Role of Chinese Acupuncture in the Treatment for Chemotherapy-Induced Cognitive Impairment in Older Patients With Cancer: Protocol for a Randomized Controlled Trial.

BACKGROUND: Older patients with cancer experience cognitive impairment and a series of neurocognitive symptoms known as chemobrain due to chemotherapy. Moreover, older populations are disproportionately affected by chemobrain and heightened negative mental health outcomes after cytotoxic chemical drug therapy. Chinese acupuncture is an emerging therapeutic option for chemotherapy-induced cognitive impairment in older patients with cancer, despite limited supporting evidence. OBJECTIVE: Our study aims to directly contribute to the existing knowledge of this novel Chinese medicine mode in older patients with cancer enrolled at the Department of Oncology/Chinese Medicine, Nanjing First Hospital, China, thereby establishing the basis for further research. METHODS: This study involves a 2-arm, prospective, randomized, assessor-blinded clinical trial in older patients with cancer experiencing chemobrain-related stress and treated with Chinese acupuncture from September 30, 2023, to December 31, 2025. We will enroll 168 older patients with cancer with clinically confirmed chemobrain. These participants will be recruited through screening by oncologists for Chinese acupuncture therapy and evaluation. Electroacupuncture will be performed by a registered practitioner of Chinese medicine. The electroacupuncture intervention will take about 30 minutes every session (2 sessions per week over 8 weeks). For the experimental group, the acupuncture points are mainly on the head, limbs, and abdomen, with a total of 6 pairs of electrically charged needles on the head, while for the control group, the acupuncture points are mainly on the head and limbs, with only 1 pair of electrically charged needles on the head. RESULTS: Eligible participants will be randomized to the control group or the experimental group in 1:1 ratio. The primary outcome of this intervention will be the scores of the Montreal Cognitive Assessment. The secondary outcomes, that is, attentional function and working memory will be determined by the Digit Span Test scores. The quality of life of the patients and multiple functional assessments will also be evaluated. These outcomes will be measured at 2, 4, 6, and 8 weeks after the randomization. CONCLUSIONS: This efficacy trial will explore whether Chinese electroacupuncture can prevent chemobrain, alleviate the related symptoms, and improve the quality of life of older patients with cancer who are undergoing or are just going to begin chemotherapy. The safety of this electroacupuncture intervention for such patients will also be evaluated. Data from this study will be used to promote electroacupuncture application in patients undergoing chemotherapy and support the design of further real-world studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT05876988; https://clinicaltrials.gov/ct2/show/NCT05876988. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53853.

Lysophosphatidic Acid Up-Regulates Hexokinase II and Glycolysis to Promote Proliferation of Ovarian Cancer Cells.

Lysophosphatidic acid (LPA), a blood-borne lipid mediator, is present in elevated concentrations in ascites of ovarian cancer patients and other malignant effusions. LPA is a potent mitogen in cancer cells. The mechanism linking LPA signal to cancer cell proliferation is not well understood. Little is known about whether LPA affects glucose metabolism to accommodate rapid proliferation of cancer cells. Here we describe that in ovarian cancer cells, LPA enhances glycolytic rate and lactate efflux. A real time PCR-based miniarray showed that hexokinase II (HK2) was the most dramatically induced glycolytic gene to promote glycolysis in LPA-treated cells. Analysis of the human HK2 gene promoter identified the sterol regulatory element-binding protein as the primary mediator of LPA-induced HK2 transcription. The effects of LPA on HK2 and glycolysis rely on LPA2, an LPA receptor subtype overexpressed in ovarian cancer and many other malignancies. We further examined the general role of growth factor-induced glycolysis in cell proliferation. Like LPA, epidermal growth factor (EGF) elicited robust glycolytic and proliferative responses in ovarian cancer cells. Insulin-like growth factor 1 (IGF-1) and insulin, however, potently stimulated cell proliferation but only modestly induced glycolysis. Consistent with their differential effects on glycolysis, LPA and EGF-dependent cell proliferation was highly sensitive to glycolytic inhibition while the growth-promoting effect of IGF-1 or insulin was more resistant. These results indicate that LPA- and EGF-induced cell proliferation selectively involves up-regulation of HK2 and glycolytic metabolism. The work is the first to implicate LPA signaling in promotion of glucose metabolism in cancer cells.

