Luming Liu

Pilot study of huachansu in patients with hepatocellular carcinoma, nonsmall-cell lung cancer, or pancreatic cancer

Huachansu, a Chinese medicine that comes from dried toad venom from the skin glands of Bufo gargarizans or B. melanostictus, has been used in the treatment of various cancers in China. The authors conducted a pilot study, using a phase 1 trial design, of huachansu in patients with advanced cancer.

The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL

miR‐21 expression in cancer tissue has been reported to be associated with the clinical outcome and activity of gemcitabine in pancreatic cancer. However, resection is possible in only a minority of patients due to the advanced stages often present at the time of diagnosis, and safely obtaining sufficient quantities of pancreatic tumor tissue for molecular analysis is difficult at the unresectable stages. In this study, we investigated whether the serum level of miR‐21 could be used as a predictor of chemosensitivity. We tested the levels of serum miR‐21 in a cohort of 177 cases of advanced pancreatic cancer who received gemcitabine‐based palliative chemotherapy. We found that a high level of miR‐21 in the serum was significantly correlated with a shortened time‐to‐progression (TTP) and a lower overall survival (OS). The serum miR‐21 level was an independent prognostic factor for both the TTP and the OS (HR 1.920; 95% CI, 1.274–2.903, p = 0.002 for TTP and HR 1.705; 95% CI, 1.147–2.535, p = 0.008 for OS). The results from a functional study showed that gemcitabine exposure down‐regulated miR‐21 expression and up‐regulated FasL expression. The increased FasL expression following gemcitabine treatment induced cancer cell apoptosis, whereas the ectopic expression of miR‐21 partially protected the cancer cells from gemcitabine‐induced apoptosis. Additionally, we confirmed that FasL was a direct target of miR‐21. Therefore, the serum level of miR‐21 may serve as a predictor of chemosensitivity in advanced pancreatic cancer. Additionally, we identified a new mechanism of chemoresistance mediated by the effects of miR‐21 on the FasL/Fas pathway.

K-ras mutational status predicts poor prognosis in unresectable pancreatic cancer

OBJECTIVE To determine the prognostic value of K-ras mutations in plasma DNA of unresectable pancreatic cancer patients. METHODS Blood samples were collected from 91 patients with unresectable pancreatic cancer prior to treatment. K-ras gene was amplified from the circulating plasma DNA. Mutations were detected by direct sequencing. The relationship between the types of K-ras gene and prognosis of unresectable pancreatic cancer was evaluated. RESULTS K-Ras codon 12 mutations were found in 30 of 91(33%) plasma DNA samples, 17mutations were c.35G>A (p.G12D), 11 were c.35G>T (p.G12V) and only 2 were c.34G>C (p.G12R)). K-ras codon 12 mutations could significantly reflect the clinical parameters, including TNM tumor staging (P=0.033) and liver metastasis (P=0.014). The median survival time of patients with K-ras mutations was shorter than that of patients with wild-type K-ras gene (3.9 months vs. 10.2 months, P<0.001). K-ras codon 12 mutation from plasma DNA was an independent negative prognostic factor for survival (hazard ratio, 7.39; 95% confidence interval, 3.69-14.89). CONCLUSION K-ras mutation in plasma DNA is a predictive biomarker for a poor prognosis of unresectable pancreatic cancer patients.

Randomized controlled trial of acupuncture for prevention of radiation‐induced xerostomia among patients with nasopharyngeal carcinoma

Xerostomia (dry mouth) after head/neck radiation is a common problem among cancer patients, and available treatments are of little benefit. The objective of this trial was to determine whether acupuncture can prevent xerostomia among head/neck patients undergoing radiotherapy.

