Study on the mechanism of"Sangu Decoction"in the treatment of bone metastatic carcinoma

Objective:To study the mechanism of"Sangu Decoction"in the treatment of bone metastatic carcinoma by network pharmacology.Methods:TCMSP,TCMID and TCM Database@Taiwan databases and literature search were used to screen the main effective components of drugs.Swiss Target and TCMSP databases were used to search the potential therapeutic targets of"Sangu Decoction".DisGeNet and Drugbank databases were used to search the genes of bone metastatic carcinoma.Drug action targets and disease genes were mapped.Cytoscape 3.8.1 software was used to visualize and screen out the core genes.GO and KEGG pathway analysis was performed on potential therapeutic targets.Results:There were 29 main active ingredients in"Sangu Decoction",which contained 413 target proteins.There are 773 disease targets of bone metastatic carcinoma,of which 112 are potential targets of"Sangu Decoction"for the treatment of bone metastatic carcinoma.Through GO and KEGG pathway analysis,it was found that"Sangu Decoction"exerted anti-cancer,inhibiting bone metastasis and immune regulation mechanism through TNF,ErbB,FoxO,PI3K-Akt,Toll-like Receptor,NOD-like Receptor,Rap1 and other signaling pathways in the treatment of bone metastatic carcinoma.The key genes of"Sangu Decoction"in treating bone metastatic carcinoma are VEGFA,AKT1,IL6,TP53,MAPK3,SRC,EGFR and CASP3 and so on.Conclusion:In this study,we constructed a a multi-level interaction"traditional Chinese medicine-compound-target-pathway"network through network pharmacology,and found that the mechanism of"Sangu Decoction"in the treatment of bone metastasis cancer involves multiple targets and pathways,which may be related to anti-cancer,inhibition of bone metastasis,regulation of immunity and so on.

Optimal sequential therapy using tyrosine kinase inhibitors as the first-line treatment in patients with metastatic renal cell carcinoma: A nationwide multicenter study

Objective:The purpose of the study was to identify the best sequence of therapy beginning with a tyrosine kinase inhibitor(TKI)as the first-line therapy for patients with metastatic renal cell carcinoma(mRCC)in terms of overall survival(OS),progression-free survival(PFS),and rates of discontinuation and adverse effects during the treatment period.Methods:This is a retrospective,nationwide multicenter study of patients with mRCC after diagnosis at 10 different tertiary medical centers in Korea from January 1992 to December 2017.We focused on patients at either“favorable”or“intermediate”risk according to the International mRCC Database Consortium criteria,and they were followed up(median 335 days).Finally,a total of 1409 patients were selected as the study population.We generated a Cox proportional hazard model adjusted for covariates,and the different therapy schemes were statistically tested in terms of OS as well as PFS.In addition,frequencies of discontinuation and adverse events were compared among the therapy schemes.Results:Of the primary patterns of treatment sequences(24 sequences),“sunitinib epazopanib”and“sunitinibeeverolimuseimmunotherapy”showed the most beneficial results in both OS and PFS with significantly lower hazards than“sunitinib”,which is the most commonly treated agent in Korea.Considering that the“TKIeTKI”structure showed relatively higher discontinuation rates with higher adverse effects,the overall beneficial sequence would be“sunitinibeeverolimuseimmunotherapy”.Conclusion:Among several sequential therapy starting with TKIs,“sunitinibeeverolimuse immunotherapy”was found to be the best scheme for mRCC patients with“favorable”or“intermediate”risks.

Irreversible electroporation for metastatic pancreatic carcinoma with liver metastasis:What does the evidence say

Irreversible electroporation is a promising non-thermal ablation method that has been shown to increase overall survival in locally advanced pancreatic cancer in some studies.However,higher quality studies with proper controls and randomization are required to establish its superiority when added with neoadjuvant chemotherapy over the current management of choice,which is chemotherapy alone.Further studies are required before establishment of any survival benefit in metastatic pancreatic carcinoma,and such evidence is lacking at present.

