Risk of hepatitis B virus reactivation in oncological patients treated with tyrosine kinase inhibitors:A case report and literature analysis

Hepatitis B virus(HBV)reactivation(HBVr)represents a severe and potentially life-threatening condition,and preventive measures are available through blood test screening or prophylactic therapy administration.The assessment of HBVr traditionally considers factors such as HBV profile,including hepatitis B surface antigen(HBsAg)and antibody to hepatitis B core antigen,along with type of medication(chemotherapy;immunomodulants).Nevertheless,consideration of possible patient’s underlying tumor and the specific malignancy type(solid or hematologic)plays a crucial role and needs to be assessed for decision-making process.

Hepatic arterial infusion chemotherapy with anti-angiogenesis agents and immune checkpoint inhibitors for unresectable hepatocellular carcinoma and meta-analysis

BACKGROUND Hepatic arterial infusion chemotherapy(HAIC)has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma(uHCC).HAIC-based treatment showed great potential for treating uHCC.However,large-scale studies on HAIC-based treatments and meta-analyses of first-line treatments for uHCC are lacking.AIM To investigate better first-line treatment options for uHCC and to assess the safety and efficacy of HAIC combined with angiogenesis inhibitors,programmed cell death of protein 1(PD-1)and its ligand(PD-L1)blockers(triple therapy)under real-world conditions.METHODS Several electronic databases were searched to identify eligible randomized controlled trials for this meta-analysis.Study-level pooled analyses of hazard ratios(HRs)and odds ratios(ORs)were performed.This was a retrospective single-center study involving 442 patients with uHCC who received triple therapy or angiogenesis inhibitors plus PD-1/PD-L1 blockades(AIPB)at Sun Yat-sen University Cancer Center from January 2018 to April 2023.Propensity score matching(PSM)was performed to balance the bias between the groups.The Kaplan-Meier method and cox regression were used to analyse the survival data,and the log-rank test was used to compare the suvival time between the groups.RESULTS A total of 13 randomized controlled trials were included.HAIC alone and in combination with sorafenib were found to be effective treatments(P values for ORs:HAIC,0.95;for HRs:HAIC+sorafenib,0.04).After PSM,176 HCC patients were included in the analysis.The triple therapy group(n=88)had a longer median overall survival than the AIPB group(n=88)(31.6 months vs 14.6 months,P<0.001)and a greater incidence of adverse events(94.3%vs 75.4%,P<0.001).CONCLUSION This meta-analysis suggests that HAIC-based treatments are likely to be the best choice for uHCC.Our findings confirm that triple therapy is more effective for uHCC patients than AIPB.

Transcatheter arterial chemoembolization combined with PD-1 inhibitors and Lenvatinib for hepatocellular carcinoma with portal vein tumor thrombus

BACKGROUND Hepatocellular carcinoma(HCC)patients complicated with portal vein tumor thrombus(PVTT)exhibit poor prognoses and treatment responses.AIM To investigate efficacies and safety of the combination of PD-1 inhibitor,transcatheter arterial chemoembolization(TACE)and Lenvatinib in HCC subjects comorbid with PVTT.METHODS From January 2019 to December 2020,HCC patients with PVTT types Ⅰ-Ⅳ were retrospectively enrolled at Beijing Ditan Hospital.They were distributed to either the PTL or TACE/Lenvatinib(TL)group.The median progression-free survival(mPFS)was set as the primary endpoint,while parameters like median overall survival,objective response rate,disease control rate(DCR),and toxicity level served as secondary endpoints.RESULTS Forty-one eligible patients were finally recruited for this study and divided into the PTL(n=18)and TL(n=23)groups.For a median follow-up of 21.8 months,the DCRs were 88.9%and 60.9%in the PTL and TL groups(P=0.046),res-pectively.Moreover,mPFS indicated significant improvement(HR=0.25;P<0.001)in PTL-treated patients(5.4 months)compared to TL-treated(2.7 months)patients.There were no treatment-related deaths or differences in adverse events in either group.CONCLUSION A triplet regimen of PTL was safe and well-tolerated as well as exhibited favorable efficacy over the TL regimen for advanced-stage HCC patients with PVTT types Ⅰ-Ⅳ.

Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer:Unravelling challenges and future directions

Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.

Comparative efficacy of sodium glucose cotransporter-2 inhibitors in the management of type 2 diabetes mellitus:A real-world experience

BACKGROUND Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are a class of drugs with modest antidiabetic efficacy,weight loss effect,and cardiovascular benefits as proven by multiple randomised controlled trials(RCTs).However,real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse.AIM To study the comparative efficacy and safety of SGLT-2i using real-world clinical data.METHODS We evaluated the comparative efficacy data of 3 SGLT-2i drugs(dapagliflozin,canagliflozin,and empagliflozin)used for treating patients with type 2 diabetes mellitus.Data on the reduction of glycated hemoglobin(HbA1c),body weight,blood pressure(BP),urine albumin creatinine ratio(ACR),and adverse effects were recorded retrospectively.RESULTS Data from 467 patients with a median age of 64(14.8)years,294(62.96%)males and 375(80.5%)Caucasians were analysed.Median diabetes duration was 16.0(9.0)years,and the duration of SGLT-2i use was 3.6(2.1)years.SGLT-2i molecules used were dapagliflozin 10 mg(n=227;48.6%),canagliflozin 300 mg(n=160;34.3%),and empagliflozin 25 mg(n=80;17.1).Baseline median(interquartile range)HbA1c in mmol/mol were:dapagliflozin-78.0(25.3),canagliflozin-80.0(25.5),and empagliflozin-75.0(23.5)respectively.The respective median HbA1c reduction at 12 months and the latest review(just prior to the study)were:66.5(22.8)&69.0(24.0),67.0(16.3)&66.0(28.0),and 67.0(22.5)&66.5(25.8)respectively(P<0.001 for all comparisons from baseline).Significant improvements in body weight(in kilograms)from baseline to study end were noticed with dapagliflozin-101(29.5)to 92.2(25.6),and canagliflozin 100(28.3)to 95.3(27.5)only.Significant reductions in median systolic and diastolic BP,from 144(21)mmHg to 139(23)mmHg;(P=0.015),and from 82(16)mmHg to 78(19)mmHg;(P<0.001)respectively were also observed.A significant reduction of microalbuminuria was observed with canagliflozin only[ACR 14.6(42.6)at baseline to 8.9(23.7)at the study end;P=0.043].Adverse effects of SGLT-2i were as follows:genital thrush and urinary infection-20(8.8%)&17(7.5%)with dapagliflozin;9(5.6%)&5(3.13%)with canagliflozin;and 4(5%)&4(5%)with empagliflozin.Diabetic ketoacidosis was observed in 4(1.8%)with dapagliflozin and 1(0.63%)with canagliflozin.CONCLUSION Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c,body weight,and better than those reported in RCTs,with low side effect profiles.A review of large-scale real-world data is needed to inform better clinical practice decision making.

In Silico Screening of Potential Inhibitors against dPLA2 from Named Chinese Herbs for Identification of Compounds with Antivenom Effects Due to Deinagkistrodon acutus Snake Bites

