Survival outcomes in early-onset oesophageal adenocarcinoma patients:A systematic review and meta-analyses

BACKGROUND The incidence of oesophageal adenocarcinoma(OAC)has been reported to be increasing in many countries.Alongside this trend,an increase in incidence of early-onset OAC,defined as OAC in adults aged under 50 years,has been observed.It is unclear whether survival outcomes for early-onset OAC patients differ from older age groups.AIM To investigate survival outcomes in early-onset OAC patients.METHODS Ovid Medline and Embase were searched from inception to January 2022 for relevant studies relating to early-onset OAC and survival outcomes.Results regarding the overall five-year survival and risk of death of younger and older patients with OAC were extracted and pooled using meta-analyses to produce pooled estimates and 95%CIs where possible.RESULTS Eleven studies which compared survival of early-onset OAC,defined as age at diagnosis of<50 years,with older patients were included.A narrative review of median and mean survival demonstrated conflicting results,with studies showing early-onset OAC patients having both better and worse outcomes compared to older age groups.A meta-analysis of five-year survival demonstrated similar outcomes across age groups,with 22%-25%of patients in the young,middle and older age groups alive after five years.A meta-analysis of four studies demon-strated that early-onset OAC patients did not have a significantly increased risk of death compared to middle-aged patients(hazard ratio 1.12,95%CI:0.85-1.47).INTRODUCTION There is concern that the incidence of oesophageal adenocarcinoma(OAC)in patients under 50,described as early-onset OAC,is increasing.However,data regarding survival of younger patients with OAC is sparse.Globally,while increasing age remains a major non-modifiable risk factor for cancer,the incidence of early-onset cancers,largely accepted to be in adults aged under 50 years,is increasing[1].This includes an observed increase in the incidence of gastrointestinal malignancies such as colorectal,oesophageal,gastric and hepatobiliary cancers[2-4].Despite oesophageal squamous cell carcinoma(OSCC)being more common globally(88%of cases)[5],a striking increase in oesophageal OAC incidence has been reported in developed countries,such as the United States and Europe[6,7].Worryingly,the United Kingdom has the highest incidence of OAC cases in the world[8].In addition to the increase in OAC,an increase in incidence of early-onset OAC,defined as OAC in adults aged under 50 years,has been observed[9,10].A population-based cohort in the Netherlands,consisting of 59584 patients,demonstrated the incidence of early-onset OAC to have tripled from 1989 to 2018,while OSCC cases declined in this age group[7].OAC usually develops in the lower third of the oesophagus and the gastro-oesophageal junction,with risk factors including obesity and gastro-oesophageal reflux disease[11].A poor prognosis is observed,with the overall five-year survival rate for oesophageal cancer between 15%-20%,even with treatment[12,13].These low survival rates are likely due to a combination of late diagnosis,intrinsic resistance to systemic therapy and the limited efficacy of surgical resection.Younger patients tend to present at a more advanced stage at diagnosis compared to those diagnosed later in life.A single centre,retrospective study found that 33.3%of patients in the younger age category(<50 years old)presented with stage IV OAC,compared to the 20.6%of the oldest age category(>70 years old)[14].Another population-based study in the Netherlands observed that OAC patients under 50 years old also presented with distant metastasis more often in comparison to older patients(50.5%vs 44.7%),and that tumour differentiation also varied between age groups[15].Reports of survival estimates in patients with early-onset OAC compared with older patients have resulted in contrasting findings to date.Some studies report that due to the advanced stage and aggressiveness of the tumours seen that the prognosis of these patients is almost always worse than their older counterparts[16].In contrast,another study found that the overall survival,as well as stage-specific survival was higher in those who were younger[17].A Dutch study which included only resectable cases found no difference in 5-year disease specific survival[18].Given the conflicting evidence to date,the aim of this systematic review was to investigate survival in OAC patients according to age at diagnosis.A protocol was composed,and the reporting of this systematic review designed,using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines[19].The protocol included:The review question,search strategy,inclusion criteria,type of quality assessment,the strategy for data analysis,and the‘population,intervention,comparator,and outcome’criteria.These are expanded below.