Update on the treatment of metastatic renal cell carcinoma

Metastatic renal cell cancer(mRCC)management has undergone a paradigm shift in recent decades.The first revolution came with the emergence of vascular endothelial growth factor inhibitors;there was a second wave with the unprecedented success of checkpoint inhibitors,and then the latest approach,which is becoming the new care standard in mRCC,of combining these two strategies in different ways.Updated results of Checkmate-214 after 42 mo of follow-up were consistent with previously published results showing the superiority of nivolumab/ipilimumab over sunitinib in progression free survival(PFS),overall survival(OS),and objective response rate(ORR)in intermediate and high-risk patients.However,several studies presented at the American Society of Clinical Oncology 2020 suggested that the best place,and so far,the only one for nivolumab/ipilimumab is the frontline setting.The update on Keynote-426 after 23 mo of follow-up showed no superiority of pembrolizumab/axitinib over sunitinib in favorable-risk mRCC,suggesting that it should no longer be the first line of choice in low-risk patients.Finally,the phase III Checkmate 9ER trial results revealed the superiority of nivolumab/cabozantinib vs sunitinib in PFS,OS,and ORR,providing a new first-line option among all International Metastatic RCC Database Consortium risk patients.Some phase II clinical trials also presented this year showed promising results with new combination therapies such as nivolumab/sitravatinib,cabozantinib/atezolizumab,and lenvatinib/pembrolizumab,providing promising grounds upon which to start phase III studies.In addition,other works are using novel therapeutic agents with different mechanisms of action,including telaglenastat(a glutaminase inhibitor),entinostat[an inhibitor of histone deacetylases(HDACs)],and olaparib and talazoparib,poly(ADP-ribose)polymerase inhibitors widely used in other tumors.However,some questions regarding mRCC management still need to be addressed,such as head-to-head comparisons between the current options,treatment sequencing,non-clear cell mRCC,and the role of biomarkers to ascertain the best treatment choice.

Practice change in the management of metastatic urothelial carcinoma after ASCO 2020

Metastatic urothelial carcinoma(mUC)is an incurable and aggressive disease.In the past decades there have been few effective treatment options that have impacted the prognosis of mUC patients.However,in the last few years,several drugs have emerged as new treatment choices that are changing the therapeutic landscape of mUC.Immune checkpoint inhibitors(ICIs)and targeted agents are useful treatment strategies that have been incorporated into our clinical practice.Nevertheless,cisplatin-based chemotherapy is still the standard of care in the first-line of metastatic disease.The results of the JAVELIN Bladder 100 phase 3 trial were presented at ASCO 2020,this trial evaluated the role of avelumab,an ICI,as maintenance therapy in patients who had not progressed after first-line platinum-based chemotherapy.The trial met its primary endpoint demonstrating an overall survival benefit with avelumab maintenance.In addition,new drugs and combinations are being evaluated to improve the outcomes of second and subsequent lines.Fibroblast growth factor receptor(FGFR)inhibitors and immunotherapy combinations were some of the strategies presented at ASCO 2020 that have shown promising results.Finally,the development of predictive biomarkers that help us in the decision-making process will be one of the most important challenges in the next years.

Progress in targeted therapy for metastatic renal cell carcinoma

In recent years, with the deepening of research on the pathogenesis of renal cell carcinoma, anti-VEGF receptor inhibitors and mTOR inhibitors have been produced, making metastatic renal cell carcinoma into the era of targeted therapy. This article analyzes the latest research results at home and abroad. For patients with metastatic renal cell carcinoma, sunitinib and pizopanib are the first choice for targeted drugs. The drug dose starts from the standard dose, and the disease can be increased as appropriate when the disease progresses;When responding, it should be treated or reduced in time. When using an anti-VEGF inhibitor, the patient's blood pressure should be closely monitored. When the patient has high blood sugar or diabetes, anti-VEGF inhibitors should be preferred.