The IL-8/CXCR1 axis is associated with cancer stem cell-like properties and correlates with clinical prognosis in human pancreatic cancer cases

CXCR1, a receptor for CXCL8/IL-8, has recently been demonstrated to be associated with cancer stem cell (CSC) populations in certain types of human cancers. However, the effect of CXCR1 on CSC and its prognostic value in human pancreatic cancer remain unknown. In this study, we evaluated the expression of CXCR1 in human pancreatic duct adenocarcinoma (PDAC) and found that positive CXCR1 expression correlated with lymph node metastasis (P = 0.017) and a poor survival rate (HR, 3.748; 95% CI, 1.822 to 7.712; P < 0.001) in patients with PDAC. In addition, we identified significant positive correlations between CXCR1 and CD44 (P = 0.002) and CD133 (P = 0.017). Further functional studies confirmed that IL-8 addition increased sphere formation, CSC populations, and cell invasion of pancreatic cancer cells and that these effects could be reversed by antagonizing CXCR1 with a CXCR1-specific antibody. Therefore, our study demonstrated that the IL-8/CXCR1 axis is associated with the CSC-like properties of pancratic cancer cells and prognosis in human pancreatic cancer. This suggested a way of targeting pancreatic CSCs by disrupting IL-8/CXCR1 axis.

Analgesic effect of high intensity focused ultrasound therapy for unresectable pancreatic cancer.

Objective: To evaluate the pain-alleviating action, feasibility and efficacy of high intensity focused ultrasound (HIFU) for palliation of inoperable pancreatic cancer in humans. Methods: Forty patients with advanced pancreatic cancer were treated with HIFU. There were 13 patients with stage III, and 27 patients with stage IV disease. The locations of the tumours were as follows: head of pancreas in 9 patients, body and/or tail of pancreas in 31 patients. Pain relief, local tumour control rate, median survival and complications were monitored after HIFU treatment. The primary endpoint was to assess pain relief rate and pain relief time (PRT). Secondary endpoints included local progression-free survival time, overall survival (OS), and side effects. Results: There were no severe complications or adverse events related to HIFU therapy in any of the patients treated. Pain relief was achieved in 87.5% of patients, median PRT was 10 weeks. The median local progression-free survival time for all patients was 5 months. The median overall survival time was 10 months for patients with stage III disease, and 6 months for patients with stage IV disease. The median OS time, 6-month and 1-year survival rate for patients as a whole were 8 months, 58.8% and 30.1%, respectively. Conclusions: Although this study may have limitations, preliminary results demonstrate the safety of clinical application of HIFU for pancreatic cancer and reveal it to be a promising mode of treatment for palliation of pain associated with pancreatic cancers.

Sham-controlled, randomised, feasibility trial of acupuncture for prevention of radiation-induced xerostomia among patients with nasopharyngeal carcinoma

BACKGROUND Xerostomia (dry mouth) after head/neck radiation is a common problem among cancer patients. Quality of life (QOL) is impaired, and available treatments are of little benefit. This trial determined the feasibility of conducting a sham-controlled trial of acupuncture and whether acupuncture could prevent xerostomia among head/neck patients undergoing radiotherapy. METHODS A sham controlled, feasibility trial was conducted at Fudan University Shanghai Cancer Center, Shanghai, China among patients with nasopharyngeal carcinoma undergoing radiotherapy. To determine feasibility of a sham procedure, 23 patients were randomised to real acupuncture (N=11) or to sham acupuncture (N=12). Patients were treated three times/week during the course of radiotherapy. Subjective measures were the Xerostomia Questionnaire (XQ) and MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN). Objective measures were unstimulated whole salivary flow rates (UWSFR) and stimulated salivary flow rates (SSFR). Patients were followed for 1 month after radiotherapy. RESULTS XQ scores for acupuncture were significantly lower than sham controls starting in week 3 and lasted through the 1-month follow-up (all Ps <0.001 except for week 3, which was 0.006), with clinically significant differences as follows: week 6 - RR 0.28 [95% confidence interval, 0.10, 0.79]; week 11 - RR 0.17 [95%CI, 0.03, 1.07]. Similar findings were seen for MDASI-HN scores and MDASI-Intrusion scores. Group differences for UWSFR and SSFR were not found. CONCLUSIONS In this small pilot study, true acupuncture given concurrently with radiotherapy significantly reduced xerostomia symptoms and improved QOL when compared with sham acupuncture. Large-scale, multi-centre, randomised and placebo-controlled trials are now needed.

