Clinical effect of double coaxial self-expandable metallic stent in management of malignant colon obstruction

PURPOSEWe aimed to evaluate the clinical effectiveness and safety of double coaxial self-expandable metallic stent (DCSEMS) in management of malignant colonic obstruction as a bridge to surgery or palliation for inoperable patients.METHODSBetween April 2006 and December 2012, 49 patients (27 males and 22 females; median age, 68 years; age range, 38–91 years) were selected to receive decompressive therapy for malignant colonic obstruction by implanting a DCSEMS. Application of DCSEMS was attempted in 49 patients under fluoroscopic guidance. The obstruction was located in the transverse colon (n=2), descending colon (n=7), sigmoid colon (n=24), rectosigmoid junction (n=6), and the rectum (n=10). The intended use of DCSEMS was as a bridge to elective surgery in 23 patients and palliation in 26 patients.RESULTSClinical success, defined as >50% dilatation of the stent with subsequent symptomatic improvement, was achieved in 48 of 49 patients (98%). The stent was properly inserted in all patients. No immediate major procedure-related complications occurred. One patient in the bridge-to-surgery group had colon perforation three days after DCSEMS application. Four patients had late migrations of the double stent.CONCLUSIONApplication of DCSEMS is safe and effective in management of malignant colonic obstruction; it prevents stent migration and tumor ingrowth and lowers perforation rate during the stent application

The combination effect of sodium butyrate and 5-Aza-2'-deoxycytidine on radiosensitivity in RKO colorectal cancer and MCF-7 breast cancer cell lines

<p>Abstract</p> <p>Background</p> <p>The overall level of chromatin compaction is an important mechanism of radiosensitivity, and modification of DNA methylation and histone deacetylation may increase radiosensitivity by altering chromatin compaction. In this study, we investigated the effect of a demethylating agent, a histone deacetylase(HDAC) inhibitor, and the two agents combined on radiosensitivity in human colon and breast cancer cell lines.</p> <p>Methods</p> <p>In this study, we used RKO colorectal cancer cell line and MCF-7 breast cancer cell lines and normal colon cell lines. On each of the cell lines, we used three different agents: the HDAC inhibitor sodium butyrate(SB), the demethylating agent 5-Aza-2'-deoxycytidine(5-aza-DC), and radiation. We then estimated the percentage of the cell survival using the XTT method and experimented to determine if there was an augmentation in the therapeutic effect by using different combinations of the two or three of the treatment methods.</p> <p>Results</p> <p>After treatment of each cell lines with 5-aza-DC, SB and 6 grays of radiation, we observed that the survival fraction was lower after the treatment with 5-aza-DC or SB than with radiation alone in RKO and MCF-7 cell lines(p < 0.001). The survival fraction was lowest when the two agents, 5-aza-DC and SB were combined with radiation in both RKO and MCF-cell lines.</p> <p>Conclusion</p> <p>In conclusion, 5-aza-DC and SB can enhance radiosensitivity in both MCF-7 and RKO cell lines. The combination effect of a demethylating agent and an HDAC inhibitor is more effective than that of single agent treatment in both breast and colon cancer cell lines.</p

Combined inhibition of Bcl-2 family members and YAP induces synthetic lethality in metastatic gastric cancer with RASA1 and NF2 deficiency

Background Targetable molecular drivers of gastric cancer (GC) metastasis remain largely unidentified, leading to limited targeted therapy options for advanced GC. We aimed to identify molecular drivers for metastasis and devise corresponding therapeutic strategies. Methods We performed an unbiased in vivo genome-wide CRISPR/Cas9 knockout (KO) screening in peritoneal dissemination using genetically engineered GC mouse models. Candidate genes were validated through in vivo transplantation assays using KO cells. We analyzed target expression patterns in GC clinical samples using immunohistochemistry. The functional contributions of target genes were studied through knockdown, KO, and overexpression approaches in tumorsphere and organoid assays. Small chemical inhibitors against Bcl-2 members and YAP were tested in vitro and in vivo. Results We identified Nf2 and Rasa1 as metastasis-suppressing genes through the screening. Clinically, RASA1 mutations along with low NF2 expression define a distinct molecular subtype of metastatic GC exhibiting aggressive traits. NF2 and RASA1 deficiency increased in vivo metastasis and in vitro tumorsphere formation by synergistically amplifying Wnt and YAP signaling in cancer stem cells (CSCs). NF2 deficiency enhanced Bcl-2-mediated Wnt signaling, conferring resistance to YAP inhibition in CSCs. This resistance was counteracted via synthetic lethality achieved by simultaneous inhibition of YAP and Bcl-2. RASA1 deficiency amplified the Wnt pathway via Bcl-xL, contributing to cancer stemness. RASA1 mutation created vulnerability to Bcl-xL inhibition, but the additional NF2 deletion conferred resistance to Bcl-xL inhibition due to YAP activation. The combined inhibition of Bcl-xL and YAP synergistically suppressed cancer stemness and in vivo metastasis in RASA1 and NF2 co-deficiency. Conclusion Our research unveils the intricate interplay between YAP and Bcl-2 family members, which can lead to synthetic lethality, offering a potential strategy to overcome drug resistance. Importantly, our findings support a personalized medicine approach where combined therapy targeting YAP and Bcl-2, tailored to NF2 and RASA1 status, could effectively manage metastatic GC.This research was supported by grants of the National Research Foundation (NRF) funded by the Korean government (NRF-RS-2023–00208984, NRF-2021M3H9A1030260, NRF-2021R1F1A1051220, NRF-2016M3A9D5A01952416)