Application of neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy in curative surgery for esophageal cancer:A metaanalysis

BACKGROUND The effectiveness of neoadjuvant therapy in esophageal cancer(EC)treatment is still a subject of debate.AIM To compare the clinical efficacy and toxic side effects between neoadjuvant chemoradiotherapy(nCRT)and neoadjuvant chemotherapy(nCT)for locally advanced EC(LAEC).METHODS A comprehensive search was conducted using multiple databases,including PubMed,EMBASE,MEDLINE,Science Direct,The Cochrane Library,China National Knowledge Infrastructure,Wanfang Database,Chinese Science and Technology Journal Database,and Chinese Biomedical Literature Database Article.Studies up to December 2022 comparing nCRT and nCT in patients with EC were selected.RESULTS The analysis revealed significant differences between nCRT and nCT in terms of disease-free survival.The results indicated that nCRT provided better outcomes in terms of the 3-year overall survival rate(OSR)[odds ratio(OR)=0.95],complete response rate(OR=3.15),and R0 clearance rate(CR)(OR=2.25).However,nCT demonstrated a better 5-year OSR(OR=1.02)than nCRT.Moreover,when compared to nCRT,nCT showed reduced risks of cardiac complications(OR=1.15)and pulmonary complications(OR=1.30).CONCLUSION Overall,both nCRT and nCT were effective in terms of survival outcomes for LAEC.However,nCT exhibited better performance in terms of postoperative complications.

Microbiome changes in esophageal cancer:implications for pathogenesis and prognosis

Esophageal cancer(EC)is an aggressive malignancy with a poor prognosis.Various factors,including dietary habits,and antacid and antibiotic use,have been shown to influence the esophageal microbiome.Conversely,enrichment and diversity of the esophageal microbiome can also impact its function.Recent studies have revealed prevalent changes in the esophageal microbiome among patients with EC,thus suggesting the potential contribution of the esophageal microbiome to EC development.Additionally,distinct microbiome compositions have been observed in patients with different responses to radiotherapy and chemotherapy,indicating the role of the esophageal microbiome in modulating treatment outcomes.In this review,we have examined previous studies on the esophageal microbiome in healthy individuals and patients with EC or other esophageal diseases,with a focus on identifying microbial communities associated with EC pathogenesis and prognosis.Understanding the role of the microbiome in EC may aid in early detection and optimized treatment strategies,ultimately leading to better outcomes for patients.

Lipid metabolism analysis in esophageal cancer and associated drug discovery

Esophageal cancer is an upper gastrointestinal malignancy with a bleak prognosis.It is still being explored in depth due to its complex molecular mechanisms of occurrence and development.Lipids play a crucial role in cells by participating in energy supply,biofilm formation,and signal transduction processes,and lipid metabolic reprogramming also constitutes a significant characteristic of malignant tumors.More and more studies have found esophageal cancer has obvious lipid metabolism abnormalities throughout its beginning,progress,and treatment resistance.The inhibition of tumor growth and the enhancement of antitumor therapy efficacy can be achieved through the regulation of lipid metabolism.Therefore,we reviewed and analyzed the research results and latest findings for lipid metabolism and associated analysis techniques in esophageal cancer,and comprehensively proved the value of lipid metabolic reprogramming in the evolution and treatment resistance of esophageal cancer,as well as its significance in exploring potential therapeutic targets and biomarkers.

Plant-based dietary patterns and risk of esophageal cancer:A prospective cohort study spanning 17 years

