Research Progress on the Mental Toughness of Family Caregivers of Children with Malignant Solid Tumors

The physical,emotional,and caregiving quality of caregivers for children with malignant solid tumors is significantly influenced by mental toughness.The definition of mental toughness,study methods,primary influencing factors,and intervention strategies for the mental toughness of caregivers of children with malignant solid tumors will be examined in this paper.To improve the mental toughness of caregivers of children with malignant solid tumors,it is recommended that future studies enhance the number of intervention research methods and establish particular evaluation tools.

Challenges and interventions of chimeric antigen receptor-T cell therapy in solid tumors

Adoptive cellular therapy is rapidly improving immunotherapy in hematologic malignancies and several solid tumors.Remarkable clinical success has been achieved in chimeric antigen receptor(CAR)-T cell therapy which represents a paradigm-shifting strategy for the treatment of hematological malignancies.However,many challenges such as resistance,antigen heterogeneity,poor immune cell infiltration,immunosuppressive microenvironment,metabolic obstructive microenvironment,and T cell exhaustion remain as barriers to broader application especially in solid tumors.Encouragingly,the development of new approaches such as multidimensional omics and biomaterials technologies was aided to overcome these barriers.Here,in this perspective,we focus on the most recent clinical advancements,challenges,and strategies of immune cellular therapy in solid tumor treatment represented by CAR-T cell therapy,to provide new ideas to further overcome the bottleneck of immune cell therapy and anticipate future clinical advances.

Immune response evaluation criteria in solid tumors for assessment of atypical responses after immunotherapy

In 2017,immune response evaluation criteria in solid tumors(iRECIST)were introduced to validate radiologic and clinical interpretations and to better analyze tumor’s response to immunotherapy,considering the different time of following and response,between this new therapy compared to the standard one.However,even if the iRECIST are worldwide accepted,to date,different aspects should be better underlined and well reported,especially in clinical practice.Clinical experience has demonstrated that in a non-negligible percentage of patients,it is challenging to determine the correct category of response(stable disease,progression disease,partial or complete response),and consequently,to define which is the best management for those patients.Approaching radiological response in patients who underwent immunotherapy,a new uncommon kind of target lesions behavior was found.This phenomenon is mainly due to the different mechanisms of action of immunotherapeutic drug.Therefore,new groups of response have been described in clinical practice,defined as“atypical responses,”and categorized into three new groups:pseudoprogression,hyperprogression,and dissociated response.This review summarizes and reports these patterns,helping clinicians and radiologists get used to atypical responses,in order to identify patients that respond best to treatment.

Strategies to enhance monoclonal antibody uptake and distribution in solid tumors

Despite the significant resources dedicated to the development of monoclonal antibody(m Ab)therapies for solid tumors,the clinical success,thus far,has been modest.Limited efficacy of m Ab in solid tumors likely relates to unique aspects of tumor physiology.Solid tumors have an aberrant vasculature and a dense extracellular matrix that slow both the convective and diffusive transport of m Abs into and within tumors.For m Abs that are directed against cellular antigens,high antigen expression and rapid antigen turnover can result in perivascular cells binding to and eliminating a significant amount of extravasated m Ab,limiting m Ab distribution to portions of the tumor that are distant from functional vessels.Many preclinical investigations have reported strategies to improve m Ab uptake and distribution;however,to our knowledge,none have translated into the clinic.Here,we provide an overview of several barriers in solid tumors that limit m Ab uptake and distribution and discuss approaches that have been utilized to overcome these barriers in preclinical studies.

The clinical association of programmed cell death protein 4(PDCD4) with solid tumors and its prognostic significance:a meta-analysis

