胆囊癌系统性治疗研究进展

胆囊癌(gallbladder cancer,GBC)恶性程度高,预后差,系统性治疗是其重要治疗手段。GBC的一线化疗常选用吉西他滨+铂类、吉西他滨+替吉奥或以其为基础的三药联合方案,二线化疗如5-氟尿嘧啶+奥沙利铂等。免疫治疗包括肿瘤疫苗、过继免疫治疗、免疫检查点抑制等,靶向程序性死亡受体1的派姆单抗、纳武利尢单抗单用或联合化疗显示出治疗前景,与靶向细胞毒性T细胞相关抗原4药物联用等联合免疫治疗方案也初获应用。靶向治疗以人表皮生长因子受体2、表皮生长因子受体、血管内皮生长因子受体等为靶点,单用或联合化疗用于晚期GBC。GBC个体精准化治疗是未来发展方向,针对GBC的大规模随机对照研究尚待开展。

Multiplex imaging reveals the architecture of the tumor immune microenvironment

The tumor immune microenvironment(TME)is composed of a variety of components,such as tumor cells,immune cells,and the extracellular matrix.The TME has been studied through transcriptomic,proteomic,metabolomic,and phosphoproteomic approaches,which have provided researchers with a wealth of TME-related molecular information.

Synergetic treatment of oxygen microcapsules and lenvatinib for enhanced therapy of HCC by alleviating hypoxia condition and activating anti-tumor immunity

Hypoxia is a typical characteristic of hepatocellular carcinoma(HCC), which causes tremendous obstacles to tumor treatments. Current first-line treatment may further deteriorate tumor hypoxia. For example,Lenvatinib, a receptor tyrosine kinase inhibitor(RTKI), suppresses tumor growth via blocking vascular endothelial growth factor(VEGF) signaling, and can also inhibit angiogenesis, thus limiting oxygen supply to tumor sites. Therefore, alleviating tumor microenvironment(TME) hypoxia holds great potential for enhancing the therapeutic effect of RTKI. Here, nanoparticle-stabilized oxygen microcapsules, a stable and biocompatible oxygen-loaded delivery system, are successfully prepared through interfacial polymerization of polydopamine nanoparticles. The microcapsules with a large loading capacity of oxygen in the core show excellent bioavailability and dispersity, which could effectively improve the hypoxic TME when they serve as oxygen delivery vehicles. Synergetic treatments of Lenvatinib and oxygen microcapsules could induce the transition of “cold tumor” in an immune-suppressed state to “hot tumor” in an immune-activated state by improving tumor hypoxic TME and reducing angiogenesis in HCC. It is revealed that combined treatments of oxygen microcapsules and Lenvatinib could polarize tumor-associated macrophages(TAMs) to anti-tumor M1 cells and activate T cell-mediated anti-tumor immune responses.The results suggest that synergetic therapy using oxygen microcapsules and Lenvatinib could alleviate the hypoxic TME and enhance the therapeutic performance of RTKI, demonstrating a promising anti-tumor strategy for enhanced therapy of HCC.

Chinese expert consensus on conversion therapy for hepatocellular carcinoma(2021 edition)

Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma(HCC)have resulted in improved response rates.This has provided an opportunity for selected patients with initially unresectable HCC to achieve adequate tumor downstaging to undergo surgical resection,a‘conversion therapy’strategy.However,conversion therapy is a new approach to the treatment of HCC and its practice and treatment protocols are still being developed.Review the evidence for conversion therapy in HCC and develop consensus statements to guide clinical practice.Evidence review:Many research centers in China have accumulated significant experience implementing HCC conversion therapy.Preliminary findings and data have shown that conversion therapy represents an important strategy to maximize the survival of selected patients with intermediate stage to advanced HCC;however,there are still many urgent clinical and scientific challenges for this therapeutic strategy and its related fields.In order to summarize and learn from past experience and review current challenges,the Chinese Expert Consensus on Conversion Therapy for Hepatocellular Carcinoma(2021 Edition)was developed based on a review of preliminary experience and clinical data from Chinese and non-Chinese studies in this field and combined with recommendations for clinical practice.Sixteen consensus statements on the implementation of conversion therapy for HCC were developed.The statements generated in this review are based on a review of clinical evidence and real clinical experience and will help guide future progress in conversion therapy for patients with HCC.

Advantages of targeting the tumor immune microenvironment over blocking immune checkpoint in cancer immunotherapy

Despite great success in cancer immunotherapy,immune checkpoint-targeting drugs are not the most popular weapon in the armory of cancer therapy.Accumulating evidence suggests that the tumor immune microenvironment plays a critical role in anticancer immunity,which may result in immune checkpoint blockade therapy being ineffective,in addition to other novel immunotherapies in cancer patients.In the present review,we discuss the deficiencies of current cancer immunotherapies.More importantly,we highlight the critical role of tumor immune microenvironment regulators in tumor immune surveillance,immunological evasion,and the potential for their further translation into clinical practice.Based on their general targetability in clinical therapy,we believe that tumor immune microenvironment regulators are promising cancer immunotherapeutic targets.Targeting the tumor immune microenvironment,alone or in combination with immune checkpoint-targeting drugs,might benefit cancer patients in the future.