Treatment patterns and survival outcomes in patients with nonmetastatic early-onset pancreatic cancer

BACKGROUND The incidence of patients with early-onset pancreatic cancer(EOPC;age≤50 years at diagnosis)is on the rise,placing a heavy burden on individuals,families,and society.The role of combination therapy including surgery,radiotherapy,and chemotherapy in non-metastatic EOPC is not well-defined.AIM To investigate the treatment patterns and survival outcomes in patients with non-metastatic EOPC.METHODS A total of 277 patients with non-metastatic EOPC who were treated at our institution between 2017 and 2021 were investigated retrospectively.Overall survival(OS),disease-free survival,and progression-free survival were estimated using the Kaplan-Meier method.Univariate and multivariate analyses with the Cox proportional hazards model were used to identify prognostic factors.RESULTS With a median follow-up time of 34.6 months,the 1-year,2-year,and 3-year OS rates for the entire cohort were 84.3%,51.5%,and 27.6%,respectively.The median OS of patients with localized disease who received surgery alone and adjuvant therapy(AT)were 21.2 months and 28.8 months,respectively(P=0.007).The median OS of patients with locally advanced disease who received radiotherapy-based combination therapy(RCT),surgery after neoadjuvant therapy(NAT),and chemotherapy were 28.5 months,25.6 months,and 14.0 months,respectively(P=0.002).The median OS after regional recurrence were 16.0 months,13.4 months,and 8.9 months in the RCT,chemotherapy,and supportive therapy groups,respectively(P=0.035).Multivariate analysis demonstrated that carbohydrate antigen 19-9 level,pathological grade,T-stage,N-stage,and resection were independent prognostic factors for non-metastatic EOPC.CONCLUSION AT improves postoperative survival in localized patients.Surgery after NAT and RCT are the preferred therapeutic options for patients with locally advanced EOPC.

Early-onset gastrointestinal cancer:An epidemiological reality with great significance and implications

During the last few years,epidemiological data from many countries suggest that the incidence and prevalence of many cancers of the digestive system are shifting from the older to the younger ages,the so-called“early-onset cancer”.This is particularly evident in colorectal cancer and secondarily in other malignant digestive neoplasms,mainly stomach and in a lesser degree pancreas,and biliary tract.It should be emphasized that data concerning digestive neoplasms,except for those referring to the colon and stomach,could be characterized as rather insufficient.The exact magnitude of the shift in younger ages is expected to become clearer shortly,as long as relevant epidemiological data from many parts of the world would be available.The most important question concerns the etiology of this phenomenon,since its magnitude cannot be explained solely by the better diagnostic methodology and the preventive programs applied in many countries.The existing data support the assumption that a number of environ-mental factors may play a primary role in influencing carcinogenesis,sometimes from childhood.Changes that have appeared in the last decades related mainly to eating habits,consistency of gut microbiome and an increase of obese people interacting with genetic factors,ultimately favor the process of carcinogenesis.Even these factors however,are not entirely sufficient to explain the age-related changes in the frequency of digestive neoplasms.Studies of the individual effect of each of the already known factors or factors likely to be involved in the etiology of this phenomenon and studies using state-of-the-art technologies to accurately determine the degree of the population exposure to these factors are required.In this article,we attempt to describe the epidemiological data supporting the age-shifting of digestive malignancies and their possible pathogenesis.Finally,we propose some measures regarding the attitude of the scientific community to this alarming phenomenon.

