Objective To systematically evaluate the overall efficacy of external application of traditional Chinese medicine(EA-TCM)in combination with oral three-step analgesic ladder therapy for patients suffering from cancer-...Objective To systematically evaluate the overall efficacy of external application of traditional Chinese medicine(EA-TCM)in combination with oral three-step analgesic ladder therapy for patients suffering from cancer-induced bone pain(CIBP).Methods We conducted a literature search of randomized controlled trials on the combination of EA-TCM and three-step analgesic ladder therapy for CIBP across ten databases and two registration systems.It included four Chinese databases[Chinese Biomedical Literature Database(SinoMed),China National Knowledge Infrastructure(CNKI),Wanfang Database,and China Science and Technology Journal Database(VIP)],six English databases(Scopus,Embase,Web of Science,PubMed,Cochrane Library,and OpenGrey),and two registration systems(Chinese Clinical Trial Registry and ClinicalTrials.gov).The timeframe for the literature search extended from the inception of each database to December 31,2023.Meta-analysis was performed using RevMan(v5.4.1),and the outcome indicators(pain relief rate,analgesic duration,quality of life,pain intensity,breakthrough pain frequency,and adverse reactions)were graded using GRADE profiler(v3.6).Results According to the established inclusion and exclusion criteria,a total of 43 studies was deemed eligible,involving 3142 participants with CIBP.The results of meta-analysis showed that compared with oral three-step analgesic ladder therapy alone,the combined therapy of EA-TCM and three-step analgesic ladder has a significant improvement in pain relief rate[risk ratio(RR)=1.32,95%confidence interval(CI):1.24 to 1.41,P<0.00001],analgesic duration[mean difference(MD)=1.33,95%CI:0.97 to 1.69,P<0.00001],and quality of life(MD=5.66,95%CI:4.88 to 6.44,P<0.00001).Furthermore,the combined therapy significantly reduced pain intensity(MD=-1.00,95%CI:-1.19 to-0.80,P<0.00001),breakthrough pain frequency(MD=-0.43,95%CI:-0.51 to-0.36,P<0.00001),and adverse reactions(RR=0.60,95%CI:0.53 to 0.68,P<0.00001)in CIBP patients.Based on the GRADE assessment,the level of evidence varied from low to moderate.Conclusion EA-TCM combined with the three-step analgesic ladder therapy can effectively alleviate pain symptoms in patients with CIBP and improve their quality of life.Additionally,the EA-TCM can effectively reduce the incidence of adverse reactions associated with threestep analgesic therapy.展开更多
Cancer-induced bone pain(CIBP)is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone metastasis.CIBP constitutes a specific pain state with distinct characteristics;however,it shares similari...Cancer-induced bone pain(CIBP)is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone metastasis.CIBP constitutes a specific pain state with distinct characteristics;however,it shares similarities with inflammatory and neuropathic pain.At present,although various therapies have been developed for this condition,complete relief from CIBP in patients with cancer is yet to be achieved.Hence,it is urgent to study the mechanism underlying CIBP to develop efficient analgesic drugs.Herein,we focused on the peripheral mechanism associated with the initiation of CIBP,which involves tissue injury in the bone and changes in the tumor microenvironment(TME)and dorsal root ganglion.The nerve–cancer and cancer–immunocyte cross-talk in the TME creates circumstances that promote tumor growth and metastasis,ultimately leading to CIBP.The peripheral mechanism of CIBP and current treatments as well as potential therapeutic targets are discussed in this review.展开更多
Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP). Rostral ventromedial medulla (RVM) is a critical component of descending nociceptive facili...Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP). Rostral ventromedial medulla (RVM) is a critical component of descending nociceptive facilitation circuitry, but so far the mechanisms are poorly known. In this study, we investigated the role of RVM glial activation in the descending nociceptive facilitation circuitry in a CIBP rat model. CIBP rats showed significant activation of microglia and astrocytes, and also up-regulation of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and pro-inflammatory mediators released by glial cells (IL-1β, IL-6, TNF-α and brain-derived neurotrophic factor) in the RVM. Stereotaxic microinjection of the glial inhibitors (minocycline and fluorocitrate) into CIBP rats’ RVM could reverse the glial activation and significantly attenuate mechanical allodynia in a time-dependent manner. RVM microinjection of p38 MAPK inhibitor (SB203580) abolished the activation of microglia, reversed the associated up-regulation of proinflammatory mediators and significantly attenuated mechanical allodynia. Taken together, these results suggest that RVM glial activation is involved in the pathogenesis of CIBP. RVM microglial p38 MAPK signaling pathway is activated and leads to the release of downstream pro-inflammatory mediators, which contribute to the descending facilitation of CIBP.展开更多