Blocking PD-L1 for anti-liver cancer immunity:USP22 represents a critical cotarget

MULTIPLE LEVELS OF PD-L1 REGULATION IN CANCER IMMUNOTHERAPY To date,the PD-1/PD-L1 blockade strategy has been tested in a variety of cancer types.However,only bladder cancer,melanoma,mismatch repair-deficient colorectal cancer,and certain hematopoietic malignancies have been highly responsive in terms of clinical outcomes.1,2 It is presumed that the expression level of the PD-L1 protein largely determines the therapeutic efficacy of PD-1/PD-L1-targeted cancer immunotherapy.3,4 Previous studies have shown that several transcriptional factors are involved in the upregulation of PD-L1 by directly binding to its promoter region.5 For instance,individual activation of STAT1,NF-κB,HIF-1α,c-Myc,or MAPK increased PD-L1 transcription and immune evasion of tumor cells.On the other hand,oncogenic RAS signaling reportedly stabilizes PD-L1 mRNA to promote tumor immunoresistance.

Eating self for not be eaten:Pancreatic cancer suppresses selfimmunogenicity by autophagy-mediated MHC-I degradation

In a recent study in Nature,1 Yamamoto et al.reported that MHC-I is a selective substrate of autophagy in tumor immune evasion.Furthermore,it was reported that autophagy-mediated lysosomal degradation of MHC-I suppresses pancreatic cancer immunogenicity and the effectiveness of immunotherapy.These findings indicate the potential of autophagy inhibition as a strategy to activate anti-pancreatic cancer immunity.

Auto-intestine transplantation for pancreatic tumors with mesenteric root involvement:a systematic review and survival-based analysis

To analyze a long-term survival outcome of an auto-intestine transplantation(aINTx)for the patients with locally advanced pancreatic tumor and identify the potential prognostic factors,databases were carefully searched for the studies reporting the patients with a locally advanced pancreatic tumor which typically underwent aINTx.We performed a database search using PubMed,the Cochrane Library,EMBASE,and MEDLINE to identify multiple case series of the patients who had pancreatic tumors with mesenteric root involvement and underwent aINTx,to evaluate the treatment outcomes,and calculated the patient survival using the Kaplan–Meier method and Cox proportional hazard regression analysis to properly identify an independent predictor of the survival.A total of 9 retrospective studies with a total of 29 patients were included in our study.The calculated 1-,2-,and 3-year survival rates for the patients with pancreatic cancer and benign or low grade pancreatic tumors were 49.64%,22.06%,and 0%versus 100%,100%,and 80%,respectively.The corresponding median survival time was 13.4months and 84months,respectively.Moreover,when stratifying the pancreatic cancer patients undergoing aINTx on the basis of neoadjuvant chemotherapy(aINTx+neoadjuvant vs aINTx-neoadjuvant)there was a significant difference in the survival(P=0.01).The 1-and 2-year survival rates were 75%and 75%versus 34.1%and 0%,respectively.Corresponding median survival times were 24months and 10months,respectively.Our analysis shows the long-term survival benefit with acceptable morbidity and mortality of pancreatoduodenectomy and aINTx for the pancreatic tumors with the mesenteric root involvement that are otherwise unresectable by the conventional surgical techniques.However,from an oncological point of view,a larger study with the control group is required to determine its safety compared to less aggressive surgical treatment.

The AKT-independent MET–V-ATPase–MTOR axis suppresses liver cancer vaccination

Despite recent progress in hepatitis treatment,there have been no significant advances in the development of liver cancer vaccines in recent years.In this study,we investigated the regulatory effect and potential mechanism of hepatocyte growth factor receptor(MET,also known as HGFR)on tumor vaccinations for liver cancer in mice.Herein,we demonstrate that MET expression is significantly associated with the immunogenicity of liver cancer in mice and humans,and that MET depletion dramatically enhances the protective efficacy of chemotherapy-based anti-liver cancer vaccination.Mechanistically,MET repressed liver cancer immunogenicity independent of the traditional PI3K–AKT cascade,and MET interacted with vacuolar ATP synthase(V-ATPase)and mediated the activation of mammalian target of rapamycin(MTOR),thus suppressing liver cancer immunogenicity.The efficacy of chemotherapy-based liver cancer vaccination was markedly enhanced by targeting the MET–V-ATPase–MTOR axis,highlighting a translational strategy for identifying MET-associated drug candidates for cancer prevention.

Guidelines for the diagnosis and treatment of pancreatic cancer in China (2021)

The incidence of pancreatic cancer has been rising worldwide,and its clinical diagnosis and treatment remain a great challenge.To present the update and improvements in the clinical diagnosis and treatment of pancreatic cancer in recent years,Chinese Pancreatic Association,the Chinese Society of Surgery,Chinese Medical Association revised the Guidelines for the Diagnosis and Treatment of Pancreatic Cancer in China(2014)after reviewing evidence-based and problem-oriented literature published during 2015-2021,mainly focusing on highlight issues regarding diagnosis and surgical treatment of pancreatic cancer,conversion strategies for locally advanced pancreatic cancer,treatment of pancreatic cancer with oligo metastasis,adjuvant and neoadjuvant therapy,standardized processing of surgical specimens and evaluation of surgical margin status,systemic treatment for unresectable pancreatic cancer,genetic testing,as well as postoperative follow up of patients with pancreatic cancer.Forty recommendation items were finally proposed based on the above issues,and the quality of evidence and strength of recommendations were graded using the Grades of Recommendation,Assessment,Development,and Evaluation system.This guideline aims to standardize the clinical diagnosis and therapy,especially surgical treatment of pancreatic cancer in China,and further improve the prognosis of patients with pancreatic cancer.

A female surgeon’s thoughts on gender attributes in surgery

There is a Chinese old saying that started in the 19th century:“A woman is vulnerable,but being a mother makes one strong”.This seems to make sense,considering the status of women in society around a hundred years ago.None of us lived in that period,but we can imagine that women who lived back then might not have been obligated to work or assume a profession.Rather.