Serum ferritin and the risk of early-onset colorectal cancer

BACKGROUND The incidence of early-onset colorectal cancer(EO-CRC)is rising in the United States,and is often diagnosed at advanced stages.Low serum ferritin is often incidentally discovered in young adults,however,the indication for endoscopy in EO-CRC is unclear.AIM To compare serum ferritin between patients with EO-CRC and healthy controls(HCs),and examine the association of serum ferritin in EO-CRC with patient-and disease-specific characteristics.METHODS A retrospective study of patients<50 years with newly-diagnosed EO-CRC was conducted from 1/2013-12/2023.Patients were included if serum ferritin was measured within 2 years prior to 1 year following CRC histologic diagnosis.To supplement the analysis,a cohort of HCs meeting similar inclusion and exclusion criteria were identified for comparison.A sensitivity analysis including only patients with serum ferritin obtained at or before diagnosis was separately performed to minimize risk of confounding.RESULTS Among 85 patients identified with EO-CRC(48 females),the median serum ferritin level was 26 ng/mL(range<1-2759 ng/mL).Compared to HCs(n=80211),there were a higher proportion of individuals with EO-CRC with serum ferritin<20 ng/mL(female 65%,male 40%)versus HCs(female 32.1%,male 7.2%)age 29-39 years(P=0.002 and P<0.00001,respectively).Stage IV disease was associated with significantly higher serum ferritin compared to less advanced stages(P<0.001).Serum ferritin obtained before or at the time of diagnosis was lower than levels obtained after diagnosis.Similar findings were confirmed in the sensitivity analysis.CONCLUSION Severe iron deficiency may indicate an increased risk of EO-CRC,particularly at earlier stages.Further studies defining the optimal serum ferritin threshold and routine incorporation of serum ferritin in screening algorithms is essential to develop more effective screening strategies for EO-CRC.

Analysis of risk factors for postpartum depression after cesarean section in women with early-onset preeclampsia

BACKGROUND Early-onset preeclampsia significantly increases maternal and fetal morbidity and mortality.Many pregnant women with early onset preeclampsia choose cesarean section as their delivery method.Although extensive research has explored the association between postpartum depression(PPD)and cesarean section,few studies have investigated the risk factors after cesarean section in women with early-onset preeclampsia.AIM To examine these risk factors through a retrospective,observational analysis of 287 women who underwent a cesarean section for early preeclampsia between June 2014 and March 2024.METHODS Participants were assessed in person during the 32nd week of pregnancy,2 days post-cesarean,and 6 weeks postpartum.According to the Edinburgh Postnatal Depression Scale(EPDS),participants who underwent cesarean section were divided into PPD(n=60)and non-PPD groups(n=227).Furthermore,PPD was diagnosed at 6 weeks postpartum according to depressive symptoms(EPDS score≥11).The demographic and clinical features of PPD were screened.Multivariate logistic regression analysis was used to identify PPD risk factors.RESULTS The prevalence of PPD was 20.9%(60/287)among the 287 women who underwent cesarean section for early-onset preeclampsia.Multivariate logistic regression analyses revealed that advanced age(age>40 years)[odds ratio(OR)=1.93,95%CI:1.31-2.82],previous preeclampsia(OR=7.15,95%CI:5.81-8.85),pre-pregnancy obesity(OR=2.42,95%CI:1.62-3.63),gestational diabetes mellitus(OR=3.52,95%CI:2.51-4.92),preexisting hypertension(OR=1.35,95%CI:1.03-1.89),PPD symptoms(EPDS≥11)at 2 days postpartum(OR=6.15,95%CI:1.32-28.35),high prenatal self-rating anxiety scale score(OR=1.13,95%CI:1.06-1.18),and pain at 6 weeks postpartum(OR=2.16,95%CI:1.28-3.66)were independently associated with PPD.CONCLUSION Risk factors for PPD after cesarean section in women with early-onset preeclampsia include advanced age(age>40 years),pre-pregnancy obesity,previous preeclampsia,gestational diabetes mellitus,preexisting hypertension,PPD symptoms(EPDS≥11)at 2 days postpartum,prenatal anxiety,and pain at 6 weeks postpartum.The early identi-fication of these factors and interventions can mitigate the risk of PPD.

