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Background Along with increasing research on acupuncture for chronic pain, the validity of sham acupuncture (SA) has also been argued. Methods Nine databases were searched for randomized controlled trials (RCTs) from the inception dates of the databases to July 5, 2022. With Markov Chain Monte Carlo methods, a Bayesian multiple-treatment network meta-analysis (NMA) with random-effects model was conducted. Results A total of 62 RCTs with 6,806 patients and four kinds of treatments (real acupuncture [RA], non-acupuncture [NA], penetrative SA [PSA], and non-penetrative SA [NPSA]) were included. The results indicated that both NPSA and PSA were not superior to NA in improving chronic pain (NPSA: mean difference [MD]= –4.77, 95% confidence interval [CI] –11.09 to 1.52; PSA: MD= –4.96, 95% CI –10.38 to 0.48). After NPSA and PSA were combined into the SA group, the weak trend of pain relief from SA was still not statistically significant (MD= –4.91, 95% CI –9.93 to 0.05). NPSA and PSA had similar effects (MD= 0.18, 95% CI –5.45 to 5.81). RA was significantly associated with pain relief, compared with NPSA and PSA (NPSA: MD= –12.03, 95% CI –16.62 to –7.41; PSA: MD= –11.85, 95% CI –15.48 to –8.23). The results were generally consistent regardless of pain phenotype, frequency, duration, acupuncture methods, analgesic intake, or detection bias. Conclusion These results suggested that acupuncture was significantly associated with reduced chronic pain. The two kinds of placebo acupuncture, NPSA and PSA, have similar effects. Both NPSA and PSA, with a weak but not significant effect, are appropriate to be inert placebo controls in RCTs for chronic pain.

Despite significant advances in targeted and immune therapy for non-small cell lung cancer (NSCLC), effective therapies for wild-type epidermal growth factor receptor/anaplastic lymphoma kinase ( EGFR/ALKWT) with low expression of programmed death ligand-1 (PD-L1) NSCLC remain elusive. Numerous studies have shown that ferroptosis plays an essential role in antitumor activity. To identify the molecular regulation patterns associated with ferroptosis, 351 EGFR/ALKWT NSCLC samples with low-level PD-L1 were extracted from The Cancer Genome Atlas (TCGA) and clustered using the k-means clustering technique. The two clusters associated with ferroptosis showed significantly different prognoses. In total, 169 differential expression genes (DEGs) were identified. Cluster differential analysis revealed that Cluster 1 had a significantly poorer overall survival (OS) and was associated with more negative immune regulation. In addition, TCGA samples were randomly assigned in a 7:3 ratio to a training group or testing group. A signature of eight genes associated with ferroptosis was established in the training cohort using DEGs and validated in the test cohort and three independent cohorts (GSE72049, GSE41271, and GSE50081). The 5-year area under the curve (AUC) was 0.713, which was significantly higher than that of other predictors, including TNM stage and age. Furthermore, the risk score was associated with immune function, immune infiltration, and immunotherapy response, with high-risk patients having a worse prognosis, an immune-suppressing phenotype, and a poor response to immune checkpoint inhibitors. This study aims to contribute to our understanding of the biological role of ferroptosis in EGFR/ALKWT NSCLC with low-level PD-L1, laying the groundwork for the development of novel therapeutic strategies.

This study aimed to assess the clinical characteristics affecting outcomes after immune checkpoint inhibitors (ICI) therapies in non-small cell lung cancer (NSCLC) patients, and the underlying mechanism in tumor immune micro-environment (TIME).A total of 144 patients treated with ICI-based strategies were retrospectively analyzed. Expression of 10 immune antibodies in tumor tissues from other 60 untreated NSCLC patients were sequentially tested using multiplexed immunofluorescence (mIF) staining method. Correlation of clinical characteristics with ICI treatment outcomes and TIME characteristics were analyzed.Multivariate logistic and cox regression indicated that BoM negatively affected disease control rate (OR = 0.32, 95%CI: 0.13-0.82, P = 0.018), progression free survival (HR = 3.44, 95% CI:1.97-6.00, P 0.001) and overall survival (HR = 3.24, 95% CI:1.62-6.50, P = 0.001), irrespective of programmed death-ligand 1 (PD-L1) expression. BoM patients were with significantly lower PD-L1, and this heterogeneity of TIME was then confirmed in the mIF staining, where 36 (61.0%) patients were clustered into immune-subtype A, with low expression of all the detected immune markers, similar to "cold" tumors, and 23 (39.0%) in cluster B with likely "hot" tumors. More patients in immune-subtype A were non-smokers (63.9% vs. 39.1% P = 0.063), with BoM (66.7% vs. 21.7%, P = 0.001), in stage IV(88.9% vs. 65.2%, P = 0.045), and with adenocarcinoma (91.7% vs. 69.6%, P = 0.037). Multivariate logistic regression indicated that BoM was independently associated with the "cold" immune characteristics (OR = 0.19, 95% CI:0.04-0.84, P = 0.028). Combination therapy with chemotherapy /antiangiogenesis or use of bisphosphonate during ICI treatment significantly improved clinical outcomes in BoM patients.BoM displays adverse impact on clinical outcomes after ICI treatments in NSCLC patients. The "cold" characteristics of TIME may be the underlying mechanism for the attenuated efficacy of ICIs in bone metastatic NSCLC patients.

