Tanreqing injection inhibits stemness and enhances sensitivity of non-small cell lung cancer models to gefitinib through ROS/STAT3 signaling pathway.

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has emerged as a significant obstacle in managing patients with EGFR-mutant non-small-cell lung cancer (NSCLC), necessitating the exploration of novel therapeutic approaches. Tanreqing injection (TRQ) is a kind of Chinese patent medicine known for its heat-clearing and detoxifying properties. Studies have shown a correlation between tumor drug resistance and enrichment of cancer stem cells (CSCs). We aim to investigate the feasibility of TRQ enhancing sensitivity to gefitinib by targeting CSCs and reactive oxygen species (ROS). In our study, TRQ significantly inhibited cell proliferation in gefitinib-resistant non-small-cell lung cancer (NSCLC) models including 2D cell lines, 3D cell spheres, tumor-bearing animal and organoids. Compared with the gefitinib group alone, addition of TRQ elevated ROS levels, attenuated upregulation of the protein levels of sex-determining region Y-box 2 (SOX2) and aldehyde dehydrogenase 1 family member A1 (ALDH1A1) induced by gefitinib treatment, and inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Scavenging ROS could restore tumor stemness, attenuate the inhibitory effect on the phosphorylation of STAT3, and promote cell proliferation. These results suggested that TRQ could enhance sensitivity of NSCLC models to gefitinib, providing a new combined treatment strategy.

Bridging the gap: exploring the causal relationship between metformin and tumors.

Objective: Numerous studies have reported that metformin can reduce the risk of tumor development. However, some of the results of these studies are conflicting, necessitating a more reliable evaluation. Methods: We conducted a Mendelian randomization phenome-wide association study (MR-PheWAS) of tumors to explore the causal relationship between metformin and tumors. Two cohorts of patients taking metformin were obtained from the UK Biobank. Complete phenotype data of the tumors were obtained from FinnGen_R10. We elucidated the causal relationship using a two-sample Mendelian randomization (MR) analysis. More importantly, we conducted a meta-analysis to ensure relatively unbiased results. In the MR analysis, we used the inverse-variance weighted (IVW) method as the main outcome indicator. Subsequently, two cohorts were integrated for the meta-analysis. Finally, we investigated the mechanisms through mediational MR analysis. Results: MR analysis revealed that metformin might have a causal relationship with 13 tumor-associated phenotypes in the training cohort. Four phenotypes were validated in the testing cohort. In the training and testing cohorts, metformin exhibited a protective effect against brain meningiomas and malignant neoplasms of the breast (HER-positive), oral cavity, tonsils, and the base of the tongue. Intriguingly, after integrating the results of the two cohorts for the meta-analysis, 12 results were statistically significant. Mediational MR analysis suggested that the effects of metformin on brain meningiomas may be weakened by the presence of the family Oxalobacteraceae. Conclusion: Metformin exhibits potential preventive and therapeutic effects on four types of tumors: brain meningioma, malignant neoplasms of the breast (HER-positive), oral cavity and tonsils, and the base of the tongue. Large randomized controlled trials are required to confirm these findings.

Molecular mechanism of basolateral amygdala involved in electroacupuncture-induced amelioration of cancer pain and concomitant depression based on transcriptomics techniques. / åŸºäºŽè½¬å½•ç»„å­¦æŠ€æœ¯æŽ¢è®¨åŸºåº•å¤–ä¾§æä»æ ¸å‚ä¸Žç”µé’ˆæ²»ç–—ç™Œç—›åŠå ¶è¯±å‘çš„æŠ‘éƒæƒ ç»ªçš„åˆ†å­æœºåˆ¶.

