extension of axons and dendrites, and postnatal remodeling and fine-tuning of neural circuits.

Role of the Rho GTPase-activating protein RICS in neurite outgrowth.

The Rho family of small GTPases, including RhoA, Rac1 and Cdc42, are critical regulators of the actin cytoskeleton. In neuronal systems, Rho GTPase-activating proteins (RhoGAPs) and their substrates, Rho GTPases, have been implicated in regulating multiple processes in the morphological development of neurons, including axonal growth and guidance, dendritic elaboration and formation of synapses. RICS is mainly expressed in the brain and functions as a RhoGAP protein for Cdc42 and Rac1 in vitro. To examine the biological function of RICS, we disrupted the RICS gene in mice. RICS knockout mice developed normally and were fertile. However, when cultured in vitro, Cdc42 activity in RICS(-/-) neurons was higher than that in wild-type neurons. Consistent with this finding, hippocampal and cerebellar granule neurons derived from RICS(-/-) mice bore longer neurites than those from wild-type mice. These findings suggest that RICS plays an important role in neurite extension by regulating Cdc42 in vivo.

Mutational analysis of the BAK gene in 192 advanced gastric and colorectal cancers.

The evasion of apoptosis has been linked to the development of cancer. A recent study of a small number of gastric and colorectal cancers found that the BAK gene, which encodes a pro-apoptotic protein, contained somatic mutations in approximately 17% of the samples analyzed. To investigate the precise frequency of BAK mutations, we examined the entire coding sequence of the BAK gene in gastric and colorectal cancers, using polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) analysis and direct sequencing. We could not detect any somatic mutations of the BAK gene in 192 colorectal and gastric cancers. We found only four single-nucleotide substitutions in the coding sequences, which were also found in corresponding normal samples. We conclude that somatic alterations of the BAK gene are rare in colorectal and gastric cancers.

RICS, a novel GTPase-activating protein for Cdc42 and Rac1, is involved in the beta-catenin-N-cadherin and N-methyl-D-aspartate receptor signaling.

Cadherin adhesion molecules are believed to be important for synaptic plasticity. beta-Catenin, which links cadherins and the actin cytoskeleton, is a modulator of cadherin adhesion and regulates synaptic structure and function. Here we show that beta-catenin interacts with a novel GTPase-activating protein, named RICS, that acts on Cdc42 and Rac1. The RICS-beta-catenin complex was found to be associated with N-cadherin, N-methyl-d-aspartate receptors, and postsynaptic density-95, and localized to the postsynaptic density. Furthermore, the GTPase-activating protein activity of RICS was inhibited by phosphorylation by Ca(2+)/calmodulin-dependent protein kinase II. These results suggest that RICS is involved in the synaptic adhesion- and N-methyl-d-aspartate-mediated organization of cytoskeletal networks and signal transduction. Thus, RICS may regulate dendritic spine morphology and strength by modulating Rho GTPases.