Deep insight into the B-cell associated tertiary lymphoid structure and tumor immunotherapy

Bod et al.1 recently published a study in Nature that garnered attention to B cell-associated anti-tumor immunity and immunotherapy of melanoma and other tumors1.As a promising supplemental immunotherapy to mainstream methods that target T and natural killer(NK)cells,B cell-associated anti-tumor immunotherapy is promising。

Roles of low?density lipoproteinreceptor?related protein 1 in tumors

Low-density lipoprotein receptor-related protein 1(LRP1,also known as CD91),a multifunctional endocytic and cell signaling receptor,is widely expressed on the surface of multiple cell types such as hepatocytes,fibroblasts,neurons,astrocytes,macrophages,smooth muscle cells,and malignant cells.Emerging in vitro and in vivo evidence demonstrates that LRP1 is critically involved in many processes that drive tumorigenesis and tumor progression.For example,LRP1 not only promotes tumor cell migration and invasion by regulating matrix metalloproteinase(MMP)-2and MMP-9 expression and functions but also inhibits cell apoptosis by regulating the insulin receptor,the serine/threonine protein kinase signaling pathway,and the expression of Caspase-3.LRPI-mediated phosphorylation of the extracellular signal-regulated kinase pathway and c-jun N-terminal kinase are also involved in tumor cell proliferation and invasion.In addition,LRP1 has been shown to be down-regulated by microRNA-205 and methylation of LRP1CpG islands.Furthermore,a novel fusion gene,LRP1-SNRNP25,promotes osteosarcoma cell invasion and migration.Only by understanding the mechanisms of these effects can we develop novel diagnostic and therapeutic strategies for cancers mediated by LRP1.

Chondroblastoma in the long bone diaphysis:a report of two cases with literature review

To investigate the clinical characteristics of chondroblastoma with an emphasis on lesions located in the long bone diaphysis,we reviewed the clinical data of 7 patients with histologically proven chondroblastoma treated in Tianjin Medical University Cancer Hospital and Fudan University Cancer Hospital between January 1995 and May 2009.There were two rare cases of chondroblastoma in the long bone diaphysis.One patient with a lesion in the tibial diaphysis underwent intralesional curettage and bone grafting,and the postoperative bone function was measured as excellent according to the Enneking scoring system.The patient was still alive upon follow-up at 60 months.The other patient with a lesion in the humeral diaphysis underwent resection,and the postoperative bone function was excellent at 48 months,at which there was no evidence of recurrence or metastasis.Thus,except for the distinctive site of the long bone diaphysis,which made diagnosis difficult,the patients' ages,symptoms,X-ray and CT images,treatment,and prognosis were in accordance with typical lesions in the epiphysis and metaphysis.The diagnosis of chondroblastoma in the long bone diaphysis significantly depends on histopathologic characteristics.

Clinical study of apatinib in the treatment of stage IV osteogenic sarcoma after failure of chemotherapy

Objective:To analyze the efficacy and safety o f apatinib in the treatment of stage IV osteogenic sarcoma after chemotherapy failure through a single-arm,prospective,and open clinical phase II study.Methods:Information on 34 patients with stage IV osteogenic sarcoma treated with apatinib after failure o f chemotherapy in Tianjin Medical University Cancer Institute and Hospital between September 2015 and December 2019 was collected and analyzed.The participants included 23 males and 11 females,with an average age of 35.24 years(11-73 years).The objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),PFS rate(PFR),and overall survival(OS)were evaluated.The treatmentrelated adverse events(AEs)and safety of apatinib were also evaluated.Results:O f the 34 patients,33 were able to be evaluated for efficacy.One patient received apatinib treatment for less than one cycle;therefore,only safety analysis was performed.The 12-week clinical evaluation showed that 2 patients had a partial response(PR),24 patients had stable disease(SD),and 7 patients had progressive disease(PD).The ORR,DCR,and PFR at 12 weeks were 6.06%(2/33),78.79%(26/33),and 82%,respectively.By the end of the follow-up,6 patients had SD(18.18%,6/33),27 patients had PD(81.82%,27/33),and 15 patients died because of disease progression(45.45%,15/33).The ORR was 0(0/33),the DCR was 18.18%(6/33),and the median PFS(mPFS)was 7.89 months(95%Cl:4.56-11.21).The median OS(mOS)was 17.61 months(95%Cl:10.85-24.37).The most common treatment-related AEs were hand-foot syndrome(35.29%,12/34),proteinuria(32.35%,11/34),and hypertension(32.35%,11/34).