OBJECTIVES: To observe the effect of electroacupuncture (EA) of "Zusanli" (ST36) and "Sanyinjiao" (SP6) on cancer pain and concomitant negative emotion in cancer pain model mice, and to explore its molecular mechanisms in the basolateral amygdala (BLA) by using transcriptomics techniques. METHODS: C57BL/6 mice were randomized into sham operation, model and EA groups, with 10 mice in each group. The cancer pain model was established by injecting PBS suspension containing Lewis lung cancer cells into the femur. The mice in the EA group received EA stimulation(1 mA, 2 Hz) on ST36 and SP6 from the 10th day after modeling, 20 min per day for 12 successive days. The bone damage of the distal femur was observed with X-ray and H.E. staining, respectively. The mechanical pain threshold (MPT) was detected by using von Frey. The depression-like behavior was detected by using sucrose-preference test (sucrose preference index in 12 h), and the immobility (feeling of despair) duration of forced swimming within 4 min. The BLA tissue was extracted for RNA sequencing (RNA library construction, and screening differential gene profiling by transcriptomic sequencing) and bioinformatics analysis. The real-time PCR was used to validate the mRNA expression of differentially expressed genes：tumor necrosis factor superfamily 8 (Tnfsf8), bone marrow stromal cell antigen 1 (Bst1), prodynorphin (Pdyn) and voltage-gated sodium channelß4 (Scn4b). RESULTS: H.E. staining and X-ray showed significant bone damage in the distal femur in cancer pain mice. In contrast to the sham operation group, the MPT on the 1st , 4th, 7th , 10th, 14th and 21st day after modeling and sucrose preference index were significantly decreased (P<0.001, P<0.000 1), and the immobility time of the forced swimming was considerably increased in the model group (P<0.001). In contrast to the model group, the MPT values on the 14th and 21st day and sucrose preference index were obviously increased (P<0.000 1, P<0.05), and the immobility time was strikingly decreased in the EA group (P<0.01). RNA sequencing showed that a total of 404 differentially expressed genes (205 up-regulated, 199 down-regulated) were screened in the model group compared with the sham operation group, and a total of 329 differentially expressed genes (206 up-regulated and 123 down-regulated) were screened in the EA group compared with the model group. Venn diagram analysis of the differentially expressed genes showed that 45 up-regulated and 28 down-regulated genes in the model group were completely reversed by EA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the screened differentially expressed genes revealed that the above differential genes were mainly enriched in the ligand receptor activity, cytokine receptor binding, and cytokine activity related to neuro-inflammation, as well as in neuropeptide signaling pathways related to neuronal excitability, and calcium ion mediated signal transduction. The analysis of KEGG pathway showed that the differentially expressed genes were mainly enriched in the inflammation-related pathways, such as interleukin-17 pathway. Validation analysis of the differentially expressed genes showed that the expression levels of Tnfsf8 and Bst1 were significantly up-regulated in the model group compared with the sham operation group (P<0.01, P<0.05), and down-regulated by EA (P<0.01, P<0.05), while the expression levels of Pdyn and Scn4b were down-regulated in the model group in comparison with the sham operation group (P<0.01), and up-regulated by EA (P<0.05, P<0.01), which was consistent with the changing trend of the gene sequencing results. CONCLUSIONS: Acupuncture of ST36 and SP6 can significantly relieve cancer pain and concomitant negative emotion in cancer pain mice, which may be related to its functions in alleviating neuro-inflammation and relieving the abnormal activities of specific neurons in the BLA.

