Cancer incidence and mortality in China,2022

Background:The National Cancer Center(NCC)of China regularly reports the nationwide statistics on cancer incidence and mortality in China.The International Agency for Research on Cancer(IARC)calculates and publishes the cancer burden of countries around the world every two years.To ensure consistency between the actual surveillance data in China and the data published by IARC,NCC has received approval from the National Health Commission and IARC to simultaneously release the cancer burden data for China in GLOBOCAN 2022.Methods:There were a total of 700 registries reporting high-quality data on cancer incidence and mortality across China in 2018,of which 106 registries with continuous monitoring from 2010 to 2018 were used to establish an age-period-cohort model to simulate the trend of cancer incidence and mortality and to estimate the incidence and mortality in China in 2022.In addition,we analyzed the temporal trends of age-standardized cancer incidence and mortality from 2000 to 2018 using data from 22 continuous cancer registries.Results:It was estimated about 4,824,700 new cancer cases and 2,574,200 new cancer deaths occurred in China in 2022.Cancers of the lung,colon-rectum,thyroid,liver and stomach were the top five cancer types,accounting for 57.42%of new cancer cases.Cancers of the lung,liver,stomach,colon-rectum and esophagus were the five leading causes of cancer deaths,accounting for 67.50%of total cancer deaths.The crude rate and age-standardized incidence rate(ASIR)were 341.75 per 100,000 and 201.61 per 100,000,respectively.The crude mortality rate was 182.34 per 100,000 and the age-standardized mortality rate(ASMR)was 96.47 per 100,000.The ASIR of all cancers combined increased by approximately 1.4%per year during 2000–2018,while the ASMR decreased by approximately 1.3%per year.We observed decreasing trends in ASIR and ASMR for cancers of the esophagus,stomach,and liver,whereas the ASIR increased significantly for cancers of the thyroid,prostate,and cervix.Conclusions:Cancer remains a major public health concern in China,with a cancer profile that reflects the coexistence of developed and developing regions.Sustained implementation of prevention and control measures has resulted in significant reductions in the incidence and mortality rates of certain historically high incidence cancers,such as esophageal,stomach and liver cancers.Adherence to the guidelines of the Healthy China Action Plan and the Cancer Prevention and Control Action Plan,along with continued efforts in comprehensive risk factor control,cancer screening,early diagnosis and treatment,and standardization of diagnostic and therapeutic protocols,are key strategies to effectively mitigate the increasing cancer burden by 2030.

Cancer survival statistics in China 2019-2021:a multicenter,population-based study

Background:A milestone goal of the Healthy China Program(2019-2030)is to achieve 5-year cancer survival at 43.3%for all cancers combined by 2022.To assess the progress towards this target,we analyzed the updated survival for all cancers combined and 25 specific cancer types in China from 2019 to 2021.Methods:We conducted standardized data collection and quality control for cancer registries across 32 provincial-level regions in China,and included 6,410,940 newly diagnosed cancer patients from 281 cancer registries during 2008-2019,with follow-up data on vital status available until December 2021.We estimated the age-standardized 5-year relative survival overall and by site,age group,and period of diagnosis using the International Cancer Survival Standard Weights,and quantified the survival changes to assess the progress in cancer control.Results:In 2019-2021,the age-standardized 5-year relative survival for all cancers combined was 43.7%(95%confidence interval[CI],43.6-43.7).The 5-year relative survival varied by cancer type,ranging from 8.5%(95%CI,8.2-8.7)for pancreatic cancer to 92.9%(95%CI,92.4-93.3)for thyroid cancer.Eight cancers had 5-year survival of over 60%,including cancers of the thyroid,breast,testis,bladder,prostate,kidney,uterus,and cervix.The 5-year relative survival was generally lower in males than in females.From 2008 to 2021,we observed significant survival improvements for cancers of the lung,prostate,bone,uterus,breast,cervix,nasopharynx,larynx,and bladder.The most significant improvement was in lung cancer.Conclusions:Progress in cancer control was evident in China.This highlights the importance of a comprehensive approach to control and prevent cancer.