Comparison of the efficacy and safety of S-1-based and capecitabine-based regimens in gastrointestinal cancer: a meta-analysis.

PURPOSE: Oral fluoropyrimidine (S-1, capecitabine) has been considered as an important part of various regimens. We aimed to evaluate the efficacy and safety of S-1-based therapy versus capecitabine -based therapy in gastrointestinal cancers. METHODS: Eligible studies were identified from Pubmed, EMBASE. Additionally, abstracts presented at American Society of Clinical Oncology (ASCO) conferences held between 2000 and 2013 were searched to identify relevant clinical trials. The outcome included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) and advent events. RESULTS: A total of 6 studies (4 RCTs and 2 retrospective analysis studies) containing 790 participants were included in this meta-analysis, including 401 patients in the S-1-based group and 389 patients in the capecitabine-based group. Results of our meta-analysis indicated that S-1-based and capecitabine-based regimens showed very similar efficacy in terms of PFS (HR 0.92, 95% CI 0.78-1.09, P = 0.360), OS (HR 1.01, 95% CI 0.84-1.21, P = 0.949), ORR (HR 1.04, 95% CI 0.87-1.25, P = 0.683) and DCR (HR 1.02, 95% CI 0.94-1.10, P = 0.639). There was also no significant difference in toxicity between regimens other than mild more hand-foot syndrome in capecitabine-based regimens. CONCLUSION: Both the S-1-based and capecitabine-based regimens are equally active and well tolerated, and have the potential of backbone chemotherapy regimen in further studies of gastrointestinal cancers.

Increased risk of developing digestive tract cancer in subjects carrying the PLCE1 rs2274223 A>G polymorphism: evidence from a meta-analysis.

BACKGROUND: To date, the association between phospholipase C epsilon 1 (PLCE1) rs2274223 A>G and risk of digestive tract cancer (DTC) remains inconclusive. To derive a more precise estimation of the association, we conducted a meta-analysis on all eligible case-control studies involving 8281 cases and 10,532 controls. METHODS: A comprehensive search was conducted to identify all eligible studies of PLCE1 rs2274223 polymorphism and digestive tract cancer risk. The pooled odds ratio (OR) and the 95% confidence interval (95% CI) were calculated using a fixed or random effect model. Heterogeneity, publication bias, and sensitivity analysis were also explored. RESULTS: Overall, the PLCE1 rs2274223 A>G polymorphism was associated with risk of DTC in all genetic models (GA vs. AA: OR = 1.21, 95% CI = 1.14-1.29, P<0.001; GG vs. AA: OR = 1.30, 95% CI = 1.06-1.60, P = 0.012; GG/GA vs. AA: OR = 1.20, 95% CI = 1.10-1.32, P<0.001; GG vs. GA/AA: OR = 1.21, 95% CI = 1.01-1.46, P = 0.040). The recessive model did not reach statistically significance when the P values were Bonferroni corrected to 0.0125. In the stratified analysis by cancer type, ethnicity, and source of controls, significantly increased risk was observed for esophagus cancer, Asians in three genetic models (heterozygote comparison, homozygote comparison and dominant model), population-based studies in all genetic models, and for gastric cancer in the heterozygote comparison and dominant model after Bonferroni correction. However, in the subsite of gastric cancer, no significant association was found either in cardia or non-cardia gastric cancer. CONCLUSION: Our study indicated that PLCE1 rs2274223 A>G polymorphism was significantly associated with increased risk of DTC, especially among Asian populations. Due to some minor limitations, our findings should be confirmed in further studies.