Objective: Plant-based diets have multiple health benefits for cancers;however, little is known about the association between plant-based dietary patterns and esophageal cancer(EC).This study presents an investigation of the prospective associations among three predefined indices of plant-based dietary patterns and the risk of EC.Methods: We performed endoscopic screening for 15,709 participants aged 40-69 years from two high-risk areas of China from January 2005 to December 2009 and followed the cohort until December 31, 2022. The overall plant-based diet index(PDI), healthful plant-based diet index(h PDI), and unhealthful plant-based diet index(u PDI), were calculated using survey responses to assess dietary patterns. We applied Cox proportional hazard regression to estimate the multivariable hazard ratios(HRs) and 95% confidence intervals(95% CIs) of EC across 3plant-based diet indices and further stratified the analysis by subgroups.Results: The final study sample included 15,184 participants in the cohort. During a follow-up of 219,365person-years, 176 patients with EC were identified. When the highest quartile was compared with the lowest quartile, the pooled multivariable-adjusted HR of EC was 0.50(95% CI, 0.32-0.77) for h PDI. In addition, the HR per 10-point increase in the h PDI score was 0.42(95% CI, 0.27-0.66) for ECs. Conversely, u PDI was positively associated with the risk of EC, and the HR was 1.80(95% CI, 1.16-2.82). The HR per 10-point increase in the u PDI score was 1.90(95% CI, 1.26-2.88) for ECs. The associations between these scores and the risk of EC were consistent in most subgroups. These results remained robust in sensitivity analyses.Conclusions: A healthy plant-based dietary pattern was associated with a reduced risk of EC. Emphasizing the healthiness and quality of plant-based diets may be important for preventing the development of EC.

Mechanisms of tumor immunosuppressive microenvironment formation in esophageal cancer

As a highly invasive malignancy,esophageal cancer(EC)is a global health issue,and was the eighth most prevalent cancer and the sixth leading cause of cancerrelated death worldwide in 2020.Due to its highly immunogenic nature,emerging immunotherapy approaches,such as immune checkpoint blockade,have demonstrated promising efficacy in treating EC;however,certain limitations and challenges still exist.In addition,tumors may exhibit primary or acquired resistance to immunotherapy in the tumor immune microenvironment(TIME);thus,understanding the TIME is urgent and crucial,especially given the importance of an immunosuppressive microenvironment in tumor progression.The aim of this review was to better elucidate the mechanisms of the suppressive TIME,including cell infiltration,immune cell subsets,cytokines and signaling pathways in the tumor microenvironment of EC patients,as well as the downregulated expression of major histocompatibility complex molecules in tumor cells,to obtain a better understanding of the differences in EC patient responses to immunotherapeutic strategies and accurately predict the efficacy of immunotherapies.Therefore,personalized treatments could be developed to maximize the advantages of immunotherapy.

Immunotherapy for esophageal cancer:Where are we now and where can we go

Immune checkpoint inhibitor therapy has dramatically improved patient prognosis,and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma(ESCC)in the past decade.Monoclonal antibodies that selectively inhibit programmed cell death-1(PD-1)activity has now become standard of care in the treatment of ESCC in metastatic settings,and has a high expectation to provide clinical benefit during perioperative period.Further,anti-cytotoxic T-lymphocyte–associated protein 4(CTLA-4)monoclonal antibody has also been approved in the treatment of recurrent/metastatic ESCC in combination with anti-PD-1 antibody.Well understanding of the existing evidence of immune-based treatments for ESCC,as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant,adjuvant,and metastatic diseases,may provide future prospects of ESCC treatment for better patient outcomes.

Circ_0003855 involvement of esophageal cancer progression through miR-622/FLOT1

To confirm the relationship between Circ_0003855 and EC,we purchased the Human esophageal carcinoma cell line Eca109 and normal human esophageal epithelial cells HEEC,and the expression levels of Circ_0003855,miR-622,and FLOT1 were detected.The results show that Circ_0003855 and FLOT1 were highly expressed in Eca109 cells,while miR-622 was lowly expressed(p<0.05).Subsequently,Circ_0003855 small interfering RNA(si-Circ_0003855)and its negative control(si-NC)were used to detect changes in cellular biological behaviors.We found that the activity of Eca109 cells was reduced after interfering with the expression of Circ_0003855,and miR-622 expression was elevated,while FLOT1 was decreased(p<0.05).Additionally,si-Circ_0003855 and miR-622 inhibitor sequence(miR-622-inhibition)were co-transfected into cells with miR-622-inhibition alone,and untreated Eca109 cells were used as a control to detect the expression of FLOT1.Co-transfection of si-Circ_0003855 and miR-622-inhibition showed no significant difference in FLOT1 expression compared to the control cells(p>0.05).Synthesizing the results of these experiments above,we believe that interfering with the expression of Circ_0003855 can inhibit the activity of EC cells,and its mechanism is related to miR-622 and FLOT1.