Helicobacter pylori eradication for primary prevention of gastric cancer:progresses and challenges

Gastric cancer remains a significant global health challenge,causing a substantial number of cancer-related deaths,particularly in China.While the exact causes of gastric cancer are still being investigated,Helicobac-ter pylori(H.pylori)infection has been identified as the primary risk factor,which triggers chronic inflammation and a multistage progression of gastric lesions that may lead to carcinogenesis over a long latency time.Since the 1990s,numerous efforts have focused on assessing the effectiveness of H.pylori eradication in preventing new cases of gastric cancer among both the general population and patients who have undergone early-stage cancer treatment.This body of work,including several community-based interventions and meta-analyses,has shown a reduction in both the incidence of and mortality from gastric cancer following H.pylori treatment,alongside a decreased risk of metachronous gastric cancer.In this review,we seek to consolidate current knowledge on the effects of H.pylori treatment on gastric cancer prevention,its systemic consequences,cost-effectiveness,and the influence of antibiotic resistance and host characteristics on treatment outcomes.We further discuss the potential for precision primary prevention of H.pylori treatment and comment on the efficient implementation of test-and-treat policies and allocation of health resources towards minimizing the burden of gastric cancer globally.

Clinicopathological and therapeutic comparisons of esophageal cancer between China and the USA:a multicenter hospital-based study

Background:Esophageal cancer(EC)remains a global health challenge due to its poor prognosis.China and the United States of America(USA)represent two distinct epicenters of EC burden.Understanding the EC disparities in these two countries is vital for tailoring prevention strategies,optimizing treatment,and enhancing outcomes in both countries.Yet,there lacks a comprehensive comparison of EC characteristics between the two countries.Methods:In this multicenter,retrospective hospital-based study,we enrolled primary EC patients who received their initial treatment at one of 23 hospitals in China during 2016-2017.Using electronic medical records and cancer registration records,information on demographics,lifestyle,and clinicopathological characteristics(in-cluding tumor site,pathology,stage,metastases,differentiation,and treatment)were collected.Additionally,we compared these data with the clinicopathological information of invasive EC patients diagnosed in 2016-2017 from the Surveillance,Epidemiology,and End Results(SEER)database in the USA.Results:A total of 6,658 EC patients in China and 8,555 EC patients in the USA were included finally.85.5%(n=5,694)of EC were esophageal squamous cell carcinoma(ESCC)in China,while esophageal adenocarcinoma(EAC)was prominent in the USA(58.9%,n=5,041).Among EC patients with known staging,the proportion of early stage was higher in China compared to the USA(48.3%vs.30.5%).Among ESCC patients,early-stage cases were higher in China than in the USA(49.8%vs.31.8%),while among EAC patients,late-stage cases were higher in China than in the USA(77.3%vs.68.5%)(all P<0.001).In China,EC mainly occurred in the middle third(60.2%)of the esophagus,whereas in the USA,it was more common in the lower third(59.9%)of the organ.Compared with EC patients with known metastatic status in the USA,China had fewer cases of lymph node metastases(51.4%vs.57.7%)and distant metastases(7.9%vs.33.8%).Regarding treatment,China had more surgical therapy(53.7%vs.22.6%),less radiotherapy(35.6%vs.53.3%),and less chemotherapy(46.7%vs.59.7%)compared to the USA.Conclusions:This study reveals notable disparities in EC between China and the USA,encompassing epidemi-ological,clinicopathological,and treatment dimensions.These findings provide insight for tailored strategies addressing regional variations in clinicopathological and therapeutic characteristics.

TDERS,an exosome RNA-derived signature predicts prognosis and immunotherapeutic response in clear cell renal cell cancer:a multicohort study