Background: Programmed cell death protein 4(PDCD4) is a novel tumor suppressor protein involved in pro?grammed cell death. Its association with cancer progression has been observed in multiple tumor models, but evidence supporting its association with solid tumors in humans remains controversial. This study aimed to determine the clinical signiicance and prognostic value of PDCD4 in solid tumors.Methods: A systematic literature review was performed to retrieve publications with available clinical informa?tion and survival data. The eligibility of the selected articles was based on the criteria of the Dutch Cochrane Centre proposed by the Meta?analysis Of Observational Studies in Epidemiology group. Pooled odds ratios(ORs), hazard ratios(HRs), and 95% conidence intervals(CIs) for survival analysis were calculated. Publication bias was examined by Begg's and Egger's tests.Results: Clinical data of 2227 cancer patients with solid tumors from 23 studies were evaluated. PDCD4 expression was signiicantly associated with the diferentiation status of head and neck cancer(OR 4.25, 95% CI 1.87–9.66) and digestive system cancer(OR 2.87, 95% CI 1.84–4.48). Down?regulation of PDCD4 was signiicantly associated with short overall survival of patients with head and neck(HR: 3.44, 95% CI 2.38–4.98), breast(HR: 1.86, 95% CI 1.36–2.54), digestive system(HR: 2.12, 95% CI 1.75–2.56), and urinary system cancers(HR: 3.16, 95% CI 1.06–9.41).Conclusions: The current evidence suggests that PDCD4 down?regulation is involved in the progression of several types of solid tumor and is a potential marker for solid tumor prognoses. Its clinical usefulness should be conirmed by large?scale prospective studies.

Comprehensive insights into the effects and regulatory mechanisms of immune cells expressing programmed death-1/programmed death ligand 1 in solid tumors

The programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway is an important mechanism in tumor immune escape,and expression of PD-L1 on tumor cells has been reported more frequently.However,accumulating evidence suggests that PD-1/PD-L1 is also widely expressed on immune cells,and that regulation is also critical for tumor immune responses.In this review,we emphasized that under solid tumor conditions,the immunoregulatory effects of immune cells expressing PD-1 or PD-L1,affected the prognoses of cancer patients.Therefore,a better understanding of the mechanisms that regulate PD-1 or PD-L1 expression on immune cells would provide clear insights into the increased efficacy of anti-PD antibodies and the development of novel tumor immunotherapy strategies.

PhaseⅠdose-escalation and expansion study of PARP inhibitor,fluzoparib(SHR3162),in patients with advanced solid tumors

Objective:Fluzoparib(SHR3162)is a novel,potent poly(ADP-ribose)polymerases(PARP)1,2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phaseⅠ,first-in-human,dose-escalation and expansion(D-Esc and D-Ex)trial in patients with advanced solid cancer.Methods:This was a 3+3 phaseⅠD-Esc trial with a 3-level D-Ex at 5 hospitals in China.Eligible patients for DEsc had advanced solid tumors refractory to standard therapies,and D-Ex enrolled patients with ovarian cancer(OC).Fluzoparib was administered orally once or twice daily(bid)at 11 dose levels from 10 to 400 mg/d.Endpoints included dose-finding,safety,pharmacokinetics,and antitumor activity.Results:Seventy-nine patients were enrolled from March,2015 to January,2018[OC(47,59.5%);breast cancer(BC)(16,20.3%);colorectal cancer(8,10.1%),other tumors(8,10.1%)];48 patients were treated in the D-Esc arm and 31 in the D-Ex arm.The maximum tolerated dose(MTD)was 150 mg bid,with a half-life of 9.14 h.Grade 3/4 adverse events included anemia(7.6%)and neutropenia(5.1%).The objective response rate(ORR)was 30%(3/10)in patients with platinum-sensitive OC and 7.7%(1/13)in patients with BC.Among patients treated with fluzoparib≥120 mg/d,median progression-free survival(m PFS)was 7.2[95%confidence interval(95%CI),1.8-9.3]months in OC,9.3(95%CI,7.2-9.3)months in platinum-sensitive OC,and 3.5(range,2.0-28.0)months in BC.In patients with germline BC susceptibility gene mutation(g BRCAMut)(11/43 OC;2/16 BC),m PFS was 8.9 months for OC(range,1.0-23.2;95%CI,1.0-16.8)and 14 and 28 months for BC(those two patients both also had somatic BRCAMut).Conclusions:The MTD of fluzoparib was 150 mg bid in advanced solid malignancies.Fluzoparib demonstrated single-agent antitumor activity in BC and OC,particularly in BRCAMut and platinum-sensitive OC.

