Long-Term Outcome of Repeat Microvascular Decompression for Hemifacial Spasm.

OBJECTIVE: Although repeat microvascular decompression (MVD) for hemifacial spasm (HFS) in patients with failed prior MVD is potentially curative, little is known about the long-term results of repeat MVD. We aimed to evaluate the long-term outcomes and complications after repeat MVD for HFS. METHODS: We performed repeat MVD on 78 consecutive patients who had undergone a prior MVD >1 year previously. Follow-up data were available for 58 patients, with a median follow-up period of 8.6 years (range, 6.9-10.2 years). The patients were assessed for intraoperative findings, relief results, and complications at discharge and at follow-up, as well as the associations between the preoperative characteristics and outcomes. RESULTS: At discharge, of 78 patients with repeat MVD, 72 (92.3%) achieved complete spasm resolution and 1 (2.6%) had significantly improved spasm resolution. Of all patients, 9% (7 of 78) presented short-term complications, including partial hearing loss, hemifacial paresis, and cerebrospinal fluid leak. At follow-up, 45 of 58 (77.6%) patients had complete relief and 10 of 58 (17.2%) had improved relief. Permanent complications occurred in 14 patients (24.1%), with partial hearing loss and mild hemifacial paresis being the most common. Despite the complications, 51 of 58 patients (91.4%) reported an excellent life quality. No significant correlation was found between preoperative characteristics, such as age, interval to prior MVD, or interval to recurrence, and outcomes including short-term or long-term relief results and complications. CONCLUSIONS: Repeat MVD provides lasting relief for most patients with persistent or recurrent HFS, albeit with a relatively high complication rate.

Gastric Lgr5(+) stem cells are the cellular origin of invasive intestinal-type gastric cancer in mice.

The cellular origin of gastric cancer remains elusive. Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is the first identified marker of gastric stem cells. However, the role of Lgr5(+) stem cells in driving malignant gastric cancer is not fully validated. Here, we deleted Smad4 and PTEN in murine gastric Lgr5(+) stem cells by the inducible Cre-LoxP system and marked mutant Lgr5(+) stem cells and their progeny with Cre-reporter Rosa26(tdTomato). Rapid onset and progression from microadenoma and macroscopic adenoma to invasive intestinal-type gastric cancer (IGC) were found in the gastric antrum with the loss of Smad4 and PTEN. In addition, invasive IGC developed at the murine gastro-forestomach junction, where a few Lgr5(+) stem cells reside. In contrast, Smad4 and PTEN deletions in differentiated cells, including antral parietal cells, pit cells and corpus Lgr5(+) chief cells, failed to initiate tumor growth. Furthermore, mutant Lgr5(+) cells were involved in IGC growth and progression. In the TCGA (The Cancer Genome Atlas) database, an increase in LGR5 expression was manifested in the human IGC that occurred at the gastric antrum and gastro-esophageal junction. In addition, the concurrent deletion of SMAD4 and PTEN, as well as their reduced expression and deregulated downstream pathways, were associated with human IGC. Thus, we demonstrated that gastric Lgr5(+) stem cells were cancer-initiating cells and might act as cancer-propagating cells to contribute to malignant progression.

Akt-p53-miR-365-cyclin D1/cdc25A axis contributes to gastric tumorigenesis induced by PTEN deficiency.

Although PTEN/Akt signaling is frequently deregulated in human gastric cancers, the in vivo causal link between its dysregulation and gastric tumorigenesis has not been established. Here we show that inactivation of PTEN in mouse gastric epithelium initiates spontaneous carcinogenesis with complete penetrance by 2 months of age. Mechanistically, activation of Akt suppresses the abundance of p53, leading to decreased transcription of miR-365, thus causing upregulation of cyclin D1 and cdc25A, which promotes gastric cell proliferation. Importantly, genetic ablation of Akt1 restores miR-365 expression and effectively rescues gastric tumorigenesis in PTEN-mutant mice. Moreover, orthotopic restoration of miR-365 represses PTEN-deficient-induced hyperplasia. In human gastric cancer tissues, miR-365 reduction correlates with poorly differentiated histology, deep invasion and advanced stage, as well as the deregulation of PTEN, phosphorylated Akt, p53, cyclin D1 and cdc25A. These data demonstrate that the PTEN-Akt-p53-miR-365-cyclin D1/cdc25A axis serves as a new mechanism underlying gastric tumorigenesis, providing potential new therapeutic targets.