PurposeThis study aimed to evaluate the clinical value of high-intensity focused ultrasound (HIFU) combined with gemcitabine (GEM) in treating unresectable pancreatic ductal adenocarcinoma (PDAC).Patients and methodsA total of 523 unresectable PDAC patients were recruited from December 30, 2007 to January 30, 2015 at Fudan University Shanghai Cancer Center. Among them, 347 received HIFU combined with GEM (with regional intra-arterial chemotherapy [RIAC] or with systemic chemotherapy) and the remaining patients received GEM only. Postoperative complications were observed, and overall survival was recorded.ResultsThe median overall survival of patients who received HIFU combined with GEM vs GEM alone was 7.4 vs 6.0 months (P=0.002); the 6-month, 10-month, 1-year, and 2-year survival rates for patients in these two groups were 66.3% vs 47.5% (P<0.0001), 31.12% vs 15.9% (P<0.0001), 21.32% vs 13.64% (P=0.033), and 2.89% vs 2.27% (P=0.78), respectively. In the combined therapy group, the most obvious survival benefits were obtained among patients who received HIFU plus RIAC and systemic chemotherapy (used in the intervals between RIAC treatments). There were no severe complications in patients undergoing HIFU treatment.ConclusionWe demonstrated the survival benefit of HIFU among PDAC patients treated with GEM. The benefit was most obvious in PDAC patients treated with HIFU plus RIAC and systemic chemotherapy.

Recent studies have suggested that sonic Hedgehog (Shh) signaling pathway is aberrantly activated in cancer stem cells (CSCs). A seven-herb Chinese medicinal formula composed of Amorphophallus rivieri Durieu, Oldenlandia diffusa (Wild) Roxb, Scutellaria barbata D. Don, Gynostemma pentaphyllum (Thunb.) Mak and Amomum cardamomum L, i.e. Qingyihuaji (QYHJ) formula, has been shown to inhibit proliferation of pancreatic CSCs by inhibiting Shh signaling pathway and thereby prolong the overall survival of pancreatic cancer patients. Mass spectrometry analysis revealed that baicalein is one of the major compounds of QYHJ formula. The objective of this study was to investigate the role of Shh pathway in pancreatic cancer and to examine the molecular mechanisms of baicalein involved in pancreatic cancer treatment. We examined the effects of baicalein on pancreatic CSCs both in vivo and in vitro. The results indicated that baicalein attenuated the pluripotency of pancreatic CSCs. Then, we investigated the underlying mechanism and found that nuclear transcription factors, such as Sox-2 and Oct-4 as well as members in Shh signaling pathway, e.g. SHH, SMO, and Gli-2, were downregulated after baicalein treatment. Furthermore, silencing Gli-2 expression by small interfering RNA decreased Sox-2 expression and blocked the inhibitory effects of baicalein, suggesting that the effects of baicalein may be mediated through inhibition of Shh pathway. Our results suggested that baicalein, an active compound in QYHJ formula, could suppress the self-renewal of pancreatic CSCs through inhibition of Shh signaling pathway.

Evidence from in vitro and in vivo studies shows that Ski may act as both a tumor proliferation-promoting factor and a metastatic suppressor in human pancreatic cancer and also may be a therapeutic target of integrative therapies. At present, pancreatic cancer stem cells (CSCs) are responsible for tumor recurrence accompanied by resistance to conventional therapies. Sonic hedgehog (Shh) signaling pathway is found to be aberrantly activated in CSCs. The objectives of this study were to investigate the role of Ski in modulating pancreatic CSCs and to examine the molecular mechanisms involved in pancreatic cancer treatment both in vivo and in vitro. In in vitro study, the results showed that enhanced Ski expression could increase the expression of pluripotency maintaining markers, such as CD24, CD44, Sox-2, and Oct-4, and also components of Shh signaling pathway, such as Shh, Ptch-1, Smo, Gli-1, and Gli-2, whereas depletion of Ski to the contrary. Then, we investigated the underlying mechanism and found that inhibiting Gli-2 expression by short interfering RNA (siRNA) can decrease the effects of Ski on the maintenance of pancreatic CSCs, indicating that Ski mediates the pluripotency of pancreatic CSCs mainly through Shh pathway. The conclusion is that Ski may be an important factor in maintaining the stemness of pancreatic CSCs through modulating Shh pathway.

Qingyihuaji formula (QYHJ), confirmed efficacious in a series of clinical trials, has been applied to human pancreatic carcinoma treatment in Shanghai Cancer Center for years. Recent evidence highlighted that pluripotent stem cells transcription factor Nanog plays a pivotal role in carcinogenesis. However, there is little published information regarding the underlying clinical significance and mechanisms of transcription factor Nanog in pancreatic cancer. In this study, our results indicated that Nanog is overexpressed in human pancreatic cancer stem cells and downregulated by QYHJ, which may contribute to explain the clinical effectiveness of QYHJ and provide advanced pancreatic cancer patients with a new therapeutic option, supporting our hypothesis that the degradation pathway is another mechanism by which QYHJ affects Nanog expression.