Analysis Of The Safety And Efficacy Of Percutaneous Microwave Ablation Combined With Cementoplasty In The Treatment Of Osteolytic Bone Metastases

Part 1:Analysis of the safety and efficacy of percutaneous microwave ablation combined with cementoplasty in the treatment of osteolytic bone metastases is long,and the complication rate can reach 24%.It is only suitable for some patients who are in good general condition and can tolerate anesthesia and surgery.Bisphosphonate therapy is the basic medicine for tumor bone metastasis,which can slow and delay the occurrence of bone-related events.The disadvantage is that long-term use requires supplementation of calcium and vitamin D,and there is a risk of mandibular necrosis and renal damage,and bisphosphonate treatment cannot replace the existing analgesic therapy,radiation therapy and other treatment methods.The development of minimally invasive technology provides a variety of treatment methods for the treatment of bone metastases.Percutaneous vertebroplasty/cementoplasty is to inject bone cement into the diseased bone under the guidance of X-ray or CT.The bone cement hardens about 8-10 minutes after it is injected into the bone.During this process,heat is released simultaneously to relieve pain and stabilize the vertebral body.However,Percutaneous vertebroplasty/cementoplasty has certain limitations in the treatment of bone metastases from malignant tumors.Bone metastases have high pressure in the tumor body and require high-pressure injection of bone cement,which not only easily leads to cement leakage,but also promotes the blood transfer of tumor cells and increases the possibility of cancer cell spread.Therefore,in order to better alleviate the pain of patients with bone metastases,improve the quality of life of patients,and increase the survival time of patients,it is imperative to seek a safe and effective treatment.Thermal ablation can effectively relieve pain and can even be used as an alternative therapy to radiotherapy and morphine therapy for bone metastases.Radiofrequency ablation is a sinusoidal current.The friction between the ions causes the tissue to heat up,which kills the tumor cells.Microwave ablation is another method of thermal ablation,which generates heat by causing high-frequency vibrations of water molecules.Radio frequency heating is easily affected by the concentration of free ions in the tissue and the conductivity of the surrounding tissue.The expansion of its coagulation range mainly depends on conduction and heat dissipation.Microwave energy makes the dipole in the tissue rotate in the microwave field and continuously accelerate the collision to generate heat energy.It has a certain penetration force in the tissue.The dipoles in the tissue within the penetrating range are all heat sources and are affected by free ions in the tissue.Concentration and electrical conductivity of surrounding tissues are less affected,rapid heating,uniform thermal field,large ablation range,and less affected by heat sinking effects.Therefore,the coagulation range of microwave ablation in bone tumors maybe greater than radiofrequency ablation,and the required ablation time shorter,the patient will be well tolerated.According to our investigation,there is no large-scale research at home and abroad focusing on the efficacy and safety of microwave ablation combined with cementoplasty in the treatment of osteolytic metastases.BackgroundMetastasis is the main cause of death in patients with malignant tumors.Bone metastasis is the third most common site of metastasis after lung and liver.About 20%of tumor patients see bone metastasis as the first symptom.Once a malignant tumor spreads to the bone and occurs bone metastasis,it is incurable at an advanced stage and will bring a series of related clinical symptoms such as refractory pain,fractures,and decreased exercise capacity,which seriously affect the quality of life of the patient.Bone metastasis pain not only has a high incidence,but also has a serious nature.The incidence of severe pain is 50%to 90%.Therefore,the overall treatment strategy for bone metastases from malignant tumors is palliative treatment with the main goals of pain relief,restoration of function,and improvement of quality of life.In recent years,comprehensive treatment methods,such as the comprehensive utilization of anti-tumor chemotherapy,analgesia,bisphosphonates,surgery and radiotherapy,have made contributions in alleviating patients' pain,restoring function,improving quality of life and prolonging patient survival.For example,radiotherapy(external beam irradiation)is the standard treatment method for the treatment of local pain in bone metastases.The pain relief rate can reach 40-80%.Data show that more than 40%of patients have a half of the pain within 1 month of radiotherapy,and about 30%have complete pain.Relief,but 57%of patients experienced recurrent pain within 4 months after radiotherapy.For vertebral metastases,radiotherapy has a poor effect on maintaining the stability of the vertebral body.Surgery can solve the problem of spinal instability.It can be selectively used for patients with pathological fractures or spinal cord compression,and it can also be used to prevent and treat patients with bone metastases at risk of pathological fractures.However,the surgical trauma is large,the healing timeObjectiveIn this study,27 patients with osteolytic bone metastases underwent CT-guided microwave ablation combined with cementoplasty treatments to observe