Metastatic Lobular Carcinoma of the Breast Presenting with Small Bowel Metastases:Case Report and Literature Review

Introduction: Invasive lobular carcinoma (ILC) is the second most common histologic type of breast cancer, representing 5% to 15% of invasive tumors. ILC tends to spread to bones, lungs, central nervous system, reproductive organs, and the gastrointestinal tract (GI tract). The most commonly affected organs in the GI tract are the stomach, small intestine, followed by colon and rectum. Case presentation: A 78-year-old woman who was referred to our institution after having a bowel obstruction that required a diagnostic laparoscopy where they identified an obstructing ulcerative lesion in the distal ileum that was managed with a segmental bowel resection. Pathology report showed an invasive lobular breast carcinoma that occluded 90% of the bowel lumen. A PET/CT scan revealed a left breast tumor with increased metabolism. The patient was staged as a clinical cT4b, cN0, cM1 left breast invasive lobular carcinoma (ER/PgR positive, HER-2 negative). She was managed with endocrine therapy with Letrozole (an eight-week course). A follow-up PET/CT showed a peritoneal hypermetabolic nodule adjacent to the previous ileal anastomosis. The lesion decreased in size and metabolic activity. In a multidisciplinary fashion, the endocrine therapy was extended for another three months. Another follow-up PET/CT scan was performed three months after the identification of the peritoneal implant that showed that the nodule increased in size and in metabolism. The lesion continued to decrease significantly in size and became metabolically inactivity. Due to the good breast response and the possibility that the ileal nodule could be a granuloma, she underwent an exploratory laparoscopy with excision of the peritoneal nodule, and a modified left radical mastectomy with immediate breast reconstruction (complex wound closure). The final pathology report of the nodule was negative for malignancy. She continued on endocrine therapy and underwent whole breast irradiation four weeks after the operation. Currently, she is free of disease with no evidence of local, regional, or distant recurrence, and she is still on endocrine therapy. Discussion: The time interval between primary breast cancer and gastrointestinal involvement may range from synchronous presentation to as long as 30 years. The clinical manifestations in GI lobular breast cancer metastasis may range from non-specific complaints to acute GI symptoms, such as a bowel obstruction. There are multiple controversies in the management of ILC. Systemic treatment should be initiated as soon as possible. Indications for postmastectomy radiotherapy are also controversial, given the propensity for multifocal/multicentric tumors and late recurrences, sometimes in atypical locations. Five years of postoperative adjuvant hormonal therapy is an option for women with poor prognosis. Remissions are observed in 32% to 53% of patients. Conclusion: Metastatic lobular carcinoma of the breast has a wide range of clinical presentations. Patients with a history of breast cancer who present with new GI tumors should have these lesions evaluated for evidence of metastasis through histopathologic and immunohistochemical analysis, this will allow for appropriate management. Currently, breast cancer management involves a multidisciplinary approach including surgery, radiotherapy, and systemic medical therapy, and the treatment must be tailored to the patient’s needs.

Comparison of gemcitabine plus nab-paclitaxel and FOLFIRINOX in metastatic pancreatic cancer

BACKGROUND Gemcitabine plus nab-paclitaxel(GA)and modified FOLFIRINOX(FFX)have been widely used as standard first-line treatment in pancreatic cancer.However,it is unclear which regimen is more efficacious.AIM To evaluate a retrospective analysis comparing the efficacy and safety of FFX and GA as first-line chemotherapeutic regimens in patients with metastatic pancreatic cancer.METHODS We retrospectively analyzed and compared outcomes in 101 patients who presented with pancreatic cancer and were treated with either GA(n=54)or FFX(n=47).Moreover,we performed subgroup analysis based on the neutrophil/lymphocyte ratio(NLR)and Eastern Cooperative Oncology Group(ECOG)performance status.RESULTS There were no significant differences between two groups in baseline characteristics,except for the ECOG performance status.The median progression-free survival(PFS)(6.43 mo vs 4.90 mo,P=0.058)was comparable between two groups;however,median overall survival(OS)(10.17 mo vs 6.93 mo,P=0.008)was longer in patients who received GA regimen.In patients with ECOG 0(PFS:8.93 mo vs 5.43 mo,P=0.002;OS:16.10 mo vs 6.97 mo,P=0.000)and those with NLR<3(PFS:8.10 mo vs 6.57 mo,P=0.008;OS:12.87 mo vs 9.93 mo,P=0.002),GA regimen showed higher efficacy.CONCLUSION GA regimen may be recommended to the patients with NLR<3 or ECOG 0 status although GA and FFX showed comparable efficacy outcomes in patients with metastatic pancreatic cancer.