Esophageal cancer screening,early detection and treatment:Current insights and future directions

Esophageal cancer ranks among the most prevalent malignant tumors globally,primarily due to its highly aggressive nature and poor survival rates.According to the 2020 global cancer statistics,there were approximately 604000 new cases of esophageal cancer,resulting in 544000 deaths.The 5-year survival rate hovers around a mere 15%-25%.Notably,distinct variations exist in the risk factors associated with the two primary histological types,influencing their worldwide incidence and distribution.Squamous cell carcinoma displays a high incidence in specific regions,such as certain areas in China,where it meets the cost-effect-iveness criteria for widespread endoscopy-based early diagnosis within the local population.Conversely,adenocarcinoma(EAC)represents the most common histological subtype of esophageal cancer in Europe and the United States.The role of early diagnosis in cases of EAC originating from Barrett's esophagus(BE)remains a subject of controversy.The effectiveness of early detection for EAC,particularly those arising from BE,continues to be a debated topic.The variations in how early-stage esophageal carcinoma is treated in different regions are largely due to the differing rates of early-stage cancer diagnoses.In areas with higher incidences,such as China and Japan,early diagnosis is more common,which has led to the advancement of endoscopic methods as definitive treatments.These techniques have demonstrated remarkable efficacy with minimal complications while preserving esophageal functionality.Early screening,prompt diagnosis,and timely treatment are key strategies that can significantly lower both the occurrence and death rates associated with esophageal cancer.

The clinical application and advancement of robot-assisted McKeown minimally invasive esophagectomy for esophageal cancer

Robotic surgery systems,as emerging minimally invasive approaches,have been increasingly applied for the treatment of esophageal cancer because they provide a high-definition three-dimensional surgical view and mechanical rotating arms that surpass the limitations of human hands,greatly enhancing the accuracy and flexibility of surgical methods.Robot-assisted McKeown esophagectomy(RAME),a common type of robotic esophagectomy,has been gradually implemented with the aim of reducing postoperative complications,improving postoperative recovery and achieving better long-term survival.Multiple centers worldwide have reported and summarized their experiences with the RAME,and some have also discussed and analyzed its perioperative effects and survival prognosis compared with those of video-assisted minimally invasive esophagectomy.Compared to traditional surgery,the RAME has significant advantages in terms of lymph node dissection although there seems to be no difference in overall survival or disease-free survival.With the continuous advancement of technology and the development of robotic technology,further development and innovation are expected in the RAME field.This review elaborates on the prospects of the application and advancement of the RAME to provide a useful reference for clinical practice.

Targeting oxidative stress with natural products: A novel strategy for esophageal cancer therapy

Esophageal cancer(ESC)is a malignant tumor that originates from the mucosal epithelium of the esophagus and is part of the digestive tract.Although the exact pathogenesis of ESC has not been fully elucidated,excessive oxidative stress is an important characteristic that leads to the development of many cancers.Abnormal expression of several proteins and transcription factors contributes to oxidative stress in ESCs,which alters the growth and proliferation of ESCs and promotes their metastasis.Natural compounds,including alkaloids,terpenes,polyphenols,and xanthine compounds,can inhibit reactive oxygen species production in ESCs.These compounds reduce oxidative stress levels and subsequently inhibit the oc-currence and progression of ESC through the regulation of targets and pathways such as the cytokine interleukins 6 and 10,superoxide dismutase,the NF-+ACY-kappa+ADs-B/MAPK pathway,and the mammalian Nrf2/ARE target pathway.Thus,targeting tumor oxidative stress has become a key focus in anti-ESC therapy.This review discusses the potential of Natural products(NPs)for treating ESCs and summarizes the application prospects of oxidative stress as a new target for ESC treatment.The findings of this review provide a reference for drug development targeting ESCs.Nonetheless,further high-quality studies will be necessary to determine the clinical efficacy of these various NPs.