Association of serum interleukin-6 with negative symptoms in stable early-onset schizophrenia

BACKGROUND Accumulating evidence suggests that the inflammatory cytokine interleukin-6(IL-6)contributes to the pathophysiology of psychiatric disorders.However,there was no study concerning the relationship between IL-6 concentrations and clinical features in the chronic phase of early-onset schizophrenia(EOS).AIM To investigate the relationship between serum IL-6 concentration and the clinical features of EOS.METHODS We measured serum IL-6 Levels from 74 patients with chronic schizophrenia,including 33 with age at onset<21 years(EOS group)and 41 with onset≥21 years in[adult-onset schizophrenia(AOS)group],and from 41 healthy controls.Symptom severities were evaluated using the Positive and Negative Syndrome Scale(PANSS).RESULTS Serum IL-6 concentrations were higher in both EOS and AOS groups than healthy controls(F=22.32,P<0.01),but did not differ significantly between EOS and AOS groups(P>0.05)after controlling for age,body mass index,and other covariates.Negative symptom scores were higher in the EOS group than the AOS group(F=6.199,P=0.015).Serum IL-6 concentrations in the EOS group were negatively correlated with both total PANSS-negative symptom score(r=-0.389,P=0.032)and avolition/asociality subscore(r=-0.387,P=0.026).CONCLUSION Patients with EOS may have more severe negative symptoms than those with adult-onset schizophrenia during the chronic phase of the illness.IL-6 signaling may regulate negative symptoms and its avolition/asociality subsymptoms among the early-onset chronic schizophrenic patients.

Research Progress in Early-onset Colorectal Cancer

Colorectal cancer used to be a common disease among middle-aged and elderly people.In recent years,the incidence of colorectal cancer(Early-onset colorectal cancer,EOCRC)under 50 years old has increased year by year.Different from the traditional late-onset colon cancer(LOCRC),the diagnosis stage of EOCRC is mostly in the late stage,with poor cell differentiation and poor diagnosis,and there is a layer of consensus and guidance on the diagnosis,treatment or screening of EOCRC at presentation.Therefore,fully understanding the disease characteristics and risk exposure factors of EOCRC is helpful to guide early screening and treatment,which ultimately reduces the mortality of EOCRC.In this review article,we summarized the epidemiology,physiology,risk exposure factors and pathological diagnosis of EOCRC,and discussed the diagnosis and treatment prospect of EOCRC.

Early-onset colorectal cancer:A review of current knowledge

Colorectal cancer(CRC)is one of the most prevalent malignancies worldwide.Although most prevalent among older people,its incidence above 50 years old has been decreasing globally in the last decades,probably as a result of better screening.Paradoxically,its incidence in patients below 50 years old[early-onset CRC(EO-CRC)]has been increasing,for reasons not yet fully understood.EOCRC’s increasing incidence is genre independent but shows racial disparities and has been described to occur worldwide.It follows a birth-cohort effect which probably reflects a change in exposure to CRC risk factors.Its incidence is predicted to double until 2030,which makes EO-CRC a serious public health issue.Both modifiable and non-modifiable risk factors have been identified-some are potential targets for preventive measures.EO-CRC is often diagnosed at advanced stages and histological features associated with poor prognosis have been described.EO-CRC presents some distinctive features:Microsatellite instability is common,but another subtype of tumours,both microsatellite and chromosome stable also seems relevant.There are no age-specific treatment protocols and studies on EO-CRC survival rates have shown conflicting data.Due to the higher germline pathological mutations found in EO-CRC patients,an accurate genetic risk evaluation should be performed.In this review,we summarize the current evidence on epidemiological,clinical,histopathological and molecular features of EO-CRC and discuss the contribution of genetics and lifestyle risk factors.We further comment on screening strategies and specific dimensions to consider when dealing with a younger cancer patient.