Therapeutic perspectives for adult soft tissue sarcoma—updates from the 2022 ASCO annual meeting

At the recent 2022 American Society of Clinical Oncology(ASCO)annual meeting,the latest progress was presented in clinical trials of various therapeutic modalities for adult soft tissue sarcoma(STS),including chemotherapy,targeted therapy,anti-immune checkpoint immunotherapy,and multiple combination treatments(Table 1).Generally,the development of clinical treatments for STS is relatively slow,owing to the complex pathological subtypes of sarcoma and their heterogeneous biological behaviors.Here,we briefly summarize updates from this year’s ASCO meeting and discuss the future therapeutic perspectives for unspecific STS.

社区教育引领社区治理创新研究

社区教育与社区治理在区域、目标、对象、主体及价值等方面具有一致性,具有紧密的内在联系。社区教育具有引领社区治理的制度优势。当前,社区教育引领社区治理存在居民参与度不高,社会组织自主性不足,社区教育制度供给不够等问题。因此,要创新社区教育引领社区治理路径,找准定位,优化体系,创新方式,丰富资源,更新手段,从而提高社会治理水平。

The efficacies and biomarker investigations of antiprogrammed death-1 (anti-PD-1)-based therapies for metastatic bone and soft tissue sarcoma

Objective:Sarcomas are a group of rare malignancies with various subtypes.Patients with metastatic sarcoma who have failed traditional treatments can possibly achieve better prognoses from using novel therapies,including anti-programmed death-1(PD-1)-based therapies.Methods:We retrospectively analyzed clinical data of 24 metastatic sarcoma patients from June 15,2016 to December 30,2019.These patients mainly received angiogenesis inhibitors combined with anti-PD-1 therapy after they became resistant to traditional treatments.Furthermore,8 patients underwent panel DNA and whole transcript sequencing.Results:Six patients received 2 cycles of anti-PD-1 therapy and were included in the safety evaluation only group.The median follow-up time was 5.77 months.The median progression-free survival was 7.59 months,the overall response rate was 16.7%and the disease control rate was 55.6%.Based on whole exome and transcript sequencing data,there was no association between TMB,TNB,MSI,HLA-LOH,and PD-L1 expressions and sarcoma types with clinical responses.Immunotherapy efficacy and bioinformatics analyses indicated higher intratumoral heterogeneity(ITH)in progressive disease(PD)patients and lower ITH in partial response(PR)and stable disease patients.A higher percentage of immune cell infiltration,especially monocytes,was observed in PR patients.Active stromal gene expression was increased in PD patients but decreased in PR patients.Enrichment analysis revealed that an increased TGF-βsignaling pathway was reversely correlated with anti-PD-1 efficacy,while a decreased inflammatory response signaling pathway was positively correlated with anti-PD-1 efficacy.Conclusions:Our study showed PD-1 inhibitors combined with anti-angiogenesis agents were effective and well-tolerated.ITH,monocyte ratio,stroma subtypes,and the status of immune-associated signaling pathways may be related with anti-PD-1 based therapy.

PYK2 mediates the BRAF inhibitor (vermurafenib)-induced invadopodia formation and metastasis in melanomas