Topical Traditional Chinese Medicines for Cancer Pain: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND AND OBJECTIVES: Safe and effective management of cancer-related pain is a worldwide challenge. In the search for treatment options, natural products used in Chinese herbal medicines (CHMs) have received attention in clinical studies for their effects on cancer-related pain. The objective of this systematic review is to evaluate the clinical evidence for topically applied CHMs as adjunctive treatments for cancer pain management. METHODS: Nine biomedical databases and 4 clinical trial registries were searched for randomized-controlled trials (RCTs) that reported measures of pain and/or quality of life. Risk of bias was assessed using the Cochrane tool. Meta-analysis employed mean difference (MD) with 95% confidence intervals (random effects). RESULTS: Twenty (20) RCTs (1636 participants) met the inclusion criteria. Meta-analyses were grouped based on the comparisons and outcome measures. For pain intensity, there was a greater reduction in the topical CHM group versus placebo (MD -0.72 [-1.04, -0.40]), no difference when compared to tramadol (MD -0.15 [-0.38, 0.08]), and a greater reduction when topical CHMs were combined with conventional analgesic medications (MD -0.67 [-0.93, -0.40]). Analgesic onset time was reduced in the CHM group compared to tramadol (MD -26.02 [-27.57, -24.47] minutes), and for CHMs combined with conventional medications (MD -19.17 [-21.83, -16.52] minutes). When CHMs were combined with analgesic medications, improvements were found for duration of analgesia (MD 1.65 [0.78, 2.51] hours), analgesic maintenance dose (MD -31.72 [-50.43, -13.01] milligrams/day), and quality of life. CONCLUSION: Addition of topical CHMs to conventional analgesic medications was associated with improved outcomes for pain intensity, some other pain-related outcomes, and measures of quality of life. Limitations included methodological issues in some studies and considerable heterogeneity in some pooled results.

BYL719 reverses gefitinib-resistance induced by PI3K/AKT activation in non-small cell lung cancer cells.

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation often obtain de novo resistance or develop secondary resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs), which restricts the clinical benefit for the patients. The activation of phosphatidylinositol 3-kinase (PI3K)/AKT signal pathway is one of the most important mechanisms for the EGFR-TKIs resistance beyond T790M mutation. There are currently no drugs simultaneously targeting EGFR and PI3K signal pathways, and combination of these two pathway inhibitors may be a possible strategy to reverse theses resistances. To test whether this combinational strategy works, we investigated the therapeutic effects and mechanisms of combining BYL719, a PI3Kα inhibitor, with gefitinib, an EGFR-TKI inhibitor in EGFR-TKIs resistance NSCLC models induced by PI3K/AKT activation. Our results demonstrated that PIK3CA mutated cells showed increased growth rate and less sensitive or even resistant to gefitinib, associated with increased PI3K/AKT expression. The combination of BYL719 and gefitinib resulted in synergistic effect compared with the single agents alone in EGFR-mutated NSCLC cells with PI3K/AKT activation. The inhibition of AKT phosphorylation by BYL719 increased the antitumor efficacy of gefitinib in these cell lines. Moreover, the combined effect and mechanism of gefitinib and BYL719 were also confirmed in the NSCLC cells and patient-derived organoids under 3D culture condition, as well as in vivo. Taken together, the data indicate that PIK3CA mutation induces more aggressive growth and gefitinib resistance in NSCLC cells, and the combination treatment with gefitinib and BYL719 is a promising therapeutic approach to overcoming EGFR-TKIs resistance induced by PI3K/AKT activation.

Electro-acupuncture for health-related quality of life and symptoms in patients with gastric cancer undergoing adjuvant chemotherapy (EAGER): a protocol for a multicenter randomized controlled trial.

BACKGROUND: Patients with local gastric cancer experience a decline of Health-related quality of life (HRQOL) during adjuvant chemotherapy following gastrectomy. Our previous pilot study has indicated the potential of acupuncture to improve HRQOL and control cancer-related symptoms burden. This full-scale trial will focus on confirming the effect of acupuncture for patients with gastric cancer. METHODS: A multicenter, open-label, three-arm randomized controlled trial with 249 patients will be conducted in China. Patients will be randomly assigned, in a ratio of 1:1:1, to receive high-dose acupuncture (HA, 7 times each chemo-cycle for 3 cycles), low-dose acupuncture (LA, 3 times each chemo-cycle for 3 cycles), or no acupuncture. The acupoints prescription consisted of bilateral ST36, PC6, SP4, DU20, EX-HN3, and selected Back-shu points. Patients-reported Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) and modified Edmonton Symptom Assessment Scale (mESAS) during the therapy will be recorded. Area under curve (AUC, 21 days/cycle × 3 cycles) and average trajectory of FACT-Ga and mESAS will be calculated. The primary outcome will be the differences in AUC of the FACT-Ga Trial Outcome Index (TOI) between HA and LA versus control groups. Secondary outcomes include AUCs and average trajectory of other FACT-Ga subscales and mESAS scores. DISCUSSION: This study aims to assess the effect of acupuncture and to compare the difference between LA and HA groups on HRQOL and symptom burden controlling in gastric cancer patients by an adequately powered trial. TRIAL REGISTRATION: This study was approved by the Ethics Committee of the Guangdong Provincial Hospital of Traditional Chinese Medicine (approval number: BF2018-118) with registration at ClinicalTrials.gov (identifier: NCT04360577).