Bone metastasis,a life-threatening complication of advanced breast cancer,is often accompanied by debilitating pain(cancer-induced bone pain,CIBP)that severely impairs life quality and survival.The concurrent treatmen...Bone metastasis,a life-threatening complication of advanced breast cancer,is often accompanied by debilitating pain(cancer-induced bone pain,CIBP)that severely impairs life quality and survival.The concurrent treatment of bone metastases and CIBP remains a clinical challenge because the therapeutic options are limited.In this study,we construct a near-infrared light-activated nano-therapeutic system to meet this conundrum.In detail,sorafenib(SRF)and photosensitizer(chlorin e6,Ce6)are encapsulated into mesoporous hydroxyapatite nanoparticles(HANPs),which are further functionalized with hyaluronic acid(HA)to obtain HA-SRF/Ce6@HANPs system.The designed nanoplatform destroys tumor cells in vitro and in vivo via the synergism of SRF(interrupting the exchange of cystine/glutamate by inhibiting SLC7A11)and photodynamic therapy(PDT,inducing reactive oxygen species generation).The decrease in tumor burden and reduction of extracellular glutamate significantly attenuate CIBP in mice model with developing bone cancer.Moreover,the combination of HA-SRF/Ce6@HANPs and PDT inhibit osteoclasts activation,promote osteoblast differentiation and accelerate bone repair.Overall,the nanoagent with good biocompatibility may provide an effective therapy method for the concurrent treatment of breast cancer bone metastasis and CIBP.展开更多
Background： Calpain, a calcium-dependent cysteine protease, has been demonstrated to regulate osteoclastogenesis, which is considered one of the major reasons for cancer-induced bone pain （CIBP）. In the present stu...Background： Calpain, a calcium-dependent cysteine protease, has been demonstrated to regulate osteoclastogenesis, which is considered one of the major reasons for cancer-induced bone pain （CIBP）. In the present study, calpain inhibitor was applied in a rat CIBP model to determine whether it could reduce CIBP through regulation of osteoclastogenesis activity. Methods： A rat CIBP model was established with intratibial injection of Walker 256 cells. Then, the efficacy of intraperitoneal administered calpain inhibitor III （MDL28170, 1 mg/kg） on mechanical withdrawal threshold （MWT） of bilateral hind paws was examined on postoperative days （PODs） 2, 5, 8, 11, and 14. On POD 14, the calpain inhibitor＇s effect on tumor bone tartrate-resistant acid phosphatase （TRAP） stain and radiology was also carefully investigated. Results： Pain behavioral tests in rats showed that the calpain inhibitor effectively attenuated MWTs of both the surgical side and contralateral side hind paws on POD 5, 8, and 11 （P 〈 0.05）. TRAP-positive cell count of the surgical side bone was significantly decreased in the calpain inhibitor group compared with the vehicle group （P 〈 0.05）. However, bone resorption and destruction measured by radiographs showed no difference between the two groups. Conclusions： Calpain inhibitor can effectively reduce CIBP of both the surgical side and nonsurgical side after tumor injection in a rat CIBP model. It may be due to the inhibition of receptor activator of nuclear factor-kappa B ligand-induced osteoclastogenesis. Whether a calpain inhibitor could be a novel therapeutic target to treat CIBP needs further investigation.展开更多
BACKGROUND Cancer-induced incomplete bowel obstruction presents numerous clinical cha-llenges,notably pain management and inflammation control.Conventional thera-pies provide limited relief,prompting investigation int...BACKGROUND Cancer-induced incomplete bowel obstruction presents numerous clinical cha-llenges,notably pain management and inflammation control.Conventional thera-pies provide limited relief,prompting investigation into complementary approa-ches.This study compares the efficacy of bottle gourd moxibustion combined with umbilical therapy(BGM-UT)plus standard palliative care vs standard Wes-tern palliative care alone in symptom alleviation and inflammation reduction.AIM To compare the efficacy of BGM-UT plus standard palliative care vs standard pa-lliative care alone in reducing inflammatory cytokine levels,alleviating symp-toms,and improving gastrointestinal recovery in cancer-induced incomplete bowel obstruction.METHODS A retrospective analysis was conducted on 109 patients aged 18-75 years with cancer-induced incomplete bowel obstruction treated at the Foshan Hospital of Traditional Chinese Medicine between October 2023 and September 2024.The participants were categorized into two groups:(1)Regular group receiving stan-dard palliative care;and(2)BGM-UT group receiving additional