Phospholipase A2 (PLA2) is the key enzyme to the venom from Deinagkistrodon acutus which is one of the highly venomous snakes in China. In addition to being a catalyst for the hydrolysis of phospholipases A2 from snake venom, its well known that it possesses a broad spectrum of pharmacological activities, such as myotoxicity, neurotoxicity, cardiotoxicity, and hemolytic, anticoagulant and antiplatelet activities. However, snakebites are not efficiently treated by conventional serum therapy. Acute wounds can still cause poisoning and death. In order to find effective inhibitors of Deinagkistrodon venom acid phospholipase A2 (dPLA2), we obtained 385 compounds in 9 Chinese herbs from the TCMSP. These compounds were further performed to virtual screen using in silico tools like ADMET analysis, molecular docking and molecular dynamics (MD) simulation. After Pharmacokinetics analysis, we found 7 candidate compounds. Besides, analysis of small molecule interactions with dPLA2 confirmed that the amino acid residues HIS47 and GLY29 are key targets. Because they bind not only to the natural substrate phosphatidylcholine and compounds known for having inhibitory functions, but also for combining with potential antidote molecules in Chinese herbal medicine. This study is the first to report experience with virtual screening for possible inhibitor of dPLA2, such as the interaction spatial structure, binding energy and binding interaction analysis, these experiences not only provide reference for further experimental research, but also have a guideline for the study of drug molecular mechanism of action.

Performance and Application of Double-layered Microcapsule Corrosion Inhibitors

Double-layered microcapsule corrosion inhibitors were developed by sodium monofluorophosphate as the core material,polymethyl methacrylate as the inner wall material,and polyvinyl alcohol as the outer wall material combining the solvent evaporation method and spray drying method.The protection by the outer capsule wall was used to prolong the service life of the corrosion inhibitor.The dispersion,encapsulation,thermal stability of microcapsules,and the degradation rate of capsule wall in concrete pore solution were analyzed by ultra-deep field microscopy,scanning electron microscopy,thermal analyzer,and sodium ion release rate analysis.The microcapsules were incorporated into mortar samples containing steel reinforcement,and the effects of double-layered microcapsule corrosion inhibitors on the performance of the cement matrix and the actual corrosion-inhibiting effect were analyzed.The experimental results show that the double-layered microcapsules have a moderate particle size and uniform distribution,and the capsules were completely wrapped.The microcapsules as a whole have good thermal stability below 230 ℃.The monolayer membrane structure microcapsules completely broke within 1 day in the simulated concrete pore solution,and the double-layer membrane structure prolonged the service life of the microcapsules to 80 days in the simulated concrete pore solution before the core material was completely released.The mortar samples containing steel reinforcement incorporated with the double-layered microcapsule corrosion inhibitors still maintained a higher corrosion potential than the monolayer microcapsule corrosion inhibitors control group at 60 days.The incorporation of double-layered microcapsules into the cement matrix has no significant adverse effect on the setting time and early strength.

Sodium-Glucose Cotransporter-2 Inhibitors: Who, When & How? Guidance for Use from a Multidisciplinary Practical Approach

Sodium-glucose cotransporter-2 inhibitors (SGLT-2 inhibitors) have transformed diabetes management by targeting renal glucose reabsorption. Designed initially as antidiabetic agents, their ability to lower blood glucose levels independently of insulin is well-documented. Beyond glycemic control, emerging research has unveiled their profound cardiorenal benefits. By inhibiting SGLT-2 protein, these drugs enhance glucose excretion in urine, reducing blood glucose levels. This mechanism has translated into significant cardiovascular and renal protection, establishing SGLT-2 inhibitors as pivotal in managing not only diabetes but also cardiovascular and renal diseases. Recent studies have illuminated the broader therapeutic potential of SGLT-2 inhibitors beyond diabetes. Evidence indicates their efficacy in managing heart failure, chronic kidney disease (CKD), and cardiovascular complications in individuals with or without diabetes. This expanded therapeutic landscape has catalyzed a paradigm shift in SGLT-2 inhibitor use, positioning them as key agents in the cardiorenal metabolic continuum. Moreover, their role in the secondary prevention of cardiovascular events and slowing CKD progression in T2DM patients has garnered considerable attention. This consensus-based review aims to offer practical guidance in an algorithmic approach to primary care healthcare professionals to optimize SGLT-2 inhibitors utilization and maximize their benefits. The review seeks to empower clinicians to effectively manage patients who may benefit from SGLT-2 inhibitor therapy by addressing common initiation barriers and optimizing treatment strategies. Additionally, it aims to raise awareness among primary care physicians regarding the multifaceted benefits of these medications and overcome clinical inertia in their adoption into routine clinical practice.