pain relief,physical improvement,and complications;patients with vertebral metastases also performed spinal function status and life Quality and spinal injury neurological function score;EuroQol five Dimensions questionnaire(EQ-5D)index(using the Japanese Time Trade-off,TTO to obtain the EQ-5D index score)and European Cancer Research Comprehensive evaluation of the patient,s quality of life with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Bone Metastases 22(EORTC QLQ-BM22,QLQ-BM22);the EQ-5D scores and QLQ-BM22 scores respectively calculated Quality-adjusted life years(Quality-adjusted life years QALYs)for survival analysis to explore the safety and efficacy of microwave ablation combined with cementoplasty in the treatment of osteolytic bone metastases.MethodsThe clinical data of 27 patients with osteolytic bone metastases who underwent microwave ablation combined with cementoplasty in the Oncology Department of Jinan Central Hospital,Shandong University from January 2019 to August 2020 were collected.All patients in the group had a clear tumor history,pathological diagnosis,and pain symptoms.CT or MR showed osteolytic bone metastases.Metastases such as liver and lung metastases are in stable condition and have no clinical positive symptoms;there is no contraindication for liver and kidney function and coagulation indexes.The whole operation of microwave ablation combined with cementoplasty is carried out under the guidance of CT.Before treatment,patients and their families shall be fully informed of the purpose,expected curative effect,main risks,possible complications and corresponding countermeasures.Precautions before and after operation,after obtaining the consent of the patient and family members,sign an informed consent form.Eating and drinking were forbidden 4 hours before operation.Local anesthesia and analgesia were used,and strictly implements the technical specifications of aseptic operation.The microwave ablation power is 30-50W,and the ablation time is 1.5-15min.During the ablation process,adjust the position,angle and depth of the ablation needle according to the CT results.The goal is to cover the mass in the ablation area.At the same time,observe the patient's vital signs and pain,and adjust the ablation power and time at any time according to the patient's tolerance during the operation.After the ablation is over,pull out the ablation needle and prepare bone cement.When the cement is in the drawing stage,the bone cement is slowly poured into the post-ablation site of the bone metastasis at low pressure.The amount of bone cement is 1.5-9ml.CT scan immediately after operation to observe the position of bone cement after treatment and evaluate intraoperative complications.The Numerical Rating Scale(NRS)was used to compare the changes in the pain scores of patients before operation,1 day,3 days,1 week,1 month,3 months,and 6 months after operation.Karnofsky's Performance Status was used(KPS scale),QLQ-BM22 scale,TTO score,low back pain Oswestry Disability Index(ODI)score and American Spinal Injury Association(American Spinal Injury Association,ASIA)score to compare patients before and after surgery.Observe whether there are postoperative complications.The EQ-5D index(TTO value)and QLQ-BM22 score were used as the quality of life scores,and the QALYs were obtained by multiplying them by the time span of each maintenance for survival analysis.Result1.As of the last follow-up,the follow-up time was 1-20 months.The 27 patients with osteolytic bone metastases were operated in accordance with standard procedures.The surgical site was determined by combining the number and symptoms of the patients with bone metastases.Among them,10 patients were treated with two metastatic sites at the same time,17 patients underwent treatment of 1 metastatic tumor,a total of 37 surgical sites.The technical success rate is 100%.2.Among the 27 patients,19 were males and 8 were females;aged 37-80 years old,with an average age of 65.7 ± 11 years,lung cancer was the most common primary disease,and adenocarcinoma was the most pathological type.Tumor diameter(cm)and ablation power is related to the amount of bone cement,but not related to ablation time;metastatic tumor volume(cm3)is related to ablation power,time,and bone cement dosage;the relationship between preoperative pain duration,ablation time and bone cement dosage,and ablation power irrelevant3.Complications:All patients underwent intensive CT examination at least once during follow-up,and no local tumor recurrence was found after treatment.There were no complications of infection,fever,re-fracture,pulmonary embolism and paraplegia;no perioperative deaths and post-ablation syndromes occurred.Peripheral tissue leakage occurred in 4 cases,blood vessels infiltrated around metastases in 2 cases,and spinal canal in 1 case.The complication rate was 18.9%,all of which were minor complications and no major complications occurred.4.Pain:The preoperative NRS score was 3-9 points,the median score was 6.52,the median NRS score was 3.44 one day after the operation,and the median NRS score continued to decrease,and it was 1.92 at 6 months after the operation,P<0.0001,difference There is statistical significance.NRS gender,age,number of bone metastases,maximum diameter of metastases,volume of metastases,and duration of preoperative pain had no significant effect on pain(P>0.05)5.Quality of life:the median KPS score increased from 61.11 preoperatively,to 63.70 one week post-operate,64.61 one