moxibustion therapy.The inclusion criteria included ongoing opioid use and a Karnofsky per-formance status score below 60.The treatments were evaluated for 3 weeks in terms of opioid consumption,gastrointestinal function recovery,brief pain inven-tory scores,traditional Chinese medicine symptom scores,and inflammatory cytokine levels.RESULTS Initially,the groups were demographically and clinically comparable.Post-treatment,the BGM-UT group showed significant reductions in opioid intake(P=0.027),improved gastrointestinal recovery times,and enhanced pain management as reflected by their lower brief pain inventory scores(P<0.05).Similarly,the improvement in traditional Chinese medicine scores was greater in the BGM-UT group than in the regular group(P<0.05).Inflam-matory markers including interleukin-6,tumor necrosis factor-α,and C-reactive protein decreased significantly in the BGM-UT group,indicating the superior anti-inflammatory effects of this treatment(P<0.05).CONCLUSION The addition of BGM-UT to standard palliative care enhances pain relief,accelerates gastrointestinal recovery,and effectively reduces inflammatory cytokine levels in patients with cancer-induced incomplete bowel obstruction.This combination therapy offers a promising complementary approach to managing this challenging condition.Further prospective studies are warranted to validate these findings and explore underlying mechanisms.展开更多
Voltage-dependent anion channel 1（VDAC1） is thought to contribute to the progression of tumor development. However, whether VDAC1 contributes to bone cancer pain remains unknown. In this study, we found that the exp...Voltage-dependent anion channel 1（VDAC1） is thought to contribute to the progression of tumor development. However, whether VDAC1 contributes to bone cancer pain remains unknown. In this study, we found that the expression of VDAC1 was upregulated in the L2–5 segments of the spinal dorsal horn at 2 and 3 weeks after injection of tumor cells into the tibial cavity. Intrathecal injection of a VDAC1 inhibitor significantly reversed the pain hypersensitivity and reduced the over-expression of Toll-like receptor 4（TLR4）. Intrathecal injection of minocycline, an inhibitor of microglia, also attenuated the pain hypersensitivity of rat models of bone cancer pain.These results suggest that VDAC1 plays a significant role in the development of complicated cancer pain, possibly by regulating the expression of TLR4.展开更多
基金Provincial Key Research and Development Project of Hunan(2018SK2127)Hunan Province Traditional Chinese Medicine Research and Development Project(201946).
文摘Objective To systematically evaluate the overall efficacy of external application of traditional Chinese medicine(EA-TCM)in combination with oral three-step analgesic ladder therapy for patients suffering from cancer-induced bone pain(CIBP).Methods We conducted a literature search of randomized controlled trials on the combination of EA-TCM and three-step analgesic ladder therapy for CIBP across ten databases and two registration systems.It included four Chinese databases[Chinese Biomedical Literature Database(SinoMed),China National Knowledge Infrastructure(CNKI),Wanfang Database,and China Science and Technology Journal Database(VIP)],six English databases(Scopus,Embase,Web of Science,PubMed,Cochrane Library,and OpenGrey),and two registration systems(Chinese Clinical Trial Registry and ClinicalTrials.gov).The timeframe for the literature search extended from the inception of each database to December 31,2023.Meta-analysis was performed using RevMan(v5.4.1),and the outcome indicators(pain relief rate,analgesic duration,quality of life,pain intensity,breakthrough pain frequency,and adverse reactions)were graded using GRADE profiler(v3.6).Results According to the established inclusion and exclusion criteria,a total of 43 studies was deemed eligible,involving 3142 participants with CIBP.The results of meta-analysis showed that compared with oral three-step analgesic ladder therapy alone,the combined therapy of EA-TCM and three-step analgesic ladder has a significant improvement in pain relief rate[risk ratio(RR)=1.32,95%confidence interval(CI):1.24 to 1.41,P<0.00001],analgesic duration[mean difference(MD)=1.33,95%CI:0.97 to 1.69,P<0.00001],and quality of life(MD=5.66,95%CI:4.88 to 6.44,P<0.00001).Furthermore,the combined therapy significantly reduced pain intensity(MD=-1.00,95%CI:-1.19 to-0.80,P<0.00001),breakthrough pain frequency(MD=-0.43,95%CI:-0.51 to-0.36,P<0.00001),and adverse reactions(RR=0.60,95%CI:0.53 to 0.68,P<0.00001)in CIBP patients.Based on the GRADE assessment,the level of evidence varied from low to moderate.Conclusion EA-TCM combined with the three-step analgesic ladder therapy can effectively alleviate pain symptoms in patients with CIBP and improve their quality of life.Additionally,the EA-TCM can effectively reduce the incidence of adverse reactions associated with threestep analgesic therapy.