Vorolanib,an oral VEGFR/PDGFR dual tyrosine kinase inhibitor for treatment of patients with advanced solid tumors:An open-label,phaseⅠdose escalation and dose expansion trial

Objective:This study evaluated the safety and preliminary efficacy of vorolanib,a novel tyrosine kinase inhibitor,for treatment of patients with advanced solid tumors.Methods:During dose escalation,patients received increasing doses of oral vorolanib(50-250 mg once daily)in cycles of four weeks for up to one year.During dose expansion,patients received recommended doses(100 and 200 mg)in 4-week cycles.The primary endpoint was to determine the safety and maximum tolerated dose and/or the recommended phase II dose(RP2 D).The severity and type of adverse drug reactions(ADRs)were assessed using the Common Terminology Criteria for Adverse Events version 4.0.The second endpoint was preliminary efficacy in terms of objective response and progression-free survival(PFS).Results:No dose-limiting toxicity occurred during dose escalation(50-250 mg).Five(26.3%)patients in the escalation cohort(n=19)and 12(48.0%)in the expansion cohort(n=25)experienced grade 3 ADRs.The most common ADRs were hair color changes,fatigue,portal hypertension,hypertriglyceridemia,and proteinuria.During dose expansion,the patients treated with 200 mg and 100 mg(once daily)showed an objective response rate of 22.2%and 5.9%,respectively;the disease control rate was 88.9%and 73.3%,respectively;the median PFS was9.9[95%confidence interval(95%CI):7.4-not reached]months and 3.8(95%CI:1.9-not reached)months,respectively.Conclusions:Oral vorolanib at a dose of 200 mg(once daily)exhibited an acceptable safety profile and favorable clinical benefit for patients with advanced solid tumors.The RP2 D for vorolanib was determined to be 200 mg as a daily regimen.

Short term safety of coronavirus disease 2019 vaccines in patients with solid tumors receiving systemic therapy

BACKGROUND There are currently three coronavirus disease 2019(COVID-19)vaccines approved by the United States Food and Drug Administration to prevent coronavirus infection.However,robust data are unavailable on the adverse events of the vaccines in patients with solid tumor malignancies undergoing systemic therapies.AIM To evaluate the safety of COVID-19 vaccines in patients with solid tumors undergoing systemic therapies.METHODS The study included patients with solid tumors treated in an academic tertiary care center who received COVID-19 vaccination between January 1,2021 and August 15,2021,while undergoing systemic therapy.Electronic medical records were accessed to collect information on patient characteristics,systemic therapies,type of vaccine received,and adverse effects associated with the vaccine administration.Adverse events(AEs)were graded according to Common Terminology Criteria for Adverse Events,version 5.0.RESULTS The analysis included 210 patients;the median age was 70 years,and 51%of patients were female.The most common chemotherapy,immunotherapy,and targeted therapy administered were taxane-based regimens 14.2%(30/210),antiprogrammed death 1(PD-1)agents 22.8%(48/210),and antiangiogenic agents 7.1%(15/210),respectively.The most common cancers were gastrointestinal 43.8%(92/210),thoracic 30.4%(64/210),and genitourinary 17.6%(37/210).Patients received the following vaccines:2 doses of BNT162b2 by Pfizer 52%(110/210),2 doses of mRNA-1273 by Moderna 42%(89/210),and 1 dose of JNJ-78436735 by Johnson&Johnson 5%(11/210).At least 1 AE attributable to the vaccine was observed in 37 patients 17.6%(37/210).The total number of AEs attributable to vaccines was 62:Fifty-three grade 1 and nine grade 2.Most adverse events occurred after the second dose 59.7%(37/62).The most frequent grade 1 AEs included fatigue 17%(9/53),fever 15%(8/53),injection site reaction 13.2%(7/53),and chills 9.4%(5/53).The most frequent grade 2 AEs were fatigue 33.3%(3/9)and generalized weakness 22.2%(2/9).Therapy was delayed by 2 wk because of the AEs possibly related to vaccine administration in 3 patients 1.4%(3/210).CONCLUSION The present study demonstrates that the adverse events associated with COVID-19 vaccination are infrequent,mild,and rarely delay treatment in patients with solid tumors receiving systemic therapies.