Is there a role for systemic targeted therapy after surgical treatment for metastases of renal cell carcinoma?

Metastatic renal cell carcinoma(m RCC) is a challenging disease. Despite the new targeted therapies, complete remissions occur only in 1%-3% of the cases, and the most effective first-line treatment drugs have reached a ceiling in overall survival(ranging from 9 to 49 mo). Metastasectomy remains to be the only curative option in most patients with m RCC. Prognostic nomograms have been recently published, so we have tools to classify patients in risk groups, allowing us to detect the cases with the higher risk of recurrence after metastasectomy. Although sparse, there is some evidence of effectiveness of neoadjuvant targeted therapy before metastasectomy; but with an increase in surgical complications due to the effects of these new drugs in tissue healing. We have aimed to answer the question: Is there a role for systemic targeted therapy after surgical treatment for metastases of renal cell carcinoma? We have made a search in Pubmed database. As far as we know, evidence is low and it's based in case reports and small series of patients treated with adjuvant drugs after neoadjuvant therapy plus metastasectomy in cases of partial response to initial systemic treatment. Despite the limitations and high risk of bias, promising results and cases with longterm survival with this approach have been described. Two ongoing clinical trials may answer the question that concerns us.

Splenectomy Suppresses Growth and Metastasis of Hepatocellular Carcinoma through Decreasing Myeloid-derived Suppressor Cells In Vivo

The function of the spleen in tumor development has been investigated for years. The relationship of the spleen with hepatocellular carcinoma（HCC）, a huge health burden worldwide, however, remains unknown. The present study aimed to examine the effect of splenectomy on the development of HCC and the possible mechanism. Mouse hepatic carcinoma lines H22 and Hepa1-6 as well as BALB/c and C57 mice were used to establish orthotopic and metastatic mouse models of liver cancer. Mice were divided into four groups, including control group, splenectomy control group（S group）, tumor group（T group） and tumor plus splenectomy group（T＋S group）. Tumor growth, metastases and overall survival were assessed at determined time points. Meanwhile, myeloid-derived suppressor cells（MDSCs） were isolated from the peripheral blood（PB）, the spleen and liver tumors, and then measured by flow cytometery. It was found that liver cancer led to splenomegaly, and increased the percentage of MDSCs in the PB and spleen in the mouse models. Splenectomy inhibited the growth and progression of liver cancer and prolonged the overall survival time of orthotopic and metastatic models, which was accompanied by decreased proportion of MDSCs in the PB and tumors of liver cancer-bearing mouse. It was suggested that splenectomy could be considered an adjuvant therapy to treat liver cancer.

Does maintenance of Bevacizumab after treatment failure have a role in metastatic colon cancer?

Objective： To study the timing of Bevacizumab （BVC） in the overall treatment strategy of advanced metastatic colorectal cancer - early use （first-line） or later use. Methods： 41 patients with progressive metastatic colorectal carcinoma were included. Patients were randomized to receive chemotherapy with or without BVC. Primary end point was objective response. Secondary end points were median survival, time to tumor progression, and toxicity. Results： Partial response with second-line BVC group constituted 25% and 18.8% in patients with first-line chemotherapy and BVC-based regimen respectively, compared to 11.8% and 5.9% with second-line chemotherapy. Median time to progression was 3.1 vs. 2.3 months for cases with first-line chemotherapy and BVC-based regimens respectively. Median survival was 8.2 vs. 4 months in both groups respectively （P = 0.019）. Conclusion： Second-line chemotherapy combined BVC had higher disease control rate （partial response and stable disease）, median time to progression and median survival in BVC-naive patients compared to patients with first-line BVC-based therapy. BVC should be maintained in the second- and third-line settings, as cases with BVC discontinuation had significantly lower median time to disease progression and median survival. Selection of patients for use of BVC was recommended with taking into consideration the cost-benefit value and that the discontinuation of BVC would increase tumor progression.