Evidence-based expert consensus on clinical management of safety of Bruton’s tyrosine kinase inhibitors(2024)

Bruton’s tyrosine kinase inhibitors(BTKis)have revolutionized the treatment of B-cell lymphomas.However,safety issues related to the use of BTKis may hinder treatment continuity and further affect clinical efficacy.A comprehensive and systematic expert consensus from a pharmacological perspective is lacking for safety issues associated with BTKi treatment.A multidisciplinary consensus working group was established,comprising 35 members from the fields of hematology,cardiovascular disease,cardio-oncology,clinical pharmacy,and evidencebased medicine.This evidence-based expert consensus was formulated using an evidence-based approach and the Delphi method.The Joanna Briggs Institute Critical Appraisal(JBI)tool and Grading of Recommendations Assessment,Development,and Evaluation(GRADE)approach were used to rate the quality of evidence and grade the strength of recommendations,respectively.This consensus provides practical recommendations for BTKis medication based on nine aspects within three domains,including the management of common adverse drug events such as bleeding,cardiovascular events,and hematological toxicity,as well as the management of drug-drug interactions and guidance for special populations.This multidisciplinary expert consensus could contribute to promoting a multi-dimensional,comprehensive and standardized management of BTKis.

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.

The synergistic regulatory effect of PTP1B and PTK inhibitors on the development of Oedaleus decorus asiaticus Bei-Bienko

Tyrosine phosphorylation is crucial for controlling normal cell growth,survival,intercellular communication,gene transcription,immune responses,and other processes.protein tyrosine phosphatase(PTP)and protein tyrosine kinases(PTK)can achieve this goal by regulating multiple signaling pathways.Oedaleus decorus asiaticus is an important pest that infests the Mongolian Plateau grassland.We aimed to evaluate the survival rate,growth rate,overall performance,and ovarian developmental morphology of the 4th instar nymphs of O.decorus asiaticus while inhibiting the activity of protein tyrosine phosphatase-1B(PTP1B)and PTK.In addition,the expression and protein phosphorylation levels of key genes in the MAPK signaling pathway and antioxidant enzyme activity were assessed.The results showed no significant differences in survival rate,growth rate,or overall performance between PTP1B inhibitor treatment and control.However,after PTK inhibitor treatment,these indexes were significantly lower than those in the control.The ovarian size of female larvae after 15 days of treatment with PTK inhibitors showed significantly slower development,while female larvae treated with PTP1B exhibited faster ovarian growth than the control group.In comparison to controls and nymphs treated with PTK inhibitors,the expression and phosphorylation levels of key genes in the MAPK signaling pathway under PTP1B inhibitor treatments were significantly higher in 4th instar nymphs.However,reactiveoxygen(ROS)species levels and the activities of NADPH oxidase and other antioxidant enzymes were considerably reduced,although they were significantly greater in the PTK inhibitor treatment.The results suggest that PTP1B and PTK feedback inhibition in the mitogen-activated-protein kinases(MAPK)signal transfer can regulate the physiological metabolism of the insect as well as its developmental rate.These findings can facilitate future uses of PTP1B and PTK inhibitors in controlling insect development to help control pest populations.

Erdafitinib and checkpoint inhibitors for first-line and second-line immunotherapy of hepatic,gastrointestinal,and urinary bladder carcinomas:Recent concept