Background:Tumor-derived exosomes are involved in tumor progression and immune invasion and might func-tion as promising noninvasive approaches for clinical management.However,there are few reports on exosom-based markers for predicting the progression and adjuvant therapy response rate among patients with clear cell renal cell carcinoma(ccRCC).Methods:The signatures differentially expressed in exosomes from tumor and normal tissues from ccRCC pa-tients were correspondingly deregulated in ccRCC tissues.We adopted a two-step strategy,including Lasso and bootstrapping,to construct a novel risk stratification system termed the TDERS(Tumor-Derived Exosome-Related Risk Score).During the testing and validation phases,we leveraged multiple external datasets containing over 2000 RCC cases from eight cohorts and one inhouse cohort to evaluate the accuracy of the TDERS.In addition,enrichment analysis,immune infiltration signatures,mutation landscape and therapy sensitivity between the high and low TDERS groups were compared.Finally,the impact of TDERS on the tumor microenvironment(TME)was also analysed in our single-cell datasets.Results:TDERS consisted of 12 mRNAs deregulated in both exosomes and tissues from patients with ccRCC.TDERS achieved satisfactory performance in both prognosis and immune checkpoint inhibitor(ICI)response across all ccRCC cohorts and other pathological types,since the average area under the curve(AUC)to predict 5-year overall survival(OS)was larger than 0.8 across the four cohorts.Patients in the TDERS high group were resistant to ICIs,while mercaptopurine might function as a promising agent for those patients.Patients with a high TDERS were characterized by coagulation and hypoxia,which induced hampered tumor antigen presentation and relative resistance to ICIs.In addition,single cells from 12 advanced samples validated this phenomenon since the interaction between dendritic cells and macrophages was limited.Finally,PLOD2,which is highly expressed in fibro-and epi-tissue,could be a potential therapeutic target for ccRCC patients since inhibiting PLOD2 altered the malignant phenotype of ccRCC in vitro.Conclusion:As a novel,non-invasive,and repeatable monitoring tool,the TDERS could work as a robust risk stratification system for patients with ccRCC and precisely inform treatment decisions about ICI therapy.

Establishing the homologous recombination score threshold in metastatic prostate cancer patients to predict the efficacy of PARP inhibitors

Background:The homologous recombination deficiency(HRD)score serves as a promising biomarker to iden-tify patients who are eligible for treatment with PARP inhibitors(PARPi).Previous studies have suggested a 3-biomarker Genomic Instability Score(GIS)threshold of≥42 as a valid biomarker to predict response to PARPi in patients with ovarian cancer and breast cancer.However,the GIS threshold for prostate cancer(PCa)is still lacking.Here,we conducted an exploratory analysis to investigate an appropriate HRD score threshold and to evaluate its ability to predict response to PARPi in PCa patients.Methods:A total of 181 patients with metastatic castration-resistant PCa were included in this study.Tumor tissue specimens were collected for targeted next-generation sequencing for homologous recombination repair(HRR)genes and copy number variation(CNV)analysis.The HRD score was calculated based on over 50,000 single-nucleotide polymorphisms(SNP)distributed across the human genome,incorporating three SNP-based as-says:loss of heterozygosity,telomeric allelic imbalance,and large-scale state transition.The HRD score threshold was set at the last 5th percentile of the HRD scores in our cohort of known HRR-deficient tumors.The relation-ship between the HRD score and the efficacy in 16 patients of our cohort who received PARPi treatment were retrospectively analyzed.Results:Genomic testing was succeeded in 162 patients.In our cohort,61 patients(37.7%)had HRR mutations(HRRm).BRCA mutations occurred in 15 patients(9.3%).The median HRD score was 4(ranged from 0 to 57)in the total cohort,which is much lower than that in breast and ovarian cancers.Patients who harbored HRRm and BRCA or TP53 mutations had higher HRD scores.CNV occured more frequently in patients with HRRm.The last 5th percentile of HRD scores was 43 in the HRR-mutant cohort and consequently HRD high was defined as HRD scores≥43.In the 16 patients who received PARPi in our cohort,4 patients with a high HRD score achieved an objective response rate(ORR)of 100%while 12 patients with a low HRD score achieved an ORR of 8.3%.Progression-free survival(PFS)in HRD high patients was longer compared to HRD low patients,regardless of HRRm.Conclusions:A HRD score threshold of 43 was established and preliminarily validated to predict the efficacy of PARPi in this study.Future studies are needed to further verify this threshold.

