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.

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。

Efficacy of vinorelbine combined with low-dose methotrexate for treatment of inoperable desmoid tumor and prognostic factor analysis

Objective： To assess the efficacy of conservative chemotherapy for inoperable desmoid tumor（DT） and analyze the prognostic factors.Methods：From November 2008 to April 2016,71 patients of inoperable DT were treated with vinorelbine and low-dose methotrexate in the Department of Bone and Soft Tissue Tumors,Peking University Cancer Hospital＆Institute,and enrolled in this retrospective study.The chemotherapy duration is one year.The efficacy of chemotherapy and the prognosis were observed.Results：Of the 71 patients,55% were female.Age of onset varied from 1 to 47 years,and the median age was 14years.Only 11（15.5%）cases suffered primary tumor.The distribution of the site of tumors was：31（43.7%）in the trunk,36（50.7%）in the limbs,and 4（5.6%）in the peritoneal and pelvic cavity.The size of tumor（the maximum diameter）differed from 2 to 37 cm with a mean of 9.3 cm.The median follow-up duration was 28（range,6–87）months.Common side effects included：nausea and vomiting,liver injury,bone marrow suppression and oral ulcers.When the chemotherapy finished,1（1.4%）case achieved complete response,24（33.8%）achieved partial response,37（52.1%）achieved stable disease and 9（12.7%）had progressive disease.The overall response rate was 87.3%.The progression-free survival（PFS）of the participants were from 6 to 87 months,and the 2-,3-and 5-year PFS was 79.9%,68.4% and 36.3%,respectively.No significant difference was identified in PFS in subgroups of gender,age of onset,age of chemotherapy,tumor site and tumor size.Conclusions：For recurrent,inoperable and progressive DT,enough course of chemotherapy with vinorelbine combined with low-dose methotrexate was an optional choice for local control.

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.

Investigation of osteosarcoma genomics and its impact on targeted therapy: an international collaboration to conquer human osteosarcoma

Osteosarcoma is a genetically unstable malignancy that most frequently occurs in children and young adults.The lack of progress in managing this devastating disease in the clinic has prompted international researchers to collaborate to profile key genomic alterations that define osteosarcoma.A team of researchers and clinicians from China,Finland,and the United States investigated human osteosarcoma by integrating transcriptome sequencing(RNA-seq),high-density genome-wide array comparative genomic hybridization(a CGH),fluorescence in situ hybridization(FISH),reverse transcription-polymerase chain reaction(RT-PCR),Sanger sequencing,cell culture,and molecular biological approaches.Systematic analysis of genetic/genomic alterations and further functional studies have led to several important findings,including novel rearrangement hotspots,osteosarcoma-specific LRP1-SNRNP25 and KCNMB4-CCND3 fusion genes,VEGF and Wnt signaling pathway alterations,deletion of the WWOX gene,and amplification of the APEX1 and RUNX2 genes.Importantly,these genetic events associate significantly with pathogenesis,prognosis,progression,and therapeutic activity in osteosarcoma,suggesting their potential impact on improved managements of human osteosarcoma.This international initiative provides opportunities for developing new treatment modalities to conquer osteosarcoma.

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.

The prognostic value of C-X-C motif chemokine receptor 4 in patients with sporadic malignant peripheral nerve sheath tumors

Background: Recent studies indicate that C-X-C motif chemokine receptor 4(CXCR4) and its ligand, C-X-C motif chemokine ligand 12(CXCL12), stimulate expression of the cell cycle regulatory protein Cyclin D1 in neurofibromatosis 1-associated malignant peripheral nerve sheath tumor(MPNST) cells and promote their proliferation. In this study, we measured the expression of CXCR4, CXCL12, and Cyclin D1 proteins in sporadic MPNST tissues from Chinese patients and investigated their prognostic values.Methods: CXCR4, CXCL12, and Cyclin D1 protein expression in samples from 58 Chinese patients with sporadic MPNST was assessed with immunohistochemical staining.Their prognostic values were evaluated with Kaplan-Meier analysis and a log-rank test. Multivariate Cox regression analysis was used to identify independent prognostic factors.Results: High expression of CXCR4, CXCL12, and Cyclin D1 was observed in 19(32.8%), 32(55.2%), and 16(27.6%)samples, respectively. CXCR4 expression was positively correlated with CXCL12 expression(r = 0.334, P = 0.010) and Cyclin D1 expression(r = 0.309, P = 0.018). Patients with high CXCR4 expression showed longer overall survival than those with low CXCR4 expression(χ~2 = 4.642, P = 0.031).Conclusion: High CXCR4 expression may define a specific subtype of sporadic MPNST with favorable prognosis.