Advantage of log odds of positive lymph nodes in prognostic evaluation of patients with early-onset colon cancer

BACKGROUND Colon cancer(CC)is one of the most common cancers of the digestive tract,the third most common cancer worldwide,and the second most common cause of cancer-related deaths.Previous studies have demonstrated a higher risk of lymph node metastasis(LNM)in young patients with CC.It might be reasonable to treat patients with early-onset locally advanced CC with extended lymph node dissection.However,few studies have focused on early-onset CC(ECC)patients with LNM.At present,the methods of predicting and evaluating the prognosis of ECC patients with LNM are controversial.From the data of patients with CC obtained from the Surveillance,Epidemiology,and End Results(SEER)database,data of young patients with ECC(≤50 years old)was screened.Patients with unknown data were excluded from the study,while the remaining patients were included.The patients were randomly divided into a training group(train)and a testing group(test)in the ratio of 7:3,while building the model.The model was constructed by the training group and verified by the testing group.Using multiple Cox regression models to compare the prediction efficiency of LNM indicators,nomograms were built based on the best model selected for overall survival(OS)and cause-specific survival(CSS).In the two groups,the performance of the nomogram was evaluated by constructing a calibration plot,time-dependent area under the curve(AUC),and decision curve analysis.Finally,the patients were grouped based on the risk score predicted by the prognosis model,and the survival curve was constructed after comparing the survival status of the high and low-risk groups.RESULTS Records of 26922 ECC patients were screened from the SEER database.N classification,positive lymph nodes(PLN),lymph node ratio(LNR)and log odds of PLN(LODDS)were considered to be independent predictors of OS and CSS.In addition,independent risk factors for OS included gender,race,marital status,primary site,histology,grade,T,and M classification,while the independent prognostic factors for CSS included race,marital status,primary site,grade,T,and M classification.The prediction model including LODDS is composed of minimal Akaike information criterion,maximal concordance indexes,and AUCs.Factors including gender,race,marital status,primary site,histology,grade,T,M classification,and LODDS were integrated into the OS nomogram,while race,marital status,primary site,grade,T,M classification,and LODDS were included into the CSS nomogram.The nomogram representing both cohorts had been successfully verified in terms of prediction accuracy and clinical practicability.CONCLUSION LODDS is superior to N-stage,PLN,and LNR of ECC.The nomogram containing LODDS might be helpful in tumor evaluation and clinical decision-making,since it provides an appropriate prediction of ECC.

Molecular genetics of early-onset colorectal cancer

Early-onset colorectal cancer(EOCRC)has been rising in global prevalence and incidence over the past several decades.Environmental influences,including generational lifestyle changes and rising obesity,contribute to these increased rates.While the rise in EOCRC is best documented in western countries,it is seen throughout the world,although EOCRC may have distinct genetic mutations in patients of different ethnic backgrounds.Pathological and molecular characterizations show that EOCRC has a distinct presentation compared with later-onset colorectal cancer(LOCRC).Recent studies have identified DNA,RNA,and protein-level alterations unique to EOCRC,revealing much-needed biomarkers and potential novel therapeutic targets.Many molecular EOCRC studies have been performed with Caucasian and Asian EOCRC cohorts,however,studies of other ethnic backgrounds are limited.In addition,certain molecular characterizations that have been conducted for LOCRC have not yet been repeated in EOCRC,including high-throughput analyses of histone modifications,mRNA splicing,and proteomics on large cohorts.We propose that the complex relationship between cancer and aging should be considered when studying the molecular underpinnings of EOCRC.In this review,we summarize current EOCRC literature,focusing on sporadic molecular alterations in tumors,and their clinical implications.We conclude by discussing current challenges and future directions of EOCRC research efforts.