Effect of Fu's subcutaneous needling for cancer pain management: protocol for a pragmatic randomised controlled trial.

INTRODUCTION: Pain is a common symptom in patients with cancer, and pain management is crucial for these patients. Fu's subcutaneous needling (FSN) is a modern acupuncture therapy based on basic medicine commonly used in patients with pain. However, evidence of its effectiveness in treating cancer pain has not been systematically proven. Therefore, this pragmatic randomised controlled trial aims to evaluate the effectiveness and safety of FSN for cancer pain management. METHODS AND ANALYSIS: Overall, 120 eligible patients will be recruited and randomly assigned into two groups using block randomisation. Both groups will be administered analgesic drugs according to the National Comprehensive Cancer Network guidelines. The treatment group will receive FSN therapy one time a day for 6 days. Additionally, we will assess analgesic consumption as the primary outcome and the Numerical Rating Scale, outbreak pain, symptom assessment and adverse events as secondary outcomes to evaluate the effect and safety of FSN in treating cancer pain. The incidence of adverse events will be monitored to assess the safety of FSN. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine (approval No: K(2021)096). The results will be published in a peer-reviewed journal, and trial participants will be informed via email and/or phone calls. TRIAL REGISTRATION NUMBER: ChiCTR2200056348.

Acidified glycerol as a one-step efficient green extraction and preservation strategy for anthocyanin from blueberry pomace: New insights into extraction and stability protection mechanism with molecular dynamic simulation.

In present work, green and efficient glycerol solvent system was coupled with pulse-probe ultrasonication for one-step extraction and preservation of anthocyanin from blueberry pomace. Under optimal conditions (40 min, 174 W, 18.6 mL/g, 20% of glycerol fraction), extraction yield was 23.07 ± 0.09 mg C3GE/g DW. The extracted anthocyanins were characterized by UPLC-Triple-TOF/MS and 10 anthocyanins compounds were tentatively identified. Stability of anthocyanins influenced by solvents were evaluated in varying temperature, pH and light exposure conditions, demonstrating higher stability of anthocyanins in glycerol solvent system than methanol one. Furthermore, mechanism of high efficiency extraction and stability of anthocyanin using glycerol were investigated by quantum chemical calculation with molecular dynamic simulation. Larger solvent accessible surface area (127.16 nm2), hydrogen bonds number (228.16) and hydrogen bonds lifetime (4.35 ps), and lower intermolecular interaction energy (-1080.48 kJ/mol) between anthocyanin and glycerol were responsible for better extraction and preservation of anthocyanins using glycerol system.

Acupuncture for cancer pain: an evidence-based clinical practice guideline.