A genetic polymorphism in TOX3 is associated with survival of gastric cancer in a Chinese population.

PURPOSE: Recently, genetic polymorphism (rs3803662C>T) in TOX3 was reported to induce the risk of breast cancer. In this study, we hypothesized that rs3803662 could influence gastric cancer survival outcomes. METHODS: With multiplex SNaPshot method, we genotyped TOX3 rs3803662 in 880 gastric patients with surgical resection. The association between genotype and survival outcomes was performed by the Kaplan-Meier method, Cox regression analysis models and the log-rank test. RESULTS: There was no association in the analyses of rs3803662 and survival of gastric cancer. However, the stratified analysis by histology showed that rs3803662 CT/TT genotype was associated with a significantly better survival for diffuse-type gastric cancer (log-rank p = 0.030, hazard ratio [HR]  = 0.67, 95% confidence interval [CI]  = 0.46-0.96), than the CC genotype. In addition, this favorable effect was especially obvious among gastric cancer patients with tumor size >5 cm, T3 and T4 depth of invasion, lymph node metastasis, no drinking, no distant metastasis, no chemotherapy and gastric cardia cancer. CONCLUSIONS: TOX3 rs3803662 might play an important role in the prognostic outcome and treatment of gastric cancer, especially perhaps further help in explaining the reduced risk of death associated with diffuse-type gastric cancer.

Overexpression of Yes-associated protein confers doxorubicin resistance in hepatocellullar carcinoma.

Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies worldwide and is highly resistant to chemotherapy. Yes-associated protein (YAP) is the downstream effector of the Hippo signaling pathway, which is frequently overexpressed in many types of cancers. Amplification of the YAP gene and overexpression of YAP in HCC have previously been reported to contribute to hepatocyte malignant transformation and tumor progression. In this study, we aimed to investigate the potential role of YAP in HCC chemoresistance. Overexpression of YAP resulted in resistance against doxorubicin-induced apoptosis in HCC cell lines, whereas suppression of the endogenous YAP expression by RNA interference demonstrated the reverse effect. Western blotting revealed that, following exposure to doxorubicin, YAP-overexpressing cells exhibited decreased cleaved PARP, increased phosphorylation of Akt and ERK1/2, and elevated Bcl-xL expression in comparison to the vector control. Inhibition of YAP expression sensitized HCC cells to doxorubicin, by exhibiting increased cleaved PARP, decreased levels of phosphorylated Akt, phosphorylated ERK1/2 and Bcl-xL expression. In addition, pretreatment with the MEK1/2 inhibitor U0126 but not the PI3-K inhibitor LY294002 significantly enhanced doxorubicin-induced apoptosis and decreased Bcl-xL expression in YAP-overexpressing HCC cells. Our data provide evidence that overexpression of YAP plays an important role in conferring doxorubicin resistance to HCC, which is at least partially mediated by YAP-induced activation of the MAP kinase pathway. Targeting YAP may be a promising adjunct for overcoming doxorubicin resistance in HCC.

Association of TERT rs2736098 polymorphism with cancer risk: a meta-analysis.

Studies have reported an association between the TERT rs2736098 single nucleotide polymorphism (SNP) and cancer susceptibility, but the results remain inconclusive. Toprovide a more precise estimation of the relationship, a meta-analysis of 8 published studies including 8,070 cases and 10,239 controls was performed. Stratification by sample size, genotyping method, source of controls and ethnicity were used to explore the source of heterogeneity. In the overall analysis, no significant association was found between the TERT rs2736098 polymorphism and cancer risk. However, the result showed the rs2736098 was significantly associated with an increased cancer risk and the heterogeneity was effectively decreased for homozygote comparison by removal of two studies: OR = 1.337 (95% CI = 1.183-1.511; Pheterogeneity = 0.087). In the subgroup analysis by ethnicity, a significantly increased risk of cancers was found among Asians (OR = 1.413, 95% CI = 1.187-1.683 for AA versus GG). Our meta-analysis did not show that the TERT rs2736098 plays an important role in cancer risk. More studies with larger sample size and well-matched controls are needed to confirm the findings.