Clinical Features and Microvascular Complications Risk Factors of Early-onset Type 2 Diabetes Mellitus

The aim of this research was to study the clinical features and microvascular complications risk factors of early-onset type 2 diabetes mellitus(T2DM).We analyzed the clinical data from 1421 T2DM inpatients at Wuhan Union Hospital.Subjects were divided into early-onset T2DM group(diagnostic age<40 years)and late-onset T2DM group(diagnostic age>40 years).All subjects underwent a standardized assessment of microvascular complications.Data were compared with independent-samples t test or Chi-square test.Multiple logistic regression was used to determine the risk factors of microvascular complications.Patients with early-onset T2DM were more inclined to have a lower systolic blood pressure(SBP),a longer duration of diabetes and higher levels of body mass index(BM1),uric acid(UA),fasting plasma glucose(FPG),total cholesterol(TC),triglyceride(TG)and glycosylated hemoglobin(HbAlc)than those with lateonset T2DM(P<0.05).The prevalence of diabetic retinopathy(DR)was significantly higher and that of diabetic peripheral neuropathy(DPN)was significantly lower in early-onset group than in late-onset group(P<0.05).For DN,UA was an independent risk factor in early-onset T2DM.SBP and TG were independent risk factors in late-onset T2DM.For DR,duration of diabetes and SBP were independent risk factors in early-onset T2DM.Duration of diabetes,SBP and HbAlc were independent risk factors in late-onset T2DM.This study demonstrated that the clinical characteristics of early-onset T2DM were metabolic disorders,including glucose metabolism,lipid metabolism and amino acid metabolism.Early-onset T2DM was more likely to be associated with DR.The potential pathogenesis of early and late-onset T2DM might be different.The management of metabolic risk factors especially HbA1c,SBP,TG and UA is advised to be performed in the early stage of diabetes.

Early-onset colorectal cancer:A sporadic or inherited disease?

Colorectal cancer is the third most common cancer diagnosed worldwide. Although epidemiology data show a marked variability around the world, its overall incidence rate shows a slow but steady decrease, mainly in developed countries. Conversely, early-onset colorectal cancer appears to display an opposite trend with an overall prevalence in United States and European Union ranging from 3.0% and 8.6%. Colorectal cancer has a substantial proportion of familial cases. In particular, early age at onset is especially suggestive of hereditary predisposition. The clinicopathological and molecular features of colorectal cancer cases show a marked heterogeneity not only between early- and late-onset cases but also within the early-onset group. Two distinct subtypes of early-onset colorectal cancers can be identified: a &#x0201c;sporadic&#x0201d; subtype, usually without family history, and an inherited subtype arising in the context of well defined hereditary syndromes. The pathogenesis of the early-onset disease is substantially well characterized in the inherited subtype, which is mainly associated to the Lynch syndrome and occasionally to other rare mendelian diseases, whereas in the &#x0201c;sporadic&#x0201d; subtype the origin of the disease may be attributed to the presence of various common/rare genetic variants, so far largely unidentified, displaying variable penetrance. These variants are thought to act cumulatively to increase the risk of colorectal cancer, and presumably to also anticipate its onset. Efforts are ongoing in the attempt to unravel the intricate genetic basis of this &#x0201c;sporadic&#x0201d; early-onset disease. A better knowledge of molecular entities and pathways may impact on family-tailored prevention and clinical management strategies.

Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer

Colorectal cancer(CRC) is the third most frequent cancer type and the incidence of this disease is increasing gradually per year in individuals younger than 50 years old. The current knowledge is that early-onset CRC(EOCRC) cases are heterogeneous population that includes both hereditary and sporadic forms of the CRC. Although EOCRC cases have some distinguishing clinical and pathological features than elder age CRC, the molecular mechanism underlying the EOCRC is poorly clarified. Given the significance of CRC in the world of medicine, the present review will focus on the recent knowledge in the molecular basis of genetic and epigenetic mechanism of the hereditary forms of EOCRC, which includes Lynch syndrome, Familial CRC type X, Familial adenomatous polyposis, Mut YH-associated polyposis, Juvenile polyposis syndrome, Peutz-Jeghers Syndrome and sporadic forms of EOCRC. Recent findings about molecular genetics and epigenetic basis of EOCRC gave rise to new alternative therapy protocols. Although exact diagnosis of these cases still remains complicated, the present review paves way for better predictions and contributes to more accurate diagnostic and therapeutic strategies into clinical approach.