Cancer immunotherapy is administered for first-line,second-line,neoadjuvant,or adjuvant treatment of advanced,metastatic,and recurrent cancer in the liver,gastrointestinal tract,and genitourinary tract,and other solid tumors.Erdafitinib is a fibroblast growth factor receptor(FGFR)inhibitor,and it is an adenosine triphosphate competitive inhibitor of FGFR1,FGFR2,FGFR3,and FGFR4.Immune checkpoint inhibitors are monoclonal antibodies that block programmed cell death protein 1(PD-1)and its ligand that exert intrinsic antitumor mechanisms.The promising results of first-line treatment of advanced and metastatic urothelial carcinoma with PD-1 blockades with single or combined agents,indicate a new concept in the treatment of advanced,metastatic,and recurrent hepatic and gastrointestinal carcinomas.Cancer immunotherapy as first-line treatment will improve overall survival and provide better quality of life.Debate is arising as to whether to apply the cancer immunotherapy as first-line treatment in invasive carcinomas,or as second-line treatment in recurrent or metastatic carcinoma following the standard chemotherapy.The literature in the field is not definite,and so far,there has been no consensus on the best approach in this situation.At present,as it is described in this editorial,the decision is applied on a case-by-case basis.

Advances in MET tyrosine kinase inhibitors in gastric cancer

Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally.Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics,the management of gastric cancer calls for better-defined,biomarker-guided,molecular-based treatment strategies.MET is a receptor tyrosine kinase mediating important physiologic processes,such as embryogenesis,tissue regeneration,and wound healing.However,mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types,including gastric cancer,and is associated with poor patient outcomes.As such,MET-targeting therapies are being actively developed and promising progress has been demonstrated,especially with MET tyrosine kinase inhibitors.This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib,tepotinib,capmatinib,and crizotinib.Building on current knowledge,this review further discusses existing challenges in MET alterations testing,possible resistance mechanisms to MET inhibitors,and future directions of MET-targeting therapies.

Development and Application of Procedures for the Management of Skin Toxicity Related to Immune Checkpoint Inhibitors in Patients with Lung Cancer

Objective: To establish the procedures for the management of skin toxicity related to immune checkpoint inhibitors in patients with lung cancer and explore the effect of application. Methods: A total of 24 evidence-based evidences were collected from 7 aspects, including risk factors, baseline screening, ICIs monitoring, daily skin care, multidisciplinary management, symptom management and health education. A total of 157 lung cancer patients and 94 nurses from 8 wards of the Oncology department of our hospital from November 2022 to May 2023 were selected by convenience sampling. A total of 77 patients and 46 nurses from ward 1 - 4 were divided into the baseline group. There were 80 patients and 48 nurses in Ward 5 - 8 as the evidence-based practice group. In the baseline group, patients were treated with routine methods such as assessing skin symptoms, taking medication according to symptoms, guiding to keep skin clean and moist, eating a light diet, and avoiding scratching. The evidence-based practice group adopts an evidence-based continuous improvement model for nursing. The differences in the severity of symptoms of skin toxicity in the second cycle of medication and the knowledge and practice of self-care of skin toxicity were compared between the two groups before and after the use of the syndrome, as well as the differences in the implementation rate of review indicators, evidence-based ability and knowledge and practice of skin toxicity care before and after the use of the syndrome. Results: The incidence and severity of cutaneous toxicity were significantly lower after treatment than before treatment (P P < 0.05). Conclusion: The implementation of immune checkpoint inhibitor-related skin toxicity management procedures can effectively reduce the incidence and severity of skin toxicity symptoms, optimize the clinical pathway, and improve the quality of care.

Overlapping approach Proton Pump Inhibitors/Nux vomica-Heel as new intervention for gastro-esophageal reflux management:Delphi consensus study