基金supported by the Zhongshan-Fudan Joint Innovation Center,Zhongshan,Guangdong Province,China(528437)the National Natural Science Foundation of China(82271258,82271248,82204830,81971056)+1 种基金Innovative Research Team of High-level Local Universities in Shanghai,Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJ Lab,Shanghai Center for Brain Science and Brain-Inspired Technology.
文摘Cancer-induced bone pain(CIBP)is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone metastasis.CIBP constitutes a specific pain state with distinct characteristics;however,it shares similarities with inflammatory and neuropathic pain.At present,although various therapies have been developed for this condition,complete relief from CIBP in patients with cancer is yet to be achieved.Hence,it is urgent to study the mechanism underlying CIBP to develop efficient analgesic drugs.Herein,we focused on the peripheral mechanism associated with the initiation of CIBP,which involves tissue injury in the bone and changes in the tumor microenvironment(TME)and dorsal root ganglion.The nerve–cancer and cancer–immunocyte cross-talk in the TME creates circumstances that promote tumor growth and metastasis,ultimately leading to CIBP.The peripheral mechanism of CIBP and current treatments as well as potential therapeutic targets are discussed in this review.
基金supported by grants from the National Natural Science Foundation of China(No.30901396,No.81070890,No.30872441and No.81171259)
文摘Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP). Rostral ventromedial medulla (RVM) is a critical component of descending nociceptive facilitation circuitry, but so far the mechanisms are poorly known. In this study, we investigated the role of RVM glial activation in the descending nociceptive facilitation circuitry in a CIBP rat model. CIBP rats showed significant activation of microglia and astrocytes, and also up-regulation of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and pro-inflammatory mediators released by glial cells (IL-1β, IL-6, TNF-α and brain-derived neurotrophic factor) in the RVM. Stereotaxic microinjection of the glial inhibitors (minocycline and fluorocitrate) into CIBP rats’ RVM could reverse the glial activation and significantly attenuate mechanical allodynia in a time-dependent manner. RVM microinjection of p38 MAPK inhibitor (SB203580) abolished the activation of microglia, reversed the associated up-regulation of proinflammatory mediators and significantly attenuated mechanical allodynia. Taken together, these results suggest that RVM glial activation is involved in the pathogenesis of CIBP. RVM microglial p38 MAPK signaling pathway is activated and leads to the release of downstream pro-inflammatory mediators, which contribute to the descending facilitation of CIBP.
基金financially supported by the National Natural Science Foundation of China(No.82001189)The Project Tackling of Key Scientific and Technical Problems of Henan Provine(No.232102311163).
文摘Bone metastasis,a life-threatening complication of advanced breast cancer,is often accompanied by debilitating pain(cancer-induced bone pain,CIBP)that severely impairs life quality and survival.The concurrent treatment of bone metastases and CIBP remains a clinical challenge because the therapeutic options are limited.In this study,we construct a near-infrared light-activated nano-therapeutic system to meet this conundrum.In detail,sorafenib(SRF)and photosensitizer(chlorin e6,Ce6)are encapsulated into mesoporous hydroxyapatite nanoparticles(HANPs),which are further functionalized with hyaluronic acid(HA)to obtain HA-SRF/Ce6@HANPs system.The designed nanoplatform destroys tumor cells in vitro and in vivo via the synergism of SRF(interrupting the exchange of cystine/glutamate by inhibiting SLC7A11)and photodynamic therapy(PDT,inducing reactive oxygen species generation).The decrease in tumor burden and reduction of extracellular glutamate significantly attenuate CIBP in mice model with developing bone cancer.Moreover,the combination of HA-SRF/Ce6@HANPs and PDT inhibit osteoclasts activation,promote osteoblast differentiation and accelerate bone repair.Overall,the nanoagent with good biocompatibility may provide an effective therapy method for the concurrent treatment of breast cancer bone metastasis and CIBP.