Molecular alterations in gastric cancer with special reference to the early-onset subtype

Currently, gastric cancer(GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the procarcinogenic activity of important genes. These factors include genetic susceptibility expressed in a singlenucleotide polymorphism, various acquired mutations(chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances(e.g., helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma(EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesisare modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC.

Circulating MicroRNAs as Novel Diagnostic Biomarkers for Very Early-onset(≤40 years) Coronary Artery Disease

Objective Very early-onset coronary artery disease （CAD） is a great challenge in cardiovascular medicine throughout the world, especially regarding its early diagnosis. This study explored whether circulating microRNAs （miRNAs） could be used as potential biomarkers for patients with very early-onset CAD. Methods We performed an initial screening of miRNA expression using RNA isolated from 20 patients with angiographically documented very early-onset CAD and 20 age- and sex-matched normal controls. For further confirmation, we prospectively examined the miRNAs selected from 40 patients with very early-onset CAD and 40 angiography-normal controls. Results A total of 22 overexpressed miRNAs and 22 underexpressed miRNAs were detected in the initial screening. RT-qPCR analysis of the miRNAs obtained from the initial screening revealed that four miRNAs including miR-196-5p, miR-3163-3p, miR-145-3p, and miR-190a-5p exhibited significantly decreased expression in patients compared with that in controls （P〈0.05）. The areas under the receiver operating characteristic curve for these miRNAs were 0.824 （95% CI, 0.731-0.917; P〈0.001）, 0.758 （95% CI, 0.651-0.864; P〈0.001）, 0.753 （95% CI, 0.643-0.863; P〈0.001）, and 0.782 （95% CI, 0.680-0.884; P〈0.001）, respectively, in the validation set. Conclusion To our knowledge, this is an advanced study to report about four serum miRNAs （miR-196-5p, miR-3163-3p, miR-145-3p, and miR-190a-5p） that could be used as novel biomarkers for the diagnosis of very early-onset CAD.

Early-onset colorectal cancer:A separate subset of colorectal cancer

Colorectal cancer(CRC)has a great impact on the world population.With increasing frequency,CRC is described according to the presenting phenotype,based on its molecular characteristics.Classification of CRC tumors according to their genetic and/or epigenetic alterations is not only important for establishing the molecular bases of the disease,but also for predicting patient outcomes and developing more individualized treatments.Early-onset CRC is a heterogeneous disease,with a strong familial component,although the disease is sporadic in an important proportion of cases.Different molecular alterations appear to contribute to the apparent heterogeneity of the early-onset population and subgroups can be distinguished with distinct histopathologic and familial characteristics.Moreover,compared with late-onset CRC,there are characteristicsthat suggest that early-onset CRC may have a different molecular basis.The purpose of this review was to analyze the current state of knowledge about earlyonset CRC with respect to clinicopathologic,familial and molecular features.Together,these features make it increasingly clear that this subset of CRC may be a separate disease,although it has much in common with late-onset CRC.

Early-onset gastric cancer:Learning lessons from the young

There is by no means a clear-cut pattern of mutations contributing to gastric cancers,and gastric cancer research can be hampered by the diversity of factors that can induce gastric cancer,such as Helicobacter pylori infection,diet,ageing and other environmental factors.Tumours are unquestionably riddled with genetic changes yet we are faced with an unsolvable puzzle with respect to a temporal relationship.It is postulated that inherited genetic factors may be more important in early-onset gastric cancer (EOGC) than in gastric cancers found in older patients as they have less exposure to environmental carcinogens.EOGC,therefore,could provide a key to unravelling the genetic changes in gastric carcinogenesis.Gastric cancers occurring in young patients provide an ideal background on which to try and uncover the initiating stages of gastric carcinogenesis.This review summarizes the literature regarding EOGC and also presents evidence that these cancers have a unique molecular-genetic phenotype,distinct from conventional gastric cancer.