BACKGROUND: This study aims to develop an evidence-based clinical practice guideline of acupuncture in the treatment of patients with moderate and severe cancer pain. METHODS: The development of this guideline was triggered by a systematic review published in JAMA Oncology in 2020. We searched databases and websites for evidence on patient preferences and values, and other resources of using acupuncture for treatment of cancer pain. Recommendations were developed through a Delphi consensus of an international multidisciplinary panel including 13 western medicine oncologists, Chinese medicine/acupuncture clinical practitioners, and two patient representatives. The certainty of evidence, patient preferences and values, resources, and other factors were fully considered in formulating the recommendations. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was employed to rate the certainty of evidence and the strength of recommendations. RESULTS: The guideline proposed three recommendations: (1) a strong recommendation for the treatment of acupuncture rather than no treatment to relieve pain in patients with moderate to severe cancer pain; (2) a weak recommendation for the combination treatments with acupuncture/acupressure to reduce pain intensity, decrease the opioid dose, and alleviate opioid-related side effects in moderate to severe cancer pain patients who are using analgesics; and (3) a strong recommendation for acupuncture in breast cancer patients to relieve their aromatase inhibitor-induced arthralgia. CONCLUSION: This proposed guideline provides recommendations for the management of patients with cancer pain. The small sample sizes of evidence limit the strength of the recommendations and highlights the need for additional research.

Acupuncture combined with opioids for cancer pain: a pilot pragmatic randomized controlled trial.

OBJECTIVE: Given the existing evidence for the analgesic effect of acupuncture, the current study aimed to assess whether acupuncture could be feasible and manageable as an adjunctive therapy for cancer pain in a real-world hospital setting. METHODS: Thirty patients in an Oncology department with moderate or severe pain were recruited and randomized to an adjunctive acupuncture group or control group, who received pharmacotherapy for pain management without acupuncture. The duration of the treatment course was 1 week with a 2-week follow-up. In total, four acupuncture sessions were administered, on days 1/2/4/6 of the trial. Pain intensity was measured using a numerical rating scale (NRS) and the daily opioid dose was recorded. RESULTS: The overall trends favored acupuncture for both pain intensity and daily opioid consumption. The proportion of participants experiencing at least a 2-point reduction in the NRS at the end of the treatment was 93% (n = 14/15) for the acupuncture group and 57% (n = 8/14) for the control group (risk difference (RD) 36.1%, 95% confidence interval (CI) [7.4%-65.0%]; relative risk (RR) 1.63, 95% CI [1.02-2.62]; p = 0.04). There were no serious adverse events and no dropouts during the treatment. CONCLUSION: This pilot study showed that adding acupuncture to routine analgesia for patients with cancer pain was feasible and acceptable to patients. The clinical effects of adding acupuncture as an adjunctive therapy need to be further evaluated. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR1800017023 (Chinese Clinical Trial Registry).

[Acupoint selection for cancer pain: based on current evidence and Delphi method].

Based on literature research and Delphi expert consensus method, the important acupoints for cancer pain was summarized to provide evidence basis for the formulation of Clinical Practice Guide of Acupuncture in the Treatment of Cancer Pain. Through systematic search of Chinese and English databases, 28 clinical studies regarding acupuncture for cancer pain were included. The acupoint selection methods and high-frequency acupoints were summarized and analyzed. Based on this, a Delphi questionnaire was designed and two rounds of questionnaire survey on 30 experts in acupuncture and tumor related fields in China and abroad were conducted. As a result, it was suggested that the individualized acupoint selection should be adopted for acupuncture treatment of cancer pain, with Zusanli (ST 36), Hegu (LI 4), Taichong (LR 3), Sanyinjiao (SP 6), Yanglingquan (GB 34) and ashi points as the main acupoints. Combined with clinical research evidence and expert consensus, the important acupoints for cancer pain were identified. However, clinical acupoint selection still needed further research and refinement.

Total saponins from Rhizoma Panacis Majoris inhibit proliferation, induce cell cycle arrest and apoptosis and influence MAPK signalling pathways on the colorectal cancer cell.