Objective:The BRAF inhibitor,vemurafenib,has been widely used in the treatment of patients with melanoma-bearing BRAFV600E mutations.While the initial response to vemurafenib is usually excellent,the majority of patients eventually develop resistance and metastatic disease.However,the underlying molecular mechanism remains elusive.The objective of this study was therefore to identify additional molecular targets responsible for vemurafenib resistance.Methods:Western blots and immunohistochemistry analyses were used to evaluate expressions of PYK2 and p-PYK2 in cultured cells and melanoma tissue microarrays.The relationships of p-PYK2 with clinicopathological parameters were statistically analyzed.Invadopodia cell invasion,and a Ca2+assay were used to determine the effect of vemurafenib resistance-induced p-PYK2 on melanoma progression.A mouse model was used to assess the effects of PYK2 on melanoma metastasis.Results:Elevated p-PYK2 levels were detected in vemurafenib-resistant melanoma cells,and PYK2 was shown to regulate invadopodia formation in melanoma cells.Vemurafenib triggered invadopodia formation by activation of PYK2.Inhibition of PYK2 with either shRNA or the small molecule inhibitor,PF562711,dramatically reduced vemurafenib-induced invadopodia formation.Furthermore,knockdown of PYK2 significantly reduced melanoma lung metastasis in vivo.Increased expressions of p-PYK2 in melanoma patients were positively correlated with advanced stage(P=0.002),metastasis(P<0.001),and Clark grade(P<0.001),and were also associated with short overall survival[hazard ratio(HR)=3.304,P=0.007]and progression-free survival(HR=2.930,P=0.001).Conclusions:PYK2 mediated vemurafenib-induced melanoma cell migration and invasion.Inhibition of PYK2 resensitized melanoma cells to vemurafenib.Phospho-PYK2 was a prognostic biomarker in melanoma patients.

The prognostic significance of non-sentinel lymph node metastasis in cutaneous and acral melanoma patients—A multicenter retrospective study

Background:Whether non-sentinel lymph node(SLN)-positive melanoma patients can benefit from completion lymph node dissection(CLND)is still unclear.The current study was performed to identify the prognostic role of nonSLN status in SLN-positive melanoma and to investigate the predictive factors of non-SLN metastasis in acral and cutaneous melanoma patients.Methods:The records of 328 SLN-positive melanoma patients who underwent radical surgery at four cancer centers from September 2009 to August 2017 were reviewed.Clinicopathological data including age,gender,Clark level,Breslow index,ulceration,the number of positive SLNs,non-SLN status,and adjuvant therapy were included for survival analyses.Patients were followed up until death or June 30,2019.Multivariable logistic regression modeling was performed to identify factors associated with non-SLN positivity.Log-rank analysis and Cox regression analysis were used to identify the prognostic factors for disease-free survival(DFS)and overall survival(OS).Results:Among all enrolled patients,220(67.1%)had acral melanoma and 108(32.9%)had cutaneous melanoma.The 5-year DFS and OS rate of the entire cohort was 31.5%and 54.1%,respectively.More than 1 positive SLNs were found in 123(37.5%)patients.Positive non-SLNs were found in 99(30.2%)patients.Patients with positive non-SLNs had significantly worse DFS and OS(log-rank P<0.001).Non-SLN status(P=0.003),number of positive SLNs(P=0.016),and adjuvant therapy(P=0.025)were independent prognostic factors for DFS,while non-SLN status(P=0.002),the Breslow index(P=0.027),Clark level(P=0.006),ulceration(P=0.004),number of positive SLNs(P=0.001),and adjuvant therapy(P=0.007)were independent prognostic factors for OS.The Breslow index(P=0.020),Clark level(P=0.012),and number of positive SLNs(P=0.031)were independently related to positive non-SLNs and could be used to develop more personalized surgical strategy.Conclusions:Non-SLN-positive melanoma patients had worse DFS and OS even after immediate CLND than those with non-SLN-negative melanoma.The Breslow index,Clark level,and number of positive SLNs were independent predictive factors for non-SLN status.

Clinicopathological features of pseudomyogenic hemangioendothelioma and precision therapy based on whole exome sequencing

Dear Editor Pseudomyogenic hemangioendothelioma(PHE)is a newly recognized subtype of hemangioendothelioma characterized by the presence of fibrohistiocytic and myoid cells arranged in a fibroma-like or dermatofibroma-like pattern[1].This rare type of tumor was first named by Hornick and Fletcher[2]and categorized as the novel soft tissue tumor classification system of the World Health Organization in 2013[3].Prior to this,it was referred to as fibroma-like variant of epithelioid sarcoma(ES)and epithelioid sarcoma-like hemangioendothelioma[4].