The prognostic role of PRUNE2 in leiomyosarcoma

PRUNE2 plays an important role in regulating tumor cell differentiation,proliferation,and invasiveness in neuroblastoma.Our previous study revealed that PRUNE2/OBSCN two-gene relative expression classifer accurately differentiated leiomyosarcoma from gastrointestinal stromal tumor.However,the association between PRUNE2 expression and prognosis in leiomyosarcoma is poorly understood.In this study,we evaluated the prognostic role of PRUNE2 in leiomyosarcoma.PRUNE2 expression was detected using immunohistochemistry in 30 formalin-fixed,paraffin-embedded leiomyosarcoma tissues from MD Anderson Cancer Center,and high expression was detected in 36.7%(11/30)of the samples.To validate these results,immunohistochemistry was performed on another cohort of 45 formalin-fixed,paraffinembedded leiomyosarcoma tissues from Tianjin Medical University Cancer Institute&Hospital,and high PRUNE2 protein expression was detected in 37.8%(17/45)of the samples.Moreover,elevated PRUNE2expression was significantly associated with tumor size(P=0.03)and hemorrhage/cyst(P=0.014),and was an independent favorable prognostic factor for overall survival in leiomyosarcoma patients from Tianjin Medical University Cancer Institute&Hospital(P<0.05).These data suggest that increased PRUNE2protein expression may serve as a favorable prognostic marker in human leiomyosarcoma.

KIF18B promotes tumor progression in osteosarcoma by activating β-catenin

Objective:Osteosarcoma is a common primary highly malignant bone tumor.Kinesin family member 18B(K1F18B)has been identified as a potential oncogene involved in the development and metastasis of several cancer types.While KIF18B overexpression in osteosarcoma tissue is clearly detected,its specific function in the disease process remains to be established.Methods:K IF18B expression was assessed in osteosarcoma tissues and cells.We additionally evaluated the effects of KIF18B on proliferation,migration,and invasion of osteosarcoma cells,both in vitro and in vivo.Results:Our results showed overexpression of KIF18B in osteosarcoma tissues and cells.Knockdown of K IF18B induced G1/S phase arrest and significantly inhibited proliferation,migration,and invasion of osteosarcoma cells,both in vitro and in vivo.K IF18B regulated P-catenin expression at the transcriptional level by controlling nuclear aggregation of ATF2 and at the post-transcriptional level by interacting with the adenomatous polyposis coli(APC)tumor suppressor gene in osteosarcoma cells.Conclusions:KIF18B plays a carcinogenic role in osteosarcoma by regulating expression ofβ-catenin transcriptionally via decreasing nuclear aggregation of ATF2 or post-transcriptionally through interactions with APC.Our collective findings support the potential utility of KIF18B as a novel prognostic biomarker for osteosarcoma.

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).

Characterization of FGFR signaling pathway as therapeutic targets for sarcoma patients

The fibroblast growth factor receptor(FGFR) family plays important roles in regulating cell growth, proliferation, survival,differentiation and angiogenesis. Deregulation of the FGF/FGFR signaling pathway has been associated with multiple development syndromes and cancers, and thus therapeutic strategies targeting FGFs and FGFR in human cancer are currently being explored.However, few studies on the FGF/FGFR pathway have been conducted in sarcoma, which has a poor outcome with traditional treatments such as surgery, chemotherapy, and radiotherapy. Hence, in the present review, we provide an overview of the role of the FGF/FGFR pathway signal in sarcoma and FGFR inhibitors, which might be new targets for the treatment of sarcomas according to recent research.

Carboxymethyl chitosan-alginate enhances bone repair effects of magnesium phosphate bone cement by activating the FAK-Wnt pathway

There is a continuing need for artificial bone substitutes for bone repair and reconstruction,Magnesium phosphate bone cement(MPC)has exceptional degradable properties and exhibits promising biocompatibility.However,its mechanical strength needs improved and its low osteo-inductive potential limits its therapeutic application in bone regeneration.We functionally modified MPC by using a polymeric carboxymethyl chitosan-sodium alginate(CMCS/SA)gel network.This had the advantages of:improved compressive strength,ease of handling,and an optimized interface for bioactive bone in-growth.The new composites with 2%CMCS/SA showed the most favorable physicochemical properties,including mechanical strength,wash-out resistance,setting time,injectable time and heat release.Biologically,the composite promoted the attachment and proliferation of osteoblast cells.It was also found to induce osteogenic differentiation in vitro,as verified by expression of osteogenic markers.In terms of molecular mechanisms,data showed that new bone cement activated the Wnt pathway through inhibition of the phosphorylation ofβ-catenin,which is dependent on focal adhesion kinase.Through micro-computed tomography and histological analysis,we found that the MPC-CMCS/SA scaffolds,compared with MPC alone,showed increased bone regeneration in a rat calvarial defect model.Overall,our study suggested that the novel composite had potential to help repair critical bone defects in clinical practice.