Therapeutic effect of Wendan Decoction combined with mosapride on gastroesophageal reflux disease after esophageal cancer surgery

BACKGROUND Gastroesophageal reflux disease(GERD)is a common complication of esophageal cancer surgery that can affect quality of life and increase the risk of esophageal stricture and anastomotic leakage.Wendan Decoction(WDD)is a traditional Chinese herbal formula used to treat various gastrointestinal disorders,such as gastritis,functional dyspepsia,and irritable bowel syndrome.Mosapride,a prokinetic agent,functions as a selective 5-hydroxytryptamine 4 agonist,enhancing gastrointestinal motility.AIM To evaluate the therapeutic effects of WDD combined with mosapride on GERD after esophageal cancer surgery.METHODS Eighty patients with GERD were randomly divided into treatment(receiving WDD combined with mosapride)and control(receiving mosapride alone)groups.The treatment was conducted from January 2021 to January 2023.The primary outcome was improved GERD symptoms as measured using the reflux disease questionnaire(RDQ).The secondary outcomes were improved esophageal motility(measured using esophageal manometry),gastric emptying(measured using gastric scintigraphy),and quality of life[measured via the Short Form-36(SF-36)Health Survey].RESULTS The treatment group showed a notably reduced RDQ score and improved esophageal motility parameters,such as lower esophageal sphincter pressure,peristaltic amplitude,and peristaltic velocity compared to the control group.The treatment group showed significantly higher gastric emptying rates and SF-36 scores(in both physical and mental domains)compared to the control group.No serious adverse effects were observed in either group.CONCLUSION WDD combined with mosapride is an effective and safe therapy for GERD after esophageal cancer surgery.It can improve GERD symptoms,esophageal motility,gastric emptying,and the quality of life of patients.Further studies with larger sample sizes and longer follow-up periods are required to confirm these findings.

Management of early oesophageal cancer:An overview

The incidence of esophageal cancer,namely the adenocarcinoma subtype,continues to increase exponentially on an annual basis.The indolent nature of the disease renders a significant proportion inoperable at first presentation,however,with the increased utilisation of endoscopy,many early lesions are now being identified which are suitable for endotherapeutic approaches.This article details the options available for dealing with early esophageal cancer by endoscopic mean obviating the need for surgery thereby avoiding the potential morbidity and mortality of such intervention.

Pivotal role of exosomes in diagnosis and treatment of esophageal cancer in a new era of precision medicine

In this editorial we comment on the article published by Ning et al,“Role of exosomes in metastasis and therapeutic resistance in esophageal cancer”.Esophageal cancer(EC)represents a significant global health concern,being the seventh most common and sixth in terms of mortality worldwide.Despite the advances in therapeutic modalities,the management of patients with EC remains challenging,with a 5-year survival rate of only 25%and a limited eligibility for curative surgery due to its late diagnosis.Conventional screening methods are impractical for the early detection of EC,given their either invasive or insensitive nature.The advent of liquid biopsy,with a focus on circulating tumor cells,circulating tumor DNA,and exosomes,heralds a non-invasive avenue for cancer detection.Exosomes,small vesicles involved in intercellular communication,are highlighted as potential biomarkers for EC diagnosis and prognosis.Along with a diverse cargo encompassing various types of RNA,DNA molecules,proteins,and metabolites,exosomes emerge as key players in tumorigenesis,tumor development,and metastasis.Their significance extends to carrying distinctive biomarkers,including microRNAs(miRNAs),long non-coding RNAs,and circular RNAs,underscoring their potential diagnostic and prognostic value.Furthermore,exosomes may be utilized for therapeutic purposes in the context of EC treatment,serving as efficient delivery vehicles for therapeutic agents such as chemotherapeutic medicines and miRNAs.In this editorial we delve into the applications of exosomes for the early detection and treatment of EC,as well as the future perspectives.

Impact of the Rapid Recovery Concept on Complications and Patient Quality of Life in the Perioperative Nursing of Robot-Assisted Radical Oesophageal Cancer

Aim: This study evaluates the impact of Enhanced Recovery After Surgery (ERAS) nursing on postoperative complications and quality of life in patients undergoing robot-assisted minimally invasive esophagectomy (RAMIE). Methods: A total of 150 patients who underwent RAMIE from January 2020 to January 2022 at our hospital were randomly assigned to either the observation group or the control group, with 75 patients in each. The control group received standard perioperative management and nursing care, while the observation group was treated with ERAS nursing strategies. Interventions continued until discharge, and outcomes such as postoperative complications, quality of life, and nutritional status were compared between the groups. Results: The observation group exhibited a significantly lower incidence of postoperative adverse reactions compared to the control group (P ionally, all dimension scores of the Short-Form 36 Health Survey (SF-36), including the total score, were higher in the observation group (P < 0.05). Furthermore, the Nutritional Risk Screening (NRS) scores for impaired nutritional status and disease severity, along with the total NRS score, were significantly lower in the observation group compared to the control group (P Conclusion: Implementing ERAS nursing in the perioperative care of patients undergoing RAMIE is associated with reduced postoperative complications and enhanced postoperative quality of life and nutritional status. .