BACKGROUND Gastro-esophageal reflux disease(GERD)may affect the upper digestive tract;up to 20%of population in Western nations are affected by GERD.Antacids,histamine H2-receptor antagonists,and Proton Pump Inhibitors(PPIs)are considered the referring medications for GERD.Nevertheless,PPIs must be managed carefully because their use,especially chronic,could be linked with some adverse effects.An effective and safe alternative pharmacological tool for GERD is needed.After the identification of potentially new medications to flank PPIs,it is mandatory to revise and improve good clinical practices even through a consensus process.AIM To optimize diagnosis and treatment guidelines for GERD through a consensus based on Delphi method.METHODS The availability of clinical studies describing the action of the multicomponent/multitarget medication Nux vomica-Heel,subject of the consensus,is the basic prerequisite for the consensus itself.A modified Delphi process was used to reach a consensus among a panel of Italian GERD specialists on the overlapping approach PPIs/Nux vomica-Heel as a new intervention model for the management of GERD.The Voting Consensus group was composed of 49 Italian Medical Doctors with different specializations:Gastroenterology,otolaryngology,geriatrics,and general medicine.A scientific committee analyzed the literature,determined areas that required investigation(in agreement with the multiple-choice questionnaire results),and identified two topics of interest:(1)GERD disease;and(2)GERD treatment.Statements for each of these topics were then formulated and validated.The Delphi process involved two rounds of questioning submitted to the panel experts using an online platform.RESULTS According to their routinary GERD practice and current clinical evidence,the panel members provided feedback to each questionnaire statement.The experts evaluated 15 statements and reached consensus on all 15.The statements regarding the GERD disease showed high levels of agreement,with consensus ranging from 70%to 92%.The statements regarding the GERD treatment also showed very high levels of agreement,with consensus ranging from 90%to 100%.This Delphi process was able to reach consensus among physicians in relevant aspects of GERD management,such as the adoption of a new approach to treat patients with GERD based on the overlapping between PPIs and Nux vomica-Heel.The consensus was unanimous among the physicians with different specializations,underlying the uniqueness of the agreement reached to identify in the overlapping approach between PPIs and Nux vomica-Heel a new intervention model for GERD management.The results support that an effective approach to deprescribe PPIs through a progressive decalage timetable(reducing PPIs administration to as-needed use),should be considered.CONCLUSION Nux vomica-Heel appears to be a valid opportunity for GERD treatment to favor the deprescription of PPIs and to maintain low disease activity together with the symptomatology remission.

Application of immune checkpoint inhibitors and microsatellite instability in gastric cancer

In this editorial we comment on the article by Li published in the recent issue of the World Journal of Gastroenterology.We focus specifically on the application of immune checkpoint inhibitors(ICIs)and microsatellite instability(MSI)in gastric cancer(GC).The four pillars of GC management have long been considered,including surgery,chemotherapy,radiotherapy and targeted therapy.However,immunotherapy has recently emerged as a“fifth pillar”,and its use is rapidly expanding.There are four principal strategies for tumor immunotherapy:ICIs,tumor vaccines,adoptive immunotherapy and nonspecific immunomodulators.Of them,ICIs are the most advanced and widespread type of cancer immunotherapy for GC.Recent breakthrough results for ICIs have paved the way to a new era of cancer immunotherapy.In particular,inhibition of the PD-1/PD-L1 axis with ICIs,including nivolumab and pembrolizumab,has emerged as a novel treatment strategy for advanced GC.Unfortunately,these therapies are sometimes associated with often subtle,potentially fatal immune-related adverse events(irAEs),including dermatitis,diarrhea,colitis,endocrinopathy,hepatotoxicity,neuropathy and pneumonitis.We must be aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges,emergency department revisits,and downstream complications.Recent studies have revealed that MSI-high or mismatch-repair-deficient tumors,regardless of their primary site,have a promising response to ICIs.So,it is important to detect MSI before applying ICIs for treatment of GC.

Efficacy comparison of fruquintinib,regorafenib monotherapy or plus programmed death-1 inhibitors for microsatellite stable metastatic colorectal cancer