Addition of vandetanib to chemotherapy in advanced solid cancers: a meta-analysis.

The addition of vandetanib to chemotherapy has been shown to have a marked effect on patients with advanced cancers who had failed previous chemotherapy. We carried out a meta-analysis to determine the efficacy and safety of vandetanib compared with chemotherapy in patients with advanced cancers. For this meta-analysis, we selected randomized clinical trials that compared vandetanib-based therapy (VBT) with the matched chemotherapy or placebo alone in patients with advanced cancers. The outcomes included overall survival (OS), progression-free survival (PFS), the objective response rate, and toxicities. Hazard ratios (HRs) and odds ratios were reported with 95% confidence intervals (CIs). A total of 14 eligible trials were included for the meta-analysis, with 2995 patients in the VBT group and 2479 patients in the control group. A significant improvement was observed in PFS (HR 0.76, 95% CI 0.68-0.86 in all cancers, HR 0.80, 95% CI 0.70-0.90 in lung cancer, HR 0.54, 95% CI 0.40-0.74 in thyroid cancer) and in objective response rate (odds ratio 2.09, 95% CI 1.42-3.07) in the VBT group. However, no significant difference was found in OS (HR 0.96, 95% CI 0.90-1.03). The subgroups of patients with non-small-cell lung cancer who benefited from vandetanib therapy were identified as those with a history of smoking (HR 0.87, 95% CI 0.80-0.95) and an adenocarcinoma histology (HR 0.85, 95% CI 0.77-0.94). In addition, patients who received VBT had an increased incidence of adverse events such as rash, diarrhea, and neutropenia. The addition of vandetanib to chemotherapy significantly improves PFS in patients with locally advanced or metastatic cancers, especially lung and thyroid cancer.

Meta-analysis of chemotherapy with irinotecan or oxaliplatin-involved regimen for untreated metastatic advanced colorectal cancer.

A large number of randomized controlled trials involving chemotherapy in the management of advanced colorectal cancer were conducted. 5-FU/LV in combination with irinotecan (IRI) or oxaliplatin (OXA) was used. The aim of the meta-analysis was to compare and evaluate the effectiveness and safety of the two therapeutic approaches for patients with advanced colorectal cancer. A literature search, study selection and assessment, data collection, and analysis were undertaken by two reviewers according to the Cochrane Handbook for Systematic Reviews of Interventions. Randomized controlled trials (RCTs) or quasi-RCTs comparing IRI versus OXA, in combination with 5-FU/LV in the treatment of advanced colorectal cancer were performed. Seven studies involving 2,107 patients met the inclusion criteria. The OXA + 5-FU/LV regimen showed a significant increase in survival by lower hazard ratios (HR) [HR 1.28; 95% CI (1.13-1.45)] and was associated with lower toxicities. The OXA + 5-FU/LV regimen was superior or equal to the IRI + 5-FU/LV regimen in prolonging time to progression and median survival. The IRI + 5-FU/LV regimen resulted in higher hazard ratios in nausea vomiting/emesis and diarrhea [HR 1.99, 95% CI (1.19-3.31); HR 1.83, 95% CI (1.38-2.44)] and lower hazard ratios in paresthesia, sensory neuropathy, and thrombocytopenia [HR 0.09, 95% CI (0.03-0.23); HR 0.04 95% CI (0.01-0.13); HR 0.19 95% CI (0.05-0.64)] than the OXA + 5-FU/LV regimen. Compared with IRI, OXA is more appropriate for the treatment of advanced colorectal cancer when combined with 5-FU/LV. OXA + 5-FU/LV should be considered as the first-line standard of care for advanced CRC patients.