Chimeric antigen receptor-immune cells against solid tumors:Structures,mechanisms,recent advances,and future developments

The advent of chimeric antigen receptor(CAR)-T cell immunotherapies has led to breakthroughs in the treatment of hematological malignancies.However,their success in treating solid tumors has been limited.CAR-natural killer(NK)cells have several advantages over CAR-T cells because NK cells can be made from pre-existing cell lines or allogeneic NK cells with a mismatched major histocompatibility complex(MHC),which means they are more likely to become an"off-the-shelf"product.Moreover,they can kill cancer cells via CAR-dependent/independent pathways and have limited toxicity.Macrophages are the most malleable immune cells in the body.These cells can efficiently infiltrate into tumors and are present in large numbers in tumor microenvironments(TMEs).Importantly,CAR-macrophages(CAR-Ms)have recently yielded exciting preclinical results in several solid tumors.Nevertheless,CAR-T,CAR-NK,and CAR-M all have their own advantages and limitations.In this review,we systematically discuss the current status,progress,and the major hurdles of CAR-T cells,CAR-NK cells,and CAR-M as they relate to five aspects:CAR structure,therapeutic mechanisms,the latest research progress,current challenges and solutions,and comparison according to the existing research in order to provide a reasonable option for treating solid tumors in the future.

Multicellular tumor spheroids bridge the gap between two-dimensional cancer cells and solid tumors: The role of lipid metabolism and distribution

Previous studies demonstrated that three-dimensional(3D) multicellular tumor spheroids(MCTS) could more closely mimic solid tumors than two-dimensional(2D) cancer cells in terms of the spatial structure, extracellular matrix-cell interaction, and gene expression pattern. However, no study has been reported on the differences in lipid metabolism and distribution among 2D cancer cells, MCTS, and solid tumors. Here, we used Hep G2 liver cancer cell lines to establish these three cancer models. The variations of lipid profiles and spatial distribution among them were explored by using mass spectrometry-based lipidomics and matrix-assisted laser desorption/ionization mass spectrometry imaging(MSI). The results revealed that MCTS, relative to 2D cells, had more shared lipid species with solid tumors. Furthermore,MCTS contained more comparable characteristics than 2D cells to solid tumors with respect to the relative abundance of most lipid classes and mass spectra patterns. MSI data showed that 46 of 71 lipids had similar spatial distribution between solid tumors and MCTS, while lipids in 2D cells had no specific spatial distribution. Interestingly, most of detected lipid species in sphingolipids and glycerolipids preferred locating in the necrotic region to the proliferative region of solid tumors and MCTS. Taken together, our study provides the evidence of lipid metabolism and distribution demonstrating that MCTS are a more suitable in vitro model to mimic solid tumors, which may offer insights into tumor metabolism and microenvironment.

Target selection and clinical chimeric antigen receptor T cell activity against solid tumors

Chimeric antigen receptor(CAR)T cell therapy is a relatively new form of targeted therapy that has demonstrated impressive success in treating hematological malignancies.It has been challenging to translate this success to solid tumors.Reasons for this include barriers to delivery,tumor heterogeneity,cancer cells'ability to evade the immune system as well as identifying the optimal target.Most CAR T clinical trials have targeted well‐characterized cancer targets with significant preclinical and in some cases clinical validation.Published results from some of these trials show signs of anti‐cancer activity that warrant encouragement,but also caution,given instances of unacceptable toxicity.The narrow therapeutic window is complicated by the ability of CAR T cells to expand in patients regardless of dose.Here,we review those trials showing encouraging results in the context of target selection.It is clear that more specific tumor targeting is required,either by affinity tuning to avoid low‐level target expression in healthy cells,logic gating,or the identification of new targets that are more cancer specific.

Minimal residual disease in solid tumors:an overview

Minimal residual disease(MRD)is termed as the small numbers of remnant tumor cells in a subset of patients with tumors.Liquid biopsy is increasingly used for the detection of MRD,illustrating the potential of MRD detection to provide more accurate management for cancer patients.As new techniques and algorithms have enhanced the performance of MRD detection,the approach is becoming more widely and routinely used to predict the prognosis and monitor the relapse of cancer patients.In fact,MRD detection has been shown to achieve better performance than imaging methods.On this basis,rigorous investigation of MRD detection as an integral method for guiding clinical treatment has made important advances.This review summarizes the development of MRD biomarkers,techniques,and strategies for the detection of cancer,and emphasizes the application of MRD detection in solid tumors,particularly for the guidance of clinical treatment.