month post-operate,54.2 three months post-operate,and then to 46.67 six months post-operate,P>0.05,which was not statistically significant.The evaluation of EQ-5D is calculated using TTO points.The median TTO score was 0.41 preoperatively,0.58 one week post-operate,0.55 one month post-operate,0.52 three months post-operate,and then to 0.45 six months post-operate.There was a general trend of improvement.The first improvement was pain,discomfort and anxiety and depression,and second It is the ability to act,and finally the ability to take care of themselves and daily activities,P>0.05,which was not statistically significant.The median score of QLQ-BM22 was 51.81 preoperatively,40.8 one week post-operate,41.80 one month post-operate,0.52 three months post-operate,and then to 38.00 six months post-operate,P=0.0013,the difference was statistically significant.Gender,age,number of bone metastases,maximum diameter and volume of metastases,and duration of preoperative pain were not related to QLQ-BM22(P>0.05)Of the 27 patients treated with microwave ablation combined with cementoplasty,there were 20 patients with spinal metastases,including 17 patients with thoracolumbar metastases.ODI score was performed on 17 patients with thoracolumbar metastasis ASIA score was performed on 20 patients with spinal metastasis.The median ODI score was 60.40%preoperatively,47.00%one week post-operate,48.18%one month post-operate,37.78%three months post-operate,and then to 39.16%six months post-operate.From severe dysfunction to moderate dysfunction,P>0.05,not statistically significant.Except for the patients who died,there was no change in the ASIA scores6.Survival analysis:The follow-up period was 1-20 months.7 patients died within six months due to the progression of the primary disease,2 died of severe lung infection,and 1 died of septic shock.The survival time of patients who died was 0.25 to 9 months,and the median survival time was 3.14 ± 3.24 months.The EQ-5D index and QLQ-BM22 score were used as the quality of life scores When using the EQ-5D index(TTO value)as the quality of life score,the median QALYs score was 0.039 preoperatively,0.488 after one month,0.0902 after three months,and 0.142 after six months,P<0.0001,the difference was statistically significant Scientific significance;when the QLQ-BM22 score was used as the quality of life score,the median QALYs score was 0.061 preoperatively,0.032 after one month,0.0653 after three months,and 0.108 after six months,P=0.0002,the difference was statistically significant significance.Conclusion1.CT-guided microwave ablation combined with cementoplasty to treat osteolytic bone metastases has a high technical success rate and strong operability.2.The maximum diameter,volume and preoperative pain duration of bone metastases are the factors that influence the power and time of microwave ablation,as well as the amount of bone cement.3.Microwave ablation combined with cementoplasty in treatment of osteolytic bone metastases has fewer complications.4.Microwave ablation combined with cementoplasty can quickly,effectively and lastingly relieve the pain of patients with osteolytic bone metastases,improve the quality of life of the patients,and prolong the high-quality survival time of the patients.5.The combination of the two treatments can complement each other's shortcomings in treatment of bone metastases.Microwave ablation can reduce the leakage complications of bone cement treatment and reduce the risk of bone cement-induced metastatic,bone cementoplasty can reduce the incidence of post-ablation syndrome.Part 2:Bioinformatics analysis of incomplete radiofrequency ablation induced dormant gene activation in colon cancer cellsBackgroundDormancy,as a survival strategy for natural organisms to adapt to the environment,is ubiquitous in bacteria,yeast,insects and mammals.In order to meet its own needs,tumors will also have a dormant state to adapt to different microenvironments.Tumor dormancy can occur in various stages of tumor occurrence and development,such as ?Remote metastasis:most tumor cells have gone through a period of dormancy from the primary site to the metastatic site.?Latent period before recurrence or metastasis after surgery:20%-45%Breast cancer and prostate cancer patients recurred several years or decades after surgery.?Disease-free stage of patients who survived asymptomatic tumors after treatment.Tumor dormancy is characterized by cancer cells entering a state of growth arrest,cell cycle arrest in G0/G1 phase,low expression of Ki-67 and proliferating cell nuclear antigen(PCNA),low metabolism,and active drug resistance mechanisms.Tumor dormancy can be divided into tumor mass dormancy and tumor cell dormancy or cell dormancy.Tumor dormant cells have different expression profiles compared to parent cells.AKT was inhibited when the tumor is dormant,which can activate the cycl in-dependent kinase inhibitors p21 and p27 that prevent the cell cycle.EGFR-mutant non-small cell lung cancer can induce dormancy of lung cancer cells after TKI treatment,and these dormant cells had drug resistance.Hypoxia could also induce dormancy Therefore,tumor dormancy may be a natural state in the evolution of tumors.Dormant tumor cells can develop non-specific mechanisms to resist cell death,such as regulating the JAK/STAT pathway and up-regulating the expression of GAS6,BMP4/7 and TGF ?.The existence of dormant tumor cells may be one of the reasons for the poor prognosis of patients.Therefore,the in-depth study of