Serial elongation-derotation-flexion casting for children with early-onset scoliosis

Various early-onset spinal deformities, particularly infantile and juvenile scoliosis(JS), still pose challenges to pediatric orthopedic surgeons. The ideal treatment of these deformities has yet to emerge, as both clinicians and surgeons still face multiple challenges including preservation of thoracic motion, spine and cage, and protection of cardiac and lung growth and function. Elongation-derotation-flexion(EDF) casting is a technique that uses a custom-made thoracolumbar cast based on a three-dimensional correction concept. EDF can control progression of the deformity and- in some cases-coax the initially-curved spine to grow straighter by acting simultaneously in the frontal, sagittal and coronal planes. Here we provide a comprehensive review of how infantile and JS can affect normal spine and thorax and how serial EDF casting can be used to manage these spinal deformities. A fresh review of the literature helps fully understand the principles of the serial EDF casting technique and the effectiveness of conservative treatment in patients with early-onset spinal deformities, particularly infantile and juvenile scolisois.

Role of DYT1 gene in early-onset primary torsion dystonia

Mutation of the DYT1 gene has been reported to cause early-onset primary torsion dystonia （DYT1） Due to DYT1 gene mutation, defective wild torsinA and the accumulation of mutant torsinA （GAG-deleted DYT1 gene encoded the mutant torsinA, torsinA＆E） play an important role in DYT1 pathogenesis. Intracellular inclusion bodies are formed, and dopamine transport and release are disturbed by interfering functions of endoplasmic reticulum, nuclear membrane, and cytoskeleton of neural cells, resulting in DYT1 onset. Small interfering RNA could serve as a potential therapy for DYT1. However, the exact function of wild torsinA and the pathological effects of torsinAAE require further studies.

Autosomal recessive 333 base pair interleukin 10 receptor alpha subunit deletion in very early-onset inflammatory bowel disease

BACKGROUND Interleukin 10 receptor alpha subunit(IL10RA)dysfunction is the main cause of very early-onset inflammatory bowel disease(VEO-IBD)in East Asians.AIM To identify disease-causing gene mutations in four patients with VEO-IBD and verify functional changes related to the disease-causing mutations.METHODS From May 2016 to September 2020,four young patients with clinically diagnosed VEO-IBD were recruited.Before hospitalization,using targeted gene panel sequencing and trio-whole-exome sequencing(WES),three patients were found to harbor a IL10RA mutation(c.301C>T,p.R101W in one patient;c.537G>A,p.T179T in two patients),but WES results of the fourth patient were not conclusive.We performed whole-genome sequencing(WGS)on patients A and B and reanalyzed the data from patients C and D.Peripheral blood mononuclear cells(PBMCs)from patient D were isolated and stimulated with lipopolysaccharide(LPS),interleukin 10(IL-10),and LPS+IL-10.Serum IL-10 levels in four patients and tumor necrosis factor-α(TNF-α)in the cell supernatant were determined by enzyme-linked immunosorbent assay.Phosphorylation of signal transducer and activator of transcription 3(STAT3)at Tyr705 and Ser727 in PBMCs was determined by western blot analysis.RESULTS The four children in our study consisted of two males and two females.The age at disease onset ranged from 18 d to 9 mo.After hospitalization,a novel 333-bp deletion encompassing exon 1 of IL10RA was found in patients A and B using WGS and was found in patients C and D after reanalysis of their WES data.Patient D was homozygous for the 333 bp deletion.All four patients had elevated serum IL-10 levels.In vitro,IL-10-stimulated PBMCs from patient D failed to induce STAT3 phosphorylation at Tyr705 and only minimally suppressed TNF-αproduction induced by LPS.Phosphorylation at Ser727 in PBMCs was not affected by LPS or LPS+IL-10 in both healthy subjects and in patient D.CONCLUSION WGS revealed a novel 333-bp deletion of IL10RA in four patients with VEO-IBD,whereas the WES results were inconclusive.