Novel anti-melanoma treatment:focus on immunotherapy

Melanoma is an intractable cancer that is aggressive, lethal, and metastatic. The prognosis of advanced melanoma is very poor because it is insensitive to chemotherapy and radiotherapy. The incidence of melanoma has been ascending stably for years worldwide, accompanied by increasing mortality. New approaches to managing this deadly disease are much anticipated to enhance the cure rate and to extend clinical benefits to patients with metastatic melanoma. Due to its high degree of immunogenicity, melanoma could be a good target for immunotherapy, which has been developed for decades and has achieved certain progress. This article provides an overview of immunotherapy for melanoma.

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].

Membrane dynamics of ATG4B and LC3 in autophagosome formation

The biogenesis of autophagosomes provides the basis for macroautophagy to capture and degrade intracellular cargoes.Binding of the autophagy-related protein ATG8/LC3 to autophagic membranes is essential to autophagosome formation,which involves the specific and dynamic processing of ATG8/LC3 by cysteine protease ATG4.However,to date,the mechanism whereby ATG4 is recruited to the membranes,the interaction of ATG4 and ATG8/LC3 on the membranes,and its role in the growth of phagophore are not completely understood.Here,we used fluorescence recovery after photobleaching to monitor the turnover of GFP-tagged ATG4B and LC3B in living animal cells.The data show that ATG4B localizes to early autophagic membranes in an LC3B-dependent manner.During autophagy,ATG4B and LC3B undergo rapid cytosol/isolation membrane exchange but not at the cytosol/completed autophagosome.In addition,ATG4B activity controls the efficiency of autophagosome formation by impacting the membrane binding/dissociation of LC3B.These data suggest that ATG4 and LC3 play interdependent roles in the formation of autophagosomes.

Enhancing the HSV-1-mediated antitumor immune response by suppressing Bach1

Background In 2015,herpes simplex virus 1(HSV-1)-derived talimogene laherparepvec(T-VEC)was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment.However,its antitumor application is limited to local treatment of melanoma,and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor immunity.We hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this virus.Methods We systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against HSV-1.Then,we tested the effect of BACH1 deficiency on immunogenic cell death induced by HSV-1.Furthermore,we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor models.Results We identified eight IFN-stimulated genes(ISGs)controlling HSV-1 replication,among which BTB and CNC homology 1(BACH1)suppressed HSV-1 replication by inhibiting the transcription of ICP4,ICP27,and UL39.Loss of Bach1 function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis,HMGB1 secretion,and calreticulin exposure in tumor cells.More importantly,hemin,an FDA-approved drug known to downregulate BACH1,significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor site.Conclusions Our studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.

Gait phase detection by using a portable system and artificial neural network

Gait phases are important to evaluate the walking function and to identify the characteristics of pathological gaits.However,it is difficult to differentiate gait phases outside gait laboratories,thus,this study aimed to develop a method to detect 8 gait sub-phases using a wearable multiple sensor system and artificial neural network(ANN).Motion sensors were used to acquire the acceleration of lower limbs,and force sensitive resistors were used to detect contact state and force between the foot and the ground.Walking was recorded using a high-speed camera.Two feed forward back-propagation(BP)neural networks were developed.The resilient BP algorithm was used to train ANN.A total of 66 volunteers participated in this study.For the stance and swing phase detection,simulation of the training data showed an accuracy of 98.0%.The data from the test set showed a recognition accuracy of 97.75%.Because the ending point of the last phase‘Terminal Swing’is always 100%GC,we only listed seven phases.The prediction accuracy of seven phases were:35.9%,63.8%,93.6%,94.9%,94.8%,97.9%and 98%using the limb acceleration data only.The average accuracy for seven phases were 68%,91.3%,97.8%,98.9%,98.8%,99.1%,and 99.5%using the limb acceleration and foot pressure data for fast,normal,and slow gait speeds.This study provides a new method for eight gait sub-phases detection with high accuracy combining a wearable system and ANN,which may make gait phase analysis possible under free-living conditions.

Mitochondria-mediated apoptosis in mammals

The mitochondria-mediated caspase activation pathway is a major apoptotic pathway characterized by mitochondrial outer membrane permeabilization （MOMP） and subsequent release of cytochrome c into the cytoplasm to activate caspases. MOMP is regulated by the Bcl-2 family of proteins. This pathway plays important roles not only in normal development, main- tenance of tissue homeostasis and the regulation of immune system, but also in human diseases such as immune disorders, neurodegeneration and cancer. In the past decades the molecular basis of this pathway and the regulatory mechanism have been comprehen- sively studied, yet a great deal of new evidence indi- cates that cytochrome c release from mitochondria does not always lead to irreversible cell death, and that caspase activation can also have non-death functions. Thus, many unsolved questions and new challenges are still remaining. Furthermore, the dysfunction of this pathway involved in cancer development is obvious, and targeting the pathway as a therapeutic strategy has been extensively explored, but the efficacy of the tar- geted therapies is still under development. In this review we will discuss the mitochondria-mediated apoptosis pathway and its physiological roles and therapeutic implications.