Enhancement of T cell infiltration via tumor-targeted Th9 cell delivery improves the efficacy of antitumor immunotherapy of solid tumors

Insufficient infiltration of T cells severely compromises the antitumor efficacy of adoptive cell therapy(ACT)against solid tumors.Here,we present a facile immune cell surface engineering strategy aiming to substantially enhance the anti-tumor efficacy of Th9-mediated ACT by rapidly identifying tumor-specific binding ligands and improving the infiltration of infused cells into solid tumors.Non-genetic decoration of Th9 cells with tumor-targeting peptide screened from phage display not only allowed precise targeted ACT against highly heterogeneous solid tumors but also substantially enhanced infiltration of CD8+T cells,which led to improved antitumor outcomes.Mechanistically,infusion of Th9 cells modified with tumor-specific binding ligands facilitated the enhanced distribution of tumor-killing cells and remodeled the immunosuppressive microenvironment of solid tumors via IL-9 mediated immunomodulation.Overall,we presented a simple,cost-effective,and cell-friendly strategy to enhance the efficacy of ACT against solid tumors with the potential to complement the current ACT.

Solid pseudopapillary tumor of the pancreas:A systematic review of clinical,surgical and oncological characteristics of 1384 patients underwent pancreatic surgery

Background:Pancreatic solid pseudopapillary tumors(SPTs)are rare clinical entity,with low malignancy and still unclear pathogenesis.They account for less than 2%of exocrine pancreatic neoplasms.This study aimed to perform a systematic review of the main clinical,surgical and oncological characteristics of pancreatic SPTs.Data sources:MEDLINE/PubMed,Web of Science and Scopus databases were systematically searched for the main clinical,surgical and oncological characteristics of pancreatic SPTs up to April 2021,in accordance with the preferred reporting items for systematic reviews and meta-analyses(PRISMA)standards.Primary endpoints were to analyze treatments and oncological outcomes.Results:A total of 823 studies were recorded,86 studies underwent full-text reviews and 28 met inclusion criteria.Overall,1384 patients underwent pancreatic surgery.Mean age was 30 years and 1181 patients(85.3%)were female.The most common clinical presentation was non-specific abdominal pain(52.6%of cases).Mean overall survival was 98.1%.Mean recurrence rate was 2.8%.Mean follow-up was 4.2 years.Conclusions:Pancreatic SPTs are rare,and predominantly affect young women with unclear pathogenesis.Radical resection is the gold standard of treatment achieving good oncological impact and a favorable prognosis in a yearly life-long follow-up.

Unraveling the enigma:A comprehensive review of solid pseudopapillary tumor of the pancreas

Solid pseudopapillary tumor of the pancreas(SPTP)is a rare neoplasm predom-inantly observed in young females.Pathologically,CTNNB1 mutations,β-catenin nuclear accumulation,and subsequent Wnt-signaling pathway activation are the leading molecular features.Accurate preoperative diagnosis often relies on imaging techniques and endoscopic biopsies.Surgical resection remains the mainstay treatment.Risk models,such as the Fudan Prognostic Index,show promise as predictive tools for assessing the prognosis of SPTP.Establishing three types of metachronous liver metastasis can be beneficial in tailoring individu-alized treatment and follow-up strategies.Despite advancements,challenges persist in understanding its etiology,establishing standardized treatments for unresectable or metastatic diseases,and developing a widely recognized grading system.This comprehensive review aims to elucidate the enigma by consolidating current knowledge on the epidemiology,clinical presentation,pathology,molecular characteristics,diagnostic methods,treatment options,and prognostic factors.