Challenge and future of cancer screening in China: Insights from esophageal cancer screening practice

Cancer stands as a prominent public health concern in China, with elusive intervention targets due to unidentified high-risk causal factors for most cancers. Consequently, emphasis has shifted towards screening, diagnosing, and treating early cancer cases within the general population. However, China faces considerable obstacles in its cancer prevention and control efforts, attributing to the complexity and heterogeneity of the occurrence, progression, and prognosis of malignant tumors across populations, time, and regions. Taking esophageal cancer screening practices as an example, this review outlines the importance and assessment of cancer screening, delineating major challenges in China's cancer prevention and control: 1) limited comprehension of cancer's natural history;2) lack of “China Evidence” supporting screening effectiveness and value;3) compromised efficiency and accuracy in current screening modality;and 4) insufficient sustainability of the current screening practices and translation of relevant scientific research achievements. To address these challenges, we propose potential coping strategies: 1)establishing tailored technologies and pathways for cancer prevention and control based on population-based and clinical epidemiological studies using high-quality designs;2) breaking conventional constraints to establish a novel cancer screening strategy aligned with real-world needs;and 3) establishing enhanced communication platforms among scientific research teams, policymakers, and industrial institutions to foster collaboration and innovation.

Progress of magnetic resonance imaging radiomics in preoperative lymph node diagnosis of esophageal cancer

Esophageal cancer,also referred to as esophagus cancer,is a prevalent disease in the cardiothoracic field and is a leading cause of cancer-related mortality in China.Accurately determining the status of lymph nodes is crucial for developing treatment plans,defining the scope of intraoperative lymph node dissection,and ascertaining the prognosis of patients with esophageal cancer.Recent advances in diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging(MRI)have improved the effectiveness of MRI for assessing lymph node involvement,making it a beneficial tool for guiding personalized treatment plans for patients with esophageal cancer in a clinical setting.Radiomics is a recently developed imaging technique that transforms radiological image data from regions of interest into high-dimensional feature data that can be analyzed.The features,such as shape,texture,and waveform,are associated with the cancer phenotype and tumor microenvironment.When these features correlate with the clinical disease outcomes,they form the basis for specific and reliable clinical evidence.This study aimed to review the potential clinical applications of MRIbased radiomics in studying the lymph nodes affected by esophageal cancer.The combination of MRI and radiomics is a powerful tool for diagnosing and treating esophageal cancer,enabling a more personalized and effectual approach.

Analysis of Significant Genes and Pathways in Esophageal Cancer Based on Gene Expression Omnibus Database

Objective To screen antigen targets for immunotherapy by analyzing over-expressed genes,and to identify significant pathways and molecular mechanisms in esophageal cancer by using bioinformatic methods such as enrichment analysis,protein-protein interaction(PPI)network,and survival analysis based on the Gene Expression Omnibus(GEO)database.Methods By screening with highly expressed genes,we mainly analyzed proteins MUC13 and EPCAM with transmembrane domain and antigen epitope from TMHMM and IEDB websites.Significant genes and pathways associated with the pathogenesis of esophageal cancer were identified using enrichment analysis,PPI network,and survival analysis.Several software and platforms including Prism 8,R language,Cytoscape,DAVID,STRING,and GEPIA platform were used in the search and/or figure creation.Results Genes MUC13 and EPCAM were over-expressed with several antigen epitopes in esophageal squamous cell carcinoma(ESCC)tissue.Enrichment analysis revealed that the process of keratinization was focused and a series of genes were related with the development of esophageal cancer.Four genes including ALDH3A1,C2,SLC6A1,and ZBTB7C were screened with significant P value of survival curve.Conclusions Genes MUC13 and EPCAM may be promising antigen targets or biomarkers for esophageal cancer.Keratinization may greatly impact the pathogenesis of esophageal cancer.Genes ALDH3A1,C2,SLC6A1,and ZBTB7C may play important roles in the development of esophageal cancer.