Second-line panitumumab as a triweekly dose for patients with wild-type KRAS exon 2 metastatic colorectal cancer:a single-institution experience

Objective: Panitumumab administered as monotherapy in colorectal cancer(CRC) has shown response and disease stabilization rates of approximately 30%. The current study aimed to evaluate the progression-free survival(PFS) and overall survival(OS) of patients with metastatic colorectal cancer(mCRC) treated with panitumumab every 3 weeks as a second line treatment.Methods: This study is a retrospective analysis of 18 patients, aged more than 18 years, with wild-type KRAS exon 2 mCRC treated with panitumumab as a second-line single agent after progression on first-line chemotherapy.Results: The median number of courses received was 10(range, 4-29), and the median duration of treatment was 30 weeks(range,12-96 weeks). After a median follow-up period of 13 months, the median PFS was 6 months(range, 4.3-7.7 months) and the median OS was 11 months(range, 7.4-14.5 months). The median PFS was 4 months for patients with < grade 2 skin toxicity and 6months(range, 4.5-7.5 months) for patients with ≥ grade 2 skin rash(P=0.05). The median OS was 9 months(range, 6.4-11.5months) and 14 months(range, 11.6-16.3 months) for the two groups of patients(P=0.002).Conclusions: Panitumumab given every 3 weeks is effective and well tolerated in patients with advanced CRC that progressed after standard chemotherapy.

Immune checkpoint inhibitors in head and neck squamous cell carcinoma:A systematic review of phase-3 clinical trials

BACKGROUND The outcomes of patients diagnosed with head and neck squamous cell carcinoma(HNSCC)who are not candidates for local salvage therapy and of those diagnosed with recurrent or metastatic disease are dismal.A relatively new systemic therapy option that emerged in recent years in the treatment of advanced HNSCC is immunotherapy using immune checkpoint inhibitors(ICIs).The safety profile and anti-tumor activity of these agents demonstrated in early phase clinical trials paved the way to the initiation of several promising phase-3 trials in the field.AIM To evaluate the evidence on the effectiveness of ICIs in HNSCC,based on published phase-3 clinical trials.METHODS We searched PubMed,Cochrane Library,Embase,and Scopus to identify published literature evaluating immunotherapy using ICIs in recurrent or metastatic HNSCC(R/M HNSCC)and locally advanced head and neck squamous cell carcinoma(LAHNSCC).We used a combination of standardized search terms and keywords including head and neck squamous cell carcinoma,recurrent,metastatic,locally advanced,immunotherapy,immune checkpoint inhibitors,monoclonal antibodies,programmed cell death protein-1(PD-1),programmed death-ligand 1(PD-L1),cytotoxic T-lymphocyte associated protein-4(CTLA-4),and phase-3 clinical trial.A sensitive search filter was used to limit our results to randomized controlled trials.RESULTS Five phase-3 clinical trials have reported the data on the effectiveness of immunotherapy in HNSCC so far:Four in R/M HNSCC and one in LAHNSCC.In patients with R/M HNSCC,anti-PD-1 agents nivolumab and pembrolizumab demonstrated improved survival benefits in the second-line treatment setting compared to the standard of care(standard singleagent systemic therapy).While the net gain in overall survival(OS)with nivolumab was 2.4 mo[hazard ratio(HR)=0.69,P=0.01],that with pembrolizumab was 1.5 mo(HR=0.80 nominal P=0.0161).The anti-PD-L1 agent durvalumab with or without the anti-cytotoxic T-lymphocyte associated protein-4 agent tremelimumab did not result in any beneficial outcomes.In the first-line setting,in R/M HNSCC,pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 mo(HR=0.77,P=0.0034)in the overall population and a net gain in OS of 4.2 mo in the PD-L1 positive(combined positive score>20)population compared to standard of care(EXTREME regime).In patients with PD-L1 positive R/M HNSCC,monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME.In LAHNSCC,immunotherapy using avelumab(an anti-PD-L1 agent)along with standard chemoradiation therapy did not result in improved outcomes compared to placebo plus chemoradiation therapy.CONCLUSION Anti-PD-1 agents provide survival benefits in R/M HNSCC in the first and second-line settings,with acceptable toxicity profiles compared to standard therapy.There is no proven efficacy in the curative setting to date.

