Zhiqiang Meng

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.

ROR functions as a ceRNA to regulate Nanog expression by sponging miR-145 and predicts poor prognosis in pancreatic cancer

lncRNAs have emerged as key regulators of tumor development and progression. ROR is a typical lncRNA that plays important regulatory roles in the pathogenesis and progression of tumors. Nevertheless, current understanding of the involvement of ROR in pancreatic adenocarcinoma tumorigenesis remains limited. In this study, we measured ROR in 61 paired cancerous and noncancerous tissue samples by qRT-PCR and investigated the biological role of ROR on the phenotypes of pancreatic cancer stem cells (PCSCs) in vitro and in vivo. The effects of ROR on PCSCs were studied by RNA interference approaches in vitro and in vivo. Insights of the mechanism of competitive endogenous RNAs (ceRNAs) were gained from bioinformatic analysis, luciferase assays and RNA binding protein immunoprecipitation. The positive ROR/Nanog interaction was identified and verified by immunohistochemistry assay. Compared with adjacent non-tumor tissues, ROR was up-regulated in most tumor tissues. Knockdown of ROR by RNA interference in PCSCs inhibited proliferation, induced apoptosis and decreased migration. Moreover, ROR silencing resulted in significantly decreased tumourigenicity of PCSCs in nude mice than controls. In particular, ROR may act as a ceRNA, effectively becoming a sink for miR-145, thereby activating the derepression of core transcription factors Nanog. In conclusions, we demonstrated that decreased ROR expression could inhibit cell proliferation, invasion, and tumourigenicity by modulating Nanog. Therefore, ROR is a potential novel prognostic marker to predict the clinical outcome of pancreatic cancer patients after surgery and may be a rational target for therapy.

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.

Safety evaluation of high-intensity focused ultrasound in patients with pancreatic cancer

Introduction: This study was performed to analyze the safety of high-intensity focused ultrasound (HIFU) for treating pancreatic cancer. Methods: 224 cases with advanced pancreatic cancer were enrolled into this study. Real-time sonographic images were taken, and vital signs, liver and kidney function, skin burns, local reactions, and systemic effects were monitored and recorded before, during, and after HIFU. Computed tomography or magnetic resonance imaging (MRI) was also performed before and after HIFU. Results: Serum amylase level increased in 16 cases (7.1%) 1 day after HIFU treatment, and 9 of these cases also had abnormal urinary amylase levels. Gastrointestinal (GI) dysfunction such as abdominal distension and anorexia with slight nausea was observed in 10 cases (4.5%) after HIFU treatment. 1 case with pancreatic head cancer developed obstructive jaundice 2 weeks after HIFU treatment. Vertebral injury, identified by MRI, occurred in 2 cases, although no symptoms were seen. No severe complications such as skin burns, lesion bleeding, GI tract bleeding or GI perforation were observed in any of the cases. Conclusion: For specific patients, HIFU treatment is a safe, non-invasive treatment for pancreatic cancer but requires careful preoperative preparation and exact operative performance.

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.