tumor dormancy can understand the future progress of the disease,it can be used as a mechanism for tumor cells to escape apoptosis and survive after drug treatment.Tumor thermal ablation refers to an inactivation technology that uses the biological effects of heat to directly cause coagulative necrosis of the target tumor.At present,the commonly used thermal ablation in clinical practice is mainly radiofrequency ablation(RFA)and microwave ablation(MWA).Thermal ablation can not only reduce tumor burden,relieve symptoms caused by tumor and improve the quality of life of patients,but also can improve the local control rate and prolong patient survival when combined with other anti-tumor drugs.Although thermal ablation has many advantages in tumor treatment,the therapeutic effect in some patients is still challenging.Including the complete ablation of tumors larger than 3cm;thermal ablation may be related to a higher tumor recurrence rate,partly because it is difficult to achieve ablation margins larger than 5mm.Studies have found that incomplete radiofrequency ablation(iRFA)can promote tumor growth.The possible cancer-promoting mechanisms are:?The normal liver tissue after iRFA can increase the production of tumor-promoting factors IL-6,HGF,c-Met and VEGF,thereby promoting tumor growth.?In vitro experiments found that rat breast cancer After cells,human breast cancer,colon cancer and other cells are subjected to moderate high temperature,the expression of factors such as IL-6,TNF,STAT3 and HGF will increase,and cell proliferation will be accelerated.It can be inferred that during thermal ablation,they will encounter moderate temperature ablation surroundings Regional tumor cells may be induced to activate.?iRFA promotes the increase of VEGF in the interstitium,leading to microangiogenesis,it can also activate VEGF upstream driving factors,such as IL-6,HGF and c-Met,and indirectly lead to microvessels driven by VEGF Growth and proliferation.? Autophagy induced by iRFA had a cancer-promoting effect.In conclusion,a number of studies have shown that iRFA can promote the growth of residual tumor cells,so there is no report on whether iRFA can lead to the activation of dormant tumor cells.ObjectiveIt is not yet verified whether incomplete radiofrequency ablation(iRFA)induces tumor progression and hypoxia related to tumor dormancy.This study downloaded the GSE138224 data set from GEO for analysis,identified differential genes,and performed functional analysis and functional clustering of differential gene expression data to explore the effect of incomplete radiofrequency ablation on the expression of colon cancer genes and the functional analysis of high-expressed genes.It is helpful to clarify the cause of tumor recurrence after thermal ablation,enrich tumor drug resistance mechanisms,and find new anti-tumor therapeutic targets.Methods1.This study downloads the GSE138224 data set from GEO,used the NetwrokAnalyst website,and used the EdgeR method to set logFC(fold change)>1,adj.P<0.05 as statistically significant data,obtained differentially expressed genes(DEGs)2.The DEGs were analyzed by KEGG and GO,and P<0.05 was statistically significant.3.Use the STRINNG database to analyze the differential gene protein interaction network(PPI)and determine the core genes.The confidence score was set to 900 or more to be statistically significant.The key PPI network selection criterion was node>3 and degree?10.Result1.After normalizing the high-throughput data in 6 samples,16161 genes were obtained,from which 656 DEGs were obtained,including 637 down-regulated genes and 19 up-regulated genes.The purpose of thermal ablation was to kill tumor cells and caused coagulative necrosis of tumor cells.Therefore,the expression of most genes was down-regulated to normal after treatment.On the contrary,up-regulated genes appear,indicating that there may be recurrence factors.Therefore,the up-regulated genes after iRFA were studied2.From the KEGG analysis of up-regulated genes,it can be seen that the signal pathways involved in differential genes include toll-like receptor signaling pathway,TNF signaling pathway,and natural killer cell-mediated cytotoxicity;GO:BP aggregation in the GO analysis of up-regulated genes,in terms of immune effect process,JAK-STAT pathway cascade reaction,STAT protein tyrosine phosphorylation process,regulation of STAT protein tyrosine phosphorylation,etc.It is worth noting that Ccl5 gene participates in the regulation of JAK-STAT signaling pathway Upregulated Differential genes GO:MF analysis genes were mainly enriched in enzyme activator activation,chemokine activation and kinase activator activity.The up-regulated genes in DEGs did not obtain statistically significant results in GO:CC analysis3.Three key PPI networks were obtained.Dormancy-related genes Bmp4 and Ccl5 were located in the key PPI networks as core genes;Bmp4 was a down-regulated gene and Ccl5 was an up-regulated gene.Conclusion1.Compared with untreated colon cancer cells,tumor cells had high expression genes after iRFA,and these high expression genes may be the cause of tumor recurrence after iRFA2.Colon cancer cells treated with iRFA highly expressed tumor dormancy-related gene Ccl5 and low-expressed dormancy suppressor gene BMP43.Colon cancer cells after iRFA treatment highly express tumor dormancy-related JAK/STAT signaling pathways4.Colon cancer cells after iRFA treatment highly express Ccl5,which may activate dormant tumor cells through JAK/STAT signaling pathway.