Solitary thyroid gland metastasis from rectal cancer:A case report and review of the literature

BACKGROUND Metastatic carcinoma of the thyroid gland is a rare encounter in clinical practice, but autopsy series showed that it is not so rare. Thyroid metastasis from colorectal cancer(CRC) is rare and has a poor prognosis. We herein report a rare case of solitary thyroid metastasis from rectal cancer combined with needle tract implantation after fine-needle aspiration(FNA) of the thyroid nodule and review the relevant literature.CASE SUMMARY A 54-year-old woman with a history of TNM stage Ⅲ CRC presented a 1.3 cm × 1.0 cm mass in the left thyroid gland. FNA and histological examination of the left thyroid lobe surgical specimen confirmed the diagnosis of isolated metastatic adenocarcinoma from the rectum. Needle tract implantation was observed in the neck 11 mo after the FNA examination. The 2.5-cm seeding lesion was successfully removed by surgery, and the patient recovered well. The literature relevant to this clinical condition, the diagnostic workup, spread pathway, and surgical management of these rare lesions is reviewed.CONCLUSION For a patient with a thyroid mass and a history of CRC, metastatic thyroid carcinoma should be considered even if the patient has no evidence of other organ metastasis from CRC. FNA cytological examination of the thyroid mass is useful in the differential diagnosis between primary thyroid disease and metastatic thyroid carcinoma. Thyroid lobectomy of the gland containing the metastatic tumor is suggested in patients with metastatic carcinoma of the thyroid.

Revisiting mechanisms of resistance to immunotherapies in metastatic clear-cell renal-cell carcinoma

Renal-cell carcinoma(RCC)remains a leading cause of cancer-related mortality worldwide.Though newer therapeutic combinations of immune checkpoint inhibitors and targeted therapies have greatly improved outcomes,resistance to these therapies is becoming a challenge for long-term control.Mechanisms of resistance have been explored in a variety of solid tumors,including RCC.Based upon our review of the current literature on the mechanisms of resistance to immunotherapies for the management of metastatic clear-cell renal cell carcinomas(mccRCC),the ensuing conclusions have been made:The management of mccRCC has progressed substantially with the advent of checkpoint inhibitors and targeted oral therapies,alone and/or in combination.Nevertheless,innate or developed resistance to these therapies remains an ongoing challenge,particularly to immune checkpoint inhibitors(ICIs).Several of the known mechanisms of resistance have been well defined,but recent progression in cellular therapies helps to expand the armamentarium of potential combination options that may overcome these modes of resistance and improve long-term disease control and survival for an otherwise dismal disease.In the ensuing review and update of the literature on the mechanisms of resistance to immunotherapies in mccRCC,we have revisited the known resistance mechanisms of immunotherapies in metastatic clear-cell RCC and explored ongoing and future strategies to overcome them.

Significance of timing of therapeutic line on effectiveness of nivolumab for metastatic renal cell carcinoma

Objectives:This study aimed to clarify the significance of therapeutic timing on the effectiveness of nivolumab for treating metastatic renal cell carcinoma.Marterials and methods:Fifty-eight patients with metastatic renal cell carcinoma treated with nivolumab monotherapy were retrospectively studied.Patients who were treated with nivolumab as second-line therapy were included in the second-line group,while the others were included in the later-line group.The clinicopathological characteristics,effects of nivolumab,and prognoses of these groups were compared.Results:Twenty and thirty-eight patients were included in the second-line and later-line groups,respectively.There were no significant differences in the distribution of International Metastatic Renal Cell Carcinoma Database Consotium risk and other clinicopathological characteristics between the 2 groups.The proportion of patients whose objective best response was progressive disease in the second-line group was significantly lower than that in the later-line group(15%vs.50%,p=0.0090).The 50%progression-free survival with nivolumab in the second-line group was significantly better than that in the later-line group(not reached and 5 months,p=0.0018).Multivariate analysis showed that the second-line setting was an independent predictive factor for better progression-free survival(p=0.0028,hazard ratio=0.108).The 50%overall survival after starting nivolumab in the second-line and later-line groups was not reached and 27.8 months,respectively(p=0.2652).Conclusions:The therapeutic efficacy of nivolumab as second-line therapy is expected to be better than that of later therapy.