To observe the efficacy of acupuncture on symptom burden in patients with gastric cancer during adjuvant chemotherapy after gastrectomy.A total of 58 patients were randomized into a high-dose acupuncture group (19 cases, 5 cases dropped off), a low-dose acupuncture group (20 cases, 6 cases dropped off) and a control group (19 cases, 2 cases dropped off). Conventional chemotherapy and antiemetic treatment were adopted in the control group. On the basis of the treatment in the control group, acupuncture was applied 7 times each chemotherapy cycle for totally 21 times in the high-dose acupuncture group, and 3 times each chemotherapy cycle for totally 9 times in the low-dose acupuncture group. Baihui (GV 20), Zusanli (ST 36), Neiguan (PC 6), etc. were selected in the two acupuncture groups, as well as back-The symptom burden was worst within 7 days of each cycle of chemotherapy in the 3 groups. After the 3rd chemotherapy cycle, the total score of ESAS in the low-dose acupuncture group was lower than the control group (Acupuncture shows promising effect in controlling symptom burden during adjuvant chemotherapy in gastric cancer patients after gastrectomy.

Along with increasing research on acupuncture for chronic pain, the validity of sham acupuncture (SA) has also been argued.Nine databases were searched for randomized controlled trials (RCTs) from the inception date to July 5, 2022. Using Markov Chain Monte Carlo methods, a Bayesian multiple treatment network meta-analysis (NMA) with random-effects model was conducted.A total of 62 RCTs with 6806 patients and four kinds of treatments (real acupuncture (RA), non-acupuncture (NA), penetrative SA (PSA) and non-penetrative SA (NPSA)) were included. The results indicated that both NPSA and PSA were not superior to NA in improving chronic pain (NPSA: MD -4.77 [95% CI, -11.09 to 1.52]; PSA: MD, -4.96 [95% CI, -10.38 to 0.48]). After combining NPSA and PSA into the SA group, the weak trend of pain relief from SA was still not statistically significant (MD, -4.91 [95% CI, -9.93 to 0.05]). NPSA and PSA had similar effects (MD, 0.18 [95% CI, -5.45 to 5.81]). RA was significantly associated with pain relief, compared with NPSA and PSA (NPSA: MD, -12.03 [95% CI, -16.62 to -7.41]; PSA: MD, -11.85 [95% CI, -15.48 to -8.23]). The results were generally consistent regardless of pain phenotype, frequency, duration, acupuncture methods, analgesic intake, or detection bias.These results suggested that acupuncture was significantly associated with reduced chronic pain. The two kinds of placebo acupuncture, NPSA and PSA, have similar effects. Both NPSA and PSA, with a weak but not significant effect, are appropriate to be inert placebo controls in RCTs for chronic pain.

Haochuan Ma,1,* Zhiyong Xu,1,* Rui Zhou,1,* Yihong Liu,2 Yanjuan Zhu,1– 4 Xuesong Chang,2 Yadong Chen,2 Haibo Zhang1– 5 1The Second Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, People’s Republic of China; 3Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 4Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, People’s Republic of China; 5State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haibo ZhangDepartment of Oncology, Guangdong Provincial Hospital of Traditional Chinese Medicine, No. 111, Dade Road, Guangzhou, Guangdong, 510120, People’s Republic of ChinaTel +86-20-81887233Fax +86-20-81874903Email haibozh@gzucm.edu.cnPurpose: This study was designed to construct and validate a nomogram that was available for predicting cancer-specific survival (CSS) in patients with pulmonary large-cell neuroendocrine carcinoma (LCNEC).Patients and Methods: Using the US Surveillance, Epidemiology, and End Results (SEER) database, we identified patients pathologically diagnosed as LCNEC from 1975 to 2016. Univariate and multivariate Cox regression was conducted to assess prognostic factors of CSS. A novel nomogram model was constructed and validated by the concordance index (C-index), calibration curves and decision curve analysis (DCA).Results: A total of 624 LCNEC patients were enrolled. Five prognostic factors for CSS were identified and merged to establish nomograms. In the training and validation cohorts, calibration curves displayed the nomogram predictions are in a good agreement with the actual survival. The C-Index of the training and validation cohorts were both higher than 0.8, and the DCA results showed that the nomogram has clinical validity and utility.Conclusion: The proposed nomogram resulted in accurate CSS prognostic prediction for patients with LCNEC.Keywords: pulmonary large-cell neuroendocrine carcinoma, prognosis, nomogram, SEER database, cancer-specific survival