BACKGROUND Regorafenib(R)and fruquintinib(F)are the standard third-line regimens for colorectal cancer(CRC)according to the National Comprehensive Cancer Network guidelines,but both have limited efficacy.Several phase 2 trials have indicated that R or F combined with immune checkpoint inhibitors can reverse immunosuppression and achieve promising efficacy for microsatellite stable or proficient mismatch repair(MSS/pMMR)CRC.Due to the lack of studies comparing the efficacy between F,R,F plus programmed death-1(PD-1)inhibitor,and R plus PD-1 inhibitors(RP),it is still unclear whether the combination therapy is more effective than monotherapy.AIM To provide critical evidence for selecting the appropriate drugs for MSS/pMMR metastatic CRC(mCRC)patients in clinical practice.METHODS A total of 2639 CRC patients were enrolled from January 2018 to September 2022 in our hospital,and 313 MSS/pMMR mCRC patients were finally included.RESULTS A total of 313 eligible patients were divided into F(n=70),R(n=67),F plus PD-1 inhibitor(FP)(n=95)and RP(n=81)groups.The key clinical characteristics were well balanced among the groups.The median progression-free survival(PFS)of the F,R,FP,and RP groups was 3.5 months,3.6 months,4.9 months,and 3.0 months,respectively.The median overall survival(OS)was 14.6 months,15.7 months,16.7 months,and 14.1 months.The FP regimen had an improved disease control rate(DCR)(P=0.044)and 6-month PFS(P=0.014)and exhibited a better trend in PFS(P=0.057)compared with F,and it was also significantly better in PFS than RP(P=0.030).RP did not confer a significant survival benefit;instead,the R group had a trend toward greater benefit with OS(P=0.080)compared with RP.No significant differences were observed between the R and F groups in PFS or OS(P>0.05).CONCLUSION FP is superior to F in achieving 6-month PFS and DCR,while RP is not better than R.FP has an improved PFS and 6-month PFS compared with RP,but F and R had similar clinical efficacy.Therefore,FP may be a highly promising strategy in the treatment of MSS/pMMR mCRC.

DNA damage response-related immune activation signature predicts the response to immune checkpoint inhibitors: from gastrointestinal cancer analysis to pan-cancer validation

Objective: DNA damage response(DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation(DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor(ICI) therapy in gastrointestinal(GI) cancer.Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts.Results: The DRIA signature includes three genes(CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients(81.8% vs. 8.8%;P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve(AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer.Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pancancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.

Renin-angiotensin system inhibitors prescriptions in Chinese hospitalized chronic kidney disease patients

BACKGROUND Many guidelines have recommended renin-angiotensin system inhibitors(RASI)as the first-line treatment for patients with chronic kidney disease(CKD).We studied RASI prescription trends from 2010 to 2019,and analyzed the characteristics associated with RASI prescription in Chinese hospitalized CKD patients.AIM To study the prescription of renin angiotensin system inhibitors in hospitalized patients with CKD in China.METHODS It was retrospectively,cross-sectional reviewed RASI prescriptions in hospitalized CKD patients in China from 2010 to 2019.RASI prescribing trends were analyzed from 2010 to 2019,and bivariate and multivariate logistic regression analyses were conducted to identify characteristics associated with RASI prescription.RESULTS A total of 35090 CKD patients were included,with 10043(28.6%)RASI prescriptions.Among these patients,18919(53.9%)met the criteria for RASI treatments based on the 2012 kidney disease:Improving global outcomes guidelines.Of these,7246(38.3%)patients received RASI prescriptions.RASI prescriptions showed an initial rapid increase from 2011 to 2012,reached its peak around 2015 and 2016,and then exhibited a subsequent slight decreasing trend.Both bivariate and multivariate analyses showed that several characteristics,including the male gender,age less than 60-year-old,nephrology department admission,lower CKD stage,history of hypertension or diabetes,proteinuria,glomerulonephritis as the CKD etiology,and non-acute kidney injury were associated with RASI prescriptions.CONCLUSION The frequency of RASI prescriptions showed an initial increase but a slight decreasing trend in more recent years.CKD patients with certain characteristics such as elderly age,advanced disease stage,surgery department admission,or acute kidney injury were less likely to receive RASI prescriptions.In the application of RASI in hospitalized CKD patients is insufficient.The actual clinical practice needs to be improved.The development of related research is helpful to guide the correct choice of clinical treatment strategy.