Colorectal cancer (CRC) ranks third in incidence and second in mortality among all types of cancer, and due to its insidious onset and lack of early symptoms, it is usually diagnosed at a later stage. Saponins, a class of compounds abundant in plants, have been reported to possess prominent anti­tumour properties. The use of ginsenoside Rg3 in the clinical setting was authorized by the National Medicinal Products Administration of China. In the present study, total saponins from Rhizoma Panacis Majoris (RPMTG) were prepared, and the pharmacological mechanisms underlying the anti­CRC effects of RPMTG were investigated. The effect of RPMTG on the proliferation, cell cycle progression and apoptosis of HCT116 and SW620 cells were detected by MTT, flow cytometry and western blotting assays, and it was demonstrated that RPMTG could inhibit the proliferation of HCT116 and SW620 cells with IC50 values of 315.8 and 355.1 µg/ml, respectively, induce cell cycle arrest in the S and G0/G1 phase, and trigger apoptosis by downregulating the expression of the anti­apoptotic proteins Bcl­2, Bcl­xL and induced myeloid leukaemia cell differentiation protein Mcl­1, and increasing the expression of the pro­apoptotic proteins Bax and Bad, cleaved caspased­3 and poly(ADP)­ribose polymerase. These findings suggested that RPMTG induced apoptosis through mitochondrial­related pathways. In addition, RPMTG also decreased the expression of phosphorylated (p)­extracellular signal­regulated kinase and increased p­c­Jun N­terminal kinase (p­JNK) and p­p38. Moreover, the effects of RPMTG on cell proliferation and apoptosis were partially reversed when the JNK and p38 mitogen­activated protein kinase (MAPK) pathways were inhibited, indicating that RPMTG triggered apoptosis mainly via regulating JNK and p38 MAPK signalling. Therefore, RPMTG may have potential as an anti­CRC agent, and further evaluations are needed.

Clinical Evidence for Association of Acupuncture and Acupressure With Improved Cancer Pain: A Systematic Review and Meta-Analysis.

Importance: Research into acupuncture and acupressure and their application for cancer pain has been growing, but the findings have been inconsistent. Objective: To evaluate the existing randomized clinical trials (RCTs) for evidence of the association of acupuncture and acupressure with reduction in cancer pain. Data Sources: Three English-language databases (PubMed, Embase, and CINAHL) and 4 Chinese-language biomedical databases (Chinese Biomedical Literature Database, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, and Wanfang) were searched for RCTs published from database inception through March 31, 2019. Study Selection: Randomized clinical trials that compared acupuncture and acupressure with a sham control, analgesic therapy, or usual care for managing cancer pain were included. Data Extraction and Synthesis: Data were screened and extracted independently using predesigned forms. The quality of RCTs was appraised with the Cochrane Collaboration risk of bias tool. Random-effects modeling was used to calculate the effect sizes of included RCTs. The quality of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. Main Outcomes and Measures: The primary outcome was pain intensity measured by the Brief Pain Inventory, Numerical Rating Scale, Visual Analog Scale, or Verbal Rating Scale. Results: A total of 17 RCTs (with 1111 patients) were included in the systematic review, and data from 14 RCTs (with 920 patients) were used in the meta-analysis. Seven sham-controlled RCTs (35%) were notable for their high quality, being judged to have a low risk of bias for all of their domains, and showed that real (compared with sham) acupuncture was associated with reduced pain intensity (mean difference [MD], -1.38 points; 95% CI, -2.13 to -0.64 points; I2 = 81%). A favorable association was also seen when acupuncture and acupressure were combined with analgesic therapy in 6 RCTs for reducing pain intensity (MD, -1.44 points; 95% CI, -1.98 to -0.89; I2 = 92%) and in 2 RCTs for reducing opioid dose (MD, -30.00 mg morphine equivalent daily dose; 95% CI, -37.5 mg to -22.5 mg). The evidence grade was moderate because of the substantial heterogeneity among studies. Conclusions and Relevance: This systematic review and meta-analysis found that acupuncture and/or acupressure was significantly associated with reduced cancer pain and decreased use of analgesics, although the evidence level was moderate. This finding suggests that more rigorous trials are needed to identify the association of acupuncture and acupressure with specific types of cancer pain and to integrate such evidence into clinical care to reduce opioid use.