Context Patients with gastric cancer experience health-related quality of life (HRQOL) decline during adjuvant chemotherapy following gastrectomy. Objectives This pilot study aimed to evaluate the preliminary effect and feasibility of electro-acupuncture (EA) for HRQOL and symptom burden in these patients. Methods In this open-label, multicenter, parallel controlled trial, gastric cancer patients who planned to receive adjuvant chemotherapy were randomly assigned to receive high-dose EA (seven times each chemotherapy cycle for three cycles), low-dose EA (three times each chemotherapy cycle), or usual care only. The acupoints prescription consisted of bilateral ST36, PC6, SP4, and DU20, EX-HN3, and selected Back-shu points. Patients completed the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) weekly, and the Edmonton Symptom Assessment System (ESAS). The primary outcome was the difference among the groups on the gastric cancer subscale (GaCS) of the FACT-Ga. Results Of the 66 randomized patients, 58 were analyzed according to intention-to-treat principle, and 45 were in the per-protocol set (PPS). The average scores in PPS of GaCS were 52.12±9.71, 51.85±12.36, and 45.37±8.61 in high-dose EA, low-dose EA, and control groups, respectively. EA was significantly associated with improved average GaCS scores when compared with control group (51.98±10.91 vs. 45.37±8.61, P = 0.039). EA treatment also produced ESAS relief at the end of intervention (14.36 ± 12.28 vs. 23.91 ± 15.52, P = 0.027). Participants in EA groups had fewer grade ≥3 leukopenia (0% vs. 15.79%, P = 0.031) and neutropenia (2.56% vs. 26.31%, P = 0.012). Conclusion EA showed promising effects in improving HRQOL, controlling symptom burden, and reducing toxicity during adjuvant chemotherapy in gastric cancer patients. Future adequately powered trials are feasible and needed to confirm the specific effect of EA.

Patients with EGFR gene mutation often obtain de novo resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) or develop secondary resistance to EGFR-TKIs after taking EGFR-TKI therapy. Traditional Chinese medicine (TCM) with different treatment principles, in combination with EGFR-TKIs, plays an important role in the treatment of cancers including resistant non-small cell lung cancer (NSCLC). However, inappropriate use of TCM herbs may induce resistance to gefitinib. Therefore, it is of a great value to evaluate which TCM treatment principle should be combined with EGFR-TKIs, and which one should be avoided, and find out the potential mechanisms. The lentiviral transfection assay was used for overexpression of PIK3CA mutation gene in PC-9 cells to construct PC-9-PIK3CA-mutation (PC-9-PIK3CA-M) cells. Cell proliferation, apoptosis, and the expression of EGFR/PI3K/AKT and EGFR/RAS/RAF/ERK in PC-9-PIK3CA-M and H1975 cells treated by the typical cooling-heat drug, Qing-kai-ling (QKL) and Tan-re-qing (TRQ), or the typical warming-yang drug, Shen-fu (SF) and gefitinib treatment, were detected by MTT, Annexin V/PI double labeling, and Western blot assays, respectively. Tumor xenograft and immunohistochemistry experiments were carried out to confirm the in vitro findings. PC-9-PIK3CA-M cells were less sensitive to gefitinib, when compared with PC-9 cells. QKL injection and TRQ injection, not SF injection, combined with gefitinib induced significantly increased cell growth inhibition and apoptosis in PC-9-PIK3CA-M and H1975 cells. SF injection antagonized the effect of gefitinib in promoting cancer cell apoptosis. QKL injection and TRQ injection increased the sensitivity of gefitinib by inhibiting the phosphorylation of AKT or ERK in H1975 and PC-9-PIK3CA-M cells. Similar findings were observed in vivo in H1975 xenograft mouse model. QKL and TRQ, with cooling-heat TCM treatment principle, should be combined with gefitinib in the treatment of NSCLC. Furthermore, warming-yang drug SF should be avoided to be used together with EGFR-TKIs.

IntroductionAlthough 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 analysisThirty 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 disseminationEthics 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 numberChiCTR1800017023