基金This study was funded by Beijing Natural Science Foundation
文摘Background： Calpain, a calcium-dependent cysteine protease, has been demonstrated to regulate osteoclastogenesis, which is considered one of the major reasons for cancer-induced bone pain （CIBP）. In the present study, calpain inhibitor was applied in a rat CIBP model to determine whether it could reduce CIBP through regulation of osteoclastogenesis activity. Methods： A rat CIBP model was established with intratibial injection of Walker 256 cells. Then, the efficacy of intraperitoneal administered calpain inhibitor III （MDL28170, 1 mg/kg） on mechanical withdrawal threshold （MWT） of bilateral hind paws was examined on postoperative days （PODs） 2, 5, 8, 11, and 14. On POD 14, the calpain inhibitor＇s effect on tumor bone tartrate-resistant acid phosphatase （TRAP） stain and radiology was also carefully investigated. Results： Pain behavioral tests in rats showed that the calpain inhibitor effectively attenuated MWTs of both the surgical side and contralateral side hind paws on POD 5, 8, and 11 （P 〈 0.05）. TRAP-positive cell count of the surgical side bone was significantly decreased in the calpain inhibitor group compared with the vehicle group （P 〈 0.05）. However, bone resorption and destruction measured by radiographs showed no difference between the two groups. Conclusions： Calpain inhibitor can effectively reduce CIBP of both the surgical side and nonsurgical side after tumor injection in a rat CIBP model. It may be due to the inhibition of receptor activator of nuclear factor-kappa B ligand-induced osteoclastogenesis. Whether a calpain inhibitor could be a novel therapeutic target to treat CIBP needs further investigation.
基金Supported by Medical Research Project of Foshan Health Bureau in 2024,No.20240243.
文摘BACKGROUND Cancer-induced incomplete bowel obstruction presents numerous clinical cha-llenges,notably pain management and inflammation control.Conventional thera-pies provide limited relief,prompting investigation into complementary approa-ches.This study compares the efficacy of bottle gourd moxibustion combined with umbilical therapy(BGM-UT)plus standard palliative care vs standard Wes-tern palliative care alone in symptom alleviation and inflammation reduction.AIM To compare the efficacy of BGM-UT plus standard palliative care vs standard pa-lliative care alone in reducing inflammatory cytokine levels,alleviating symp-toms,and improving gastrointestinal recovery in cancer-induced incomplete bowel obstruction.METHODS A retrospective analysis was conducted on 109 patients aged 18-75 years with cancer-induced incomplete bowel obstruction treated at the Foshan Hospital of Traditional Chinese Medicine between October 2023 and September 2024.The participants were categorized into two groups:(1)Regular group receiving stan-dard palliative care;and(2)BGM-UT group receiving additional moxibustion therapy.The inclusion criteria included ongoing opioid use and a Karnofsky per-formance status score below 60.The treatments were evaluated for 3 weeks in terms of opioid consumption,gastrointestinal function recovery,brief pain inven-tory scores,traditional Chinese medicine symptom scores,and inflammatory cytokine levels.RESULTS Initially,the groups were demographically and clinically comparable.Post-treatment,the BGM-UT group showed significant reductions in opioid intake(P=0.027),improved gastrointestinal recovery times,and enhanced pain management as reflected by their lower brief pain inventory scores(P<0.05).Similarly,the improvement in traditional Chinese medicine scores was greater in the BGM-UT group than in the regular group(P<0.05).Inflam-matory markers including interleukin-6,tumor necrosis factor-α,and C-reactive protein decreased significantly in the BGM-UT group,indicating the superior anti-inflammatory effects of this treatment(P<0.05).CONCLUSION The addition of BGM-UT to standard palliative care enhances pain relief,accelerates gastrointestinal recovery,and effectively reduces inflammatory cytokine levels in patients with cancer-induced incomplete bowel obstruction.This combination therapy offers a promising complementary approach to managing this challenging condition.Further prospective studies are warranted to validate these findings and explore underlying mechanisms.
基金supported by grants from the National Key Research and Development Program of China (2016YFC1302200)the National Natural Science Foundation of China (31730040, 81070884, and 81471137)+2 种基金the Suzhou Health Planning Commission’s Key Clinical Diagnosis and Treatment Program (LCZX201606)the Priority Academic Program Development of Jiangsu Higher Education Institutions of Chinasubject to the Preponderant Clinic Discipline Group Project funding from the Second Affiliated Hospital of Soochow University (XKQ2015008)
文摘Voltage-dependent anion channel 1（VDAC1） is thought to contribute to the progression of tumor development. However, whether VDAC1 contributes to bone cancer pain remains unknown. In this study, we found that the expression of VDAC1 was upregulated in the L2–5 segments of the spinal dorsal horn at 2 and 3 weeks after injection of tumor cells into the tibial cavity. Intrathecal injection of a VDAC1 inhibitor significantly reversed the pain hypersensitivity and reduced the over-expression of Toll-like receptor 4（TLR4）. Intrathecal injection of minocycline, an inhibitor of microglia, also attenuated the pain hypersensitivity of rat models of bone cancer pain.These results suggest that VDAC1 plays a significant role in the development of complicated cancer pain, possibly by regulating the expression of TLR4.