Acupuncture for cancer pain: protocol for a pilot pragmatic randomised controlled trial.

INTRODUCTION: Although acupuncture has been recommended for alleviating cancer pain by clinical guidelines, the level of the supporting evidence needs to be improved. A pragmatic randomised controlled trial (pRCT) in a hospital setting would provide real-world assessments of the overall clinical effects of acupuncture. This pilot trial aims to explore the feasibility and provide data for sample size calculations for a pRCT evaluating the effectiveness of acupuncture as an adjunctive therapy to routine medical care for cancer pain. METHODS AND ANALYSIS: Thirty patients with cancer admitted to the oncology department with moderate or severe pain will be recruited. Participants will be randomised at a ratio of 1:1 to the adjunctive acupuncture group or a control group which receives routine pain management without acupuncture. The standardised section of the acupuncture protocol will be developed based on the results of reviews of the literature, recommendations in clinical guidelines and interviews with clinical experts. The acupuncturist will be allowed to tailor the protocol according to the individual situation of each participant. Primary outcomes relevant to the feasibility of conducting a fully powered trial include: numbers and proportions of participants recruited, screened, consented and randomised; numbers and reasons for withdrawals and dropouts; numbers and types of adverse events; feasibility of implementing the trial procedures; evaluation of the comprehensiveness and ease-of-use of the case report form. Secondary outcomes are clinical measurements of the effectiveness of the treatment that are intended for use in the full-scale trial. Analysis of feasibility will be descriptive and pain intensity measures will be analysed using mixed-effects regression. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Institutional Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine (approval no: Z2017-184-01) and RMIT University Human Research Ethics Committee (reference no: 21361). Results will be disseminated in a peer-reviewed journal, and trial participants will be informed via email and/or phone calls. TRIAL REGISTRATION NUMBER: ChiCTR1800017023.

Effectiveness of acupuncture for cancer pain: protocol for an umbrella review and meta-analyses of controlled trials.

INTRODUCTION: The National Comprehensive Cancer Network guidelines for adult cancer pain indicate that acupuncture and related therapies may be valuable additions to pharmacological interventions for pain management. Of the systematic reviews related to this topic, some concluded that acupuncture was promising for alleviating cancer pain, while others argued that the evidence was insufficient to support its effectiveness. METHODS AND ANALYSIS: This review will consist of three components: (1) synthesis of findings from existing systematic reviews; (2) updated meta-analyses of randomised clinical trials and (3) analyses of results of other types of clinical studies. We will search six English and four Chinese biomedical databases, dissertations and grey literature to identify systematic reviews and primary clinical studies. Two reviewers will screen results of the literature searches independently to identify included reviews and studies. Data from included articles will be abstracted for assessment, analysis and summary. Two assessors will appraise the quality of systematic reviews using Assessment of Multiple Systematic Reviews; assess the randomised controlled trials using the Cochrane Collaboration's risk of bias tool and other types of studies according to the Newcastle-Ottawa Scale. We will use 'summary of evidence' tables to present evidence from existing systematic reviews and meta-analyses. Using the primary clinical studies, we will conduct meta-analysis for each outcome, by grouping studies based on the type of acupuncture, the comparator and the specific type of pain. Sensitivity analyses are planned according to clinical factors, acupuncture method, methodological characteristics and presence of statistical heterogeneity as applicable. For the non-randomised studies, we will tabulate the characteristics, outcome measures and the reported results of each study. Consistencies and inconsistencies in evidence will be investigated and discussed. Finally, we will use the Grading of Recommendations Assessment, Development and Evaluation approach to evaluate the quality of the overall evidence. ETHICS AND DISSEMINATION: There are no ethical considerations associated with this review. The findings will be disseminated in peer-reviewed journals or conference presentations. PROSPERO REGISTRATION NUMBER: CRD42017064113.