Famitinib in metastatic renal cell carcinoma： a single center study

Background Famitinib is a novel and potent multitargeting receptor tyrosine kinase inhibitor. The phase I clinical study showed that famitinib was well tolerated and had a broad anti-tumor spectrum. The purpose of this study was to examine the efficacy and safety of famitinib for the treatment of metastatic renal cell carcinoma （mRCC）. Methods The data of famitinib in treating patients with mRCC from the single-center phases I and II clinical trials were analyzed. Famitinib was administered orally at the dose of 13-30 mg once daily until tumor progression, occurrence of intolerable adverse reactions or withdrawal of the informed consent. Results A total of 24 patients with mRCC were treated including 17 patients at a dose of 25 mg once daily, 4 patients at a dose of 27 mg and 1 patient each at a dose of 13 rag, 20 mg and 30 mg, respectively. Twelve （50.0%） patients achieved partial response （PR） and 9 patients achieved stable disease （SD）. Progressive disease was found in 3 （12.5%） patients. The disease control rate was 87.5%. The median follow-up time was 17.6 months; the median progression free survival （PFS） was 10.7 （95% CI 7.0-14.4） months; and the estimated median overall survival （OS） time was 33.0 （95% CI 8.7-57.3） months. The adverse drug reactions mainly included hypertension （54.1%）, hand-foot skin reactions （45.8%）, diarrhea （33.3%）, mucositis （29.2%）, neutropenia （45.8%）, thrombocytopenia （29.2%）, hyperlipidemia （41.7%） and proteinuria （41.7%）. The incidence rate of grades 3 and 4 adverse events was low, mainly including hypertension 12.5%, hand-foot skin reactions 4.2%, neutropenia 4.2%, thrombocytopenia 4.2%, hyperlipidemia 4.2% and proteinuria 12.5%. Conclusions Famitinib has significant anti-tumor activity in mRCC. The common adverse reactions are generally manageable.

Magnetic Resonance Gd？RGD Imaging Study of Hepatocellular Carcinoma with High and Low Metastatic Potential before and after Human Bone Marrow？derived Mesenchymal Stem Cell Intervention

Background： Biotherapy based on human bone marrow-derived mesenchymal stem cells （BMSCs） is currently the focus of research, especially in the field of autologous stem cell transplantation. A novel type of metastasis-associated magnetic resonance （MR） molecular imaging probe was constructed, and the changes in metastasis and proliferation of hepatocellular carcinoma （HCC） before and after BMSC intervention were observed through MR imaging （MRI）. Methods：Metastasis-associatedMRmolecularimagingprobe,integrin αvβ3 ligandcRGD-PEG-DGL-DTPA-Gd （Gd-RGD）,wereconstructed. After human BMSC intervention was performed for 6weeks, tumor weight inhibition rates were calculated, and the RGD molecular probe was imaged through MRI with molecular imaging agent Gd-DTPAas control.The signal-to-noise ratio （SNR） and contrast-to-noise ratio （CNR） in the MRI experiment were used as semi-quantitative indicators. Polymerase chain reaction method was performed to detect proliferation- and metastasis-associated indicators, transforming growth factor β-1 （TGFβ1）, osteopontin （OPN）, and integrin subunit αv and β3. Results： The highest tumor weight inhibition rates were observed 3 weeks after the BMSC transplantation. The MR Gd-RGD in the HCC tissues after the BMSC intervention showed less enhancement than Gd-DTPA. The Gd-DTPAMRI of control group had higher SNR and CNR than Gd-RGD MRI in the experimental groups （P 〈 0.05）. For high metastatic potential hepatocellular carcinoma （MHCC97-H）, significant differenceswereobservedintheSNRsandCNRsofGd-RGDMRIbeforeandaftertheBMSCintervention（P〈0.05）.Forlowmetastaticpotential hepatocellular carcinoma （MHCC97-L）, the CNRs of Gd-RGD MRI were statistically different before and after BMSC intervention （P 〈 0.05）. With regard to MHCC97-H, OPN, β3, and TGFβ1 expression significantly decreased after BMSC intervention （P 〈 0.05）. In MHCC97-L and OPN, β3, TGFβ1, and αv expression after BMSC intervention decreased, and the difference was statistically significant （P 〈 0.05）. Conclusions： The CNR index of MRI is a good indicator for distinguishing high- and low-metastatic potential HCC tissues.After BMSC transplantation of MRI through the two kinds of tracer, the SNR and CNR indexes can distinguish two kinds of high and low metastatic potential HCC tissues, and Gd-RGD imaging is more suitable in distinguishing the metastatic potential changes through BMSC intervention.