Targeting cancer-related inflammation: Chinese herbal medicine inhibits epithelial-to-mesenchymal transition in pancreatic cancer.

Pancreatic cancer is an almost universally fatal disease resulting from early invasion of adjacent structures and metastasis and the lack of an effective treatment modality. Our previous studies have shown that Qingyihuaji Formula (QYHJ), a seven-herb Chinese medicine formula, had significant anti-cancer effects in pancreatic cancer. Here, we examined the effects of QYHJ on pancreatic cancer cell invasion and metastasis and the potential associated mechanism(s). We found that QYHJ inhibited both tumor growth and metastasis in nude mice with human pancreatic cancer cell xenografts. Further study indicated that QYHJ inhibited epithelial-to-mesenchymal transition (EMT), which is characterized by increased E-cadherin expression and decreased vimentin, N-cadherin and Slug expression. Interleukin 6 (IL-6), a pro-inflammatory cytokine produced mainly by macrophages, could promote cancer cell EMT and invasion. In contrast, treatment with QYHJ inhibited cancer-related inflammation in tumors by decreasing infiltration of tumor-associated macrophages and IL-6 production, thus preventing cell invasion and metastasis. These results suggested that the Chinese herbal medicine QYHJ could inhibit pancreatic cancer cell invasion and metastasis in part by reversing tumor-supporting inflammation.

Oxidative Stress and Apoptosis of Human Brain Microvascular Endothelial Cells Induced by Free Fatty Acids

Damage to endothelial cells is a key event in the pathogenesis of atherosclerosis and vascular disease. This study aimed to determine whether free fatty acids (FFAs) induced oxidative stress and apoptosis in human brain microvascular endothelial cells (HBMVECs) in vitro and, if so, which signalling pathway mediated these effects. After culture in different concentrations of FFAs for 24-72 h, cell viability/proliferation was determined using a cell counting kit, apoptosis was detected by measuring caspase-3 activity and by using annexin V-conjugated fluorescein isothiocyanate/propidium iodide staining, and oxidative stress was evaluated by measuring the levels of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). The HBMVECs exposed to FFAs showed significantly decreased cell proliferation, increased apoptosis and ROS levels, and decreased MMP. In conclusion, the results showed that high levels of FFAs induced oxidative stress, which damaged HBMVECs and resulted in apoptosis.

Multimodality treatment of pancreatic cancer with liver metastases using chemotherapy, radiation therapy, and/or Chinese herbal medicine.

Objective: To explore the utility of multidisciplinary approaches in the treatment of patients with pancreatic cancer with liver metastases (PCLM). Methods: From 2002 to 2007, a total of 164 consecutive patients with PCLM treated with chemotherapy, radiation therapy, and/or Chinese herbal medicine were included in this study. Clinical parameters, treatments received, and survival time from initial diagnosis were analyzed. Results: Of the 164 patients, 113 (69%) were men and 51 (31%) were women, with median age of 58 years. One hundred thirty-two patients (80%) had synchronous liver metastases, and 57 patients (35%) had extrahepatic metastases. Overall median survival time of the 164 patients was 4.7 months; 23 (14%) were alive at least 12 months after initial diagnosis of liver metastases. Karnofsky performance status of less than 80, weight loss (>10% within 6 months), ascites, and carbohydrate antigen 19-9 of 1000 U/mL or greater were the most relevant predictors of poor survival. Multivariate analysis showed that chemotherapy and Chinese herbal medicine were protective factors. Conclusions: Multimodality treatment is well tolerated by patients with PCLM and may be effective in prolonging their survival. Awareness of the implications of these prognostic factors may assist in evaluating the survival potential of patients and selecting the most appropriate treatments.