Targeting the JAK/STAT pathway in solid tumors

Aberrant activation of signal transducer and activator of transcription(STAT)proteins is associated with the development and progression of solid tumors.However,as transcription factors,these proteins are difficult to target directly.In this review,we summarize the role of targeting Janus kinases(JAKs),upstream activators of STATs,as a strategy for decreasing STAT activation in solid tumors.Preclinical studies in solid tumor cell line models show that JAK inhibitors decrease STAT activation,cell proliferation,and cell survival;in in vivo models,they also inhibit tumor growth.JAK inhibitors,particularly the JAK1/2 inhibitor ruxolitinib,sensitize cell lines and murine models to chemotherapy,immunotherapy,and oncolytic viral therapy.Ten JAK inhibitors have been or are actively being tested in clinical trials as monotherapy or in combination with other agents in patients with solid tumors;two of these inhibitors are already Food and Drug Administration(FDA)approved for the treatment of myeloproliferative disorders and rheumatoid arthritis,making them attractive agents for use in patients with solid tumors as they are known to be well-tolerated.Four JAK inhibitors(two of which are FDA approved for other indications)have exhibited promising anti-cancer effects in preclinical studies;however,clinical studies specifically assessing their activity against the JAK/STAT pathway in solid tumors have not yet been conducted.In summary,JAK inhibition is a viable option for targeting the JAK/STAT pathway in solid tumors and merits further testing in clinical trials.

The potential prognostic and predictive roles of programmed cell death protein 1 expressed by tumor-infiltrating lymphocytes in solid tumors:a meta-analysis

Aim:Several previous studies have evaluated the potential role of programmed cell death protein 1(PD-1)expressed by tumor-infiltrating lymphocytes(TILs)in various solid tumors and performed its prognosis role in patients’survival with inconsistent results.This study aims to further systematically evaluate the association of PD-1 by TILs with clinicopathological parameters and clinical outcomes in solid tumor patients.Methods:A comprehensive search was conducted in PubMed,Embase,Web of Science,CNKI and Wanfang databases for relevant studies.The potential prognostic and predictive roles of PD-1 were assessed by pooled hazard ratio(HR),odds ratio(OR)and 95%confidence intervals(CI).A total of 1863 patients were selected for in-depth analysis.Results:The results demonstrated that PD-1 by TILs was correlated to overall survival for ovarian cancer(HR=0.40,95%CI:0.26-0.61,P<0.00001).Higher PD-1 expression was associated with lymph node metastasis(OR=2.55,95%CI:1.22-5.29,P=0.01)and tumor grade(OR=3.08,95%CI:2.07-4.57,P<0.00001).Conclusion:The prognostic role of PD-1 by TILs is variant in different tumor types,which highlights the role of PD-1 by TILs as a potential predictive and prognostic biomarker and the development of strategies against the PD-L1/PD-1 axis would be a promising therapeutic target for some solid tumors.

A phase I study of toripalimab, an anti-PD-1 antibody, in patients with refractory malignant solid tumors

Background:Several programmed cell death ligand 1(PD-L1)/programmed cell death protein 1(PD-1)antibodies have been approved for cancer treatmentworldwide.Their pharmacokinetic and pharmacodynamic characteristics have been reported mainly in western countries,but related data in Chinese patients are limited.This study was conducted to investigate the safety,efficacy,pharmacokinetics,and pharmacodynamics of an anti-PD-1 antibody,toripalimab,in Chinese patients.Methods:A single-center phase I study was conducted in Sun Yat-sen University Cancer Center.Eligible patients were adults with histologically confirmed,treatment-refractory,advanced,solitary malignant tumors.Toripalimab was intravenously infused every 2 weeks in dose-escalating cohorts at 0.3mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg.The study followed standard 3+3 design.Results:Between 15th March 2016 and 27th September 2016,25 patients were enrolled,of whom 3(12.0%),7(28.0%),6(24.0%),6(24.0%),3(12.0%)received 0.3 mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg toripalimab,respectively.After a median follow-up time of 5.0 months(range:1.5-19.8 months),we observed that the commonest treatment-related adverse events(TRAEs)were fatigue(64.0%)and rash(24.0%).No grade 3 or higher TRAEs were observed.No dose-limiting toxicity,treatment-related serious adverse events(SAEs),or treatment-related death occurred.Objective response ratewas 12.5%.The half-life of toripalimabwas 150-222 h after a single dose infusion.Most patients,including those from the 0.3 mg/kg group,maintained complete PD-1 receptor occupancy(>80%)on activated T cells since receiving the first dose of toripalimab.Conclusions:Toripalimab is a promising anti-PD-1 antibody,which was well tolerated and demonstrated anti-tumor activity in treatment-refractory advanced solitary malignant tumors.Further exploration in various tumors and combination therapies is warranted.