Long-term efficacy and predictors of pembrolizumab-based regimens in patients with advanced esophageal cancer in the real world

BACKGROUND Pembrolizumab combined with chemotherapy has been proven effective as firstline therapy in patients with advanced esophageal cancer.Few trials have assessed the safety and efficacy of this treatment in patients with locally advanced disease.AIM To analyze long-term outcomes of pembrolizumab in locally advanced or metastatic esophageal squamous cell carcinoma(ESCC)in the real world.METHODS Patients with advanced ESCC admitted to our center from October 2019 to October 2021 were enrolled in this study.Clinical staging of the patients was based on the 8th edition of the American Joint Committee on Cancer TNM staging system.The patients received different treatments based on clinical stage.In brief,patients with locally advanced and resectable ESCC received neoadjuvant therapy combined with surgery.For those who were not candidates for resection,radical concurrent chemoradiotherapy plus pembrolizumab was more preferable.Patients with metastatic ESCC or who were unsuitable for radiotherapy underwent chemotherapy in combination with pembrolizumab.Long-term survival outcomes such as overall survival(OS),progression-free survival,disease-free survival,long-term adverse effects(AEs),immune maintenance therapy and predictors of immune checkpoint inhibitors(ICIs)efficacy were evaluated.RESULTS A total of 55 patients with advanced ESCC were enrolled in this retrospective,observational study.The median age was 61 years(range 44-74),with 47.3%(26/55)of the patients in stage IV and 45.5%of the patients had the tumor(25/55)located in the middle third of the esophagus.The median OS in all patients was not reached.The 12-mo OS rate among all patients was 78.8%and the 18-mo OS rate was 72.7%.9 patients died due to tumor progression and 7 patients died due to treatment-related complications.The therapeutic effect evaluated at the interim evaluation was significantly reflected in the long-term outcome.Patients with complete response or partial response in all patients(P=0.005)and in the chemoradiotherapy plus pembrolizumab group(P=0.007)obtained a better prognosis than non-responders.A total of 20 patients(20/55,36%)received immune maintenance therapy.Baseline peripheral blood biomarkers of the neutrophil-to-lymphocyte ratio,platelet-to-lymphocyte ratio,and neutrophil-to-(leukocyte-neutrophil)ratio did not predict the efficacy of ICIs.CONCLUSION Pembrolizumab combined with chemotherapy or radiotherapy resulted in favorable long-term survival in patients with locally advanced or metastatic ESCC,with safe and manageable long-term AEs.

Role of exosomes in metastasis and therapeutic resistance in esophageal cancer

Esophageal cancer(EC)has a high incidence and mortality rate and is emerging as one of the most common health problems globally.Owing to the lack of sensitive detection methods,uncontrollable rapid metastasis,and pervasive treatment resistance,EC is often diagnosed in advanced stages and is susceptible to local recurrence.Exosomes are important components of intercellular communication and the exosome-mediated crosstalk between the cancer and surrounding cells within the tumor microenvironment plays a crucial role in the metastasis,progression,and therapeutic resistance of EC.Considering the critical role of exosomes in tumor pathogenesis,this review focused on elucidating the impact of exosomes on EC metastasis and therapeutic resistance.Here,we summarized the relevant signaling pathways involved in these processes.In addition,we discussed the potential clinical applications of exosomes for the early diagnosis,prognosis,and treatment of EC.

Update of latest data for combined therapy for esophageal cancer using radiotherapy and immunotherapy:A focus on efficacy,safety,and biomarkers

Esophageal cancer usually has a poor prognosis.Given the significant breakthrough with tumor immunotherapy,an increasing number of clinical studies have demonstrated that the combination of radiotherapy and immune checkpoint inhibitors(ICIs)may have a synergistic effect and good outcome in esophageal cancer.Clinical studies of immunoradiotherapy(iRT)for esophageal cancer have proliferated enormously from 2021 to the present.However,a summary of the efficacy and toxicity of combined therapy to guide esophageal cancer treatment in clinical practice is lacking.For this review,we integrate the latest data to analyze and assess the efficacy and safety of iRT for esophageal cancer.In addition,we discuss better predictive biomarkers,therapeutic options for specific populations,and other challenges to identify directions for future research design.