Cryoablation combined with radiotherapy for hepatic malignancy:Five case reports

BACKGROUND The survival of patients treated with monotherapy for hepatic malignancies is not ideal.A comprehensive program of cryoablation combined with radiotherapy for the treatment of hepatic malignancies results in less trauma to the patients.It may provide an option for the treatment of patients with advanced hepatic malignancies.CASE SUMMARY We reported 5 cases of advanced-stage hepatic malignancies treated in our hospital from 2017-2018,including 3 cases of primary hepatocellular carcinoma and 2 cases of metastatic hepatic carcinoma.They first received cryoablation therapy on their liver lesions.The procedure consisted of 2 freeze-thaw cycles,and for each session,the duration of freezing was 13-15 min,and the natural rewarming period was 2-8 min.Depending on the tumor size,the appropriate cryoprobes were selected to achieve complete tumor ablation to the greatest extent possible.After cryoablation surgery,intensity-modulated radiotherapy(IMRT)for liver lesions was performed,and the radiotherapy regimen was 5400 cGy/18f and 300 cGy/f.None of the 5 patients had adverse events above grade II,and their quality of life was significantly improved.Among them,4 patients were free of disease progression in the liver lesions under local control,and their survival was prolonged;3 patients are still alive.CONCLUSION Our clinical practice demonstrated that cryoablation combined with IMRT could be implemented safely.The definitive efficacy for hepatic malignancies needs to be confirmed in larger-size sample prospective studies.

Impact of Cytoreductive Nephrectomy on Survival in Patients with Metastatic Renal Cell Carcinoma Treated by Targeted Therapy

Background：The metastatic renal cell carcinoma （mRCC） patients treated with upfront cytoreductive nephrectomy combined with α-interferon yields additional overall survival （OS） benefits.It is unclear whether mRCC patients treated with vascular endothelial growth factor receptor-tyrosine kinase inhibitor （VEGFR-TKI） will benefit from such cytoreductive nephrectomy either.The aim of the study was to identify variables for selection of patients who would benefit from upfront cytoreductive nephrectomy for mRCC treated with VEGFR-TKI.Methods：Clinical data on 74 patients enrolled in 5 clinical trials conducted in Cancer Hospital （Institute）,Chinese Academy of Medical Sciences from January 2006 to January 2014 were reviewed retrospectively.The survival analysis was performed by the Kaplan-Meier method.Comparisons between patient groups were performed by Chi-square test.A Cox regression model was adopted for analysis of multiple factors affecting survival,with a significance level of α =0.05.Results：Fifty-one patients underwent cytoreductive nephrectomy followed by targeted therapy （cytoreductive nephrectomy group） and 23 patients were treated with targeted therapy alone （noncytoreductive nephrectomy group）.The median OS was 32.2 months and 23.0 months in cytoreductive nephrectomy and noncytoreductive nephrectomy groups,respectively （P =0.041）.Age ≤45 years （P =0.002）,a low or high body mass index （BMI 〈19 or 〉30 kg/m2） （P =0.008）,a serum lactate dehydrogenase （LDH） concentration 〉 1.5 × upper limit of normal （P =0.025）,a serum calcium concentration 〉1 0 mg/ml （P =0.034）,and 3 or more metastatic sites （P =0.023） were independent preoperative risk factors for survival.The patients only with 0-2 risk factors benefited from upfront cytoreductive nephrectomy in terms of OS when compared with the patients treated with targeted therapy alone （40.0 months vs.23.2 months,P =0.042）,while those with more than 2 risk factors did not.Conclusions：Five risk factors （age,BMI,LDH,serum calcium,and number of metastatic sites） seemed to be helpful for selecting patients who would benefit from undergoing upfront cytoreductive nephrectomy.