Construction and application of a three-dimensional vascular variation-based nephrometry scoring system for completely endophytic renal tumors

Background:Completely endophytic renal tumors(CERT)pose significant challenges due to their anatomical complexity and loss of visual clues about tumor location.A facile scoring model based on three-dimensional(3D)reconstructed images will assist in better assessing tumor location and vascular variations.Methods:In this retrospective study,80 patients diagnosed with CERT were included.Forty cases underwent preoperative assessment using 3D reconstructed imaging(3D-Cohort),while the remaining 40 cases were assessed using two-dimensional imaging(2D-Cohort).Vascular variations were evaluated by ascertaining the presence of renal arteries>1,prehilar branching arteries,and arteries anterior to veins.The proposed scoring system,termed RAL,encompassed three critical components:(R)adius(maximal tumor diameter in cm),(A)rtery(occurrence of arterial variations),and(L)ocation relative to the polar line.Comparison of the RAL scoring system was made with established nephrometry scoring systems.Results:A total of 48(60%)patients exhibited at least one vascular variation.In the 2D-Cohort,patients with vascular variations experienced significantly prolonged operation time,increased bleeding volume,and extended warm ischemia time compared with those without vascular variations.Conversely,the presence of vascular vari-ations did not significantly affect operative parameters in the 3D-Cohort.Furthermore,the 2D-Cohort demon-strated a notable decline in both short-and long-term estimated glomerular filtration rate(eGFR)changes com-pared with the 3D-Cohort,a trend consistent across patients with warm ischemia time≥25 min and those with vascular variations.Notably,the 2D-Cohort exhibited a larger margin of normal renal tissue compared with the 3D-Cohort.Elevated RAL scores correlated with larger tumor size,prolonged operation time,extended warm is-chemia time,and substantial postoperative eGFR decrease.The RAL scoring system displayed superior predictive capabilities in assessing postoperative eGFR changes compared with conventional nephrometry scoring systems.Conclusions:Our proposed 3D vascular variation-based nephrometry scoring system offers heightened proficiency in preoperative assessment,precise prediction of surgical complexity,and more accurate evaluation of postoper-ative renal function in CERT patients.

The role of radiotherapy in patients with refractory Hodgkin’s lymphoma after treatment with brentuximab vedotin and/or immune checkpoint inhibitors

Background:Approximately 10%–30%of patients with Hodgkin’s lymphoma(HL)experience relapse or refractory(R/R)disease after first-line standard therapy.Brentuximab vedotin(BV)and immune checkpoint inhibitors(ICIs)have important roles in the salvage treatment of R/R HL.However,subsequent treatment for HL refractory to BV and/or ICI treatment is challenging.Methods:We retrospectively analyzed patients in two institutions who had R/R HL,experienced BV or ICI treatment failure,and received radiotherapy(RT)thereafter.The overall response rate(ORR),duration of response(DOR),progression-free survival(PFS),and overall survival(OS)were analyzed.Results:Overall,19 patients were enrolled.First-line systemic therapy comprised doxorubicin,bleomycin,vinblastine,and dacarbazine(ABVD,84.2%);AVD plus ICIs(10.5%);and bleomycin,etoposide,doxorubicin,cyclophosphamide,vincristine,procarbazine,and prednisone(BEACOPP,5.3%).After first-line therapy,15(78.9%)and four patients(21.1%)had refractory disease and relapsed,respectively.After R/R HL diagnosis,six(31.6%),two(10.5%),and 11(57.9%)patients received BV and ICIs concurrently,BV monotherapy,and ICI monotherapy,respectively.All patients received intensity-modulated RT(n=12,63.2%)or volumetric modulated arc therapy(VMAT;n=7,36.8%).The ORR as well as the complete response(CR)rate was 100%;the median DOR to RT was 17.2 months(range,7.9–46.7 months).Two patients showed progression outside the radiation field;one patient had extensive in-field,out-of-field,nodal,and extranodal relapse.With a median follow-up time of 16.2 months(range,9.2–23.2 months),the 1-year PFS and OS were 84.4%and 100%,respectively.PFS was associated with extranodal involvement(P=0.019)and gross tumor volume(P=0.044).All patients tolerated RT well without adverse events of grade≥3.Conclusion:RT is effective and safe for treating HL refractory to BV or ICIs and has the potential to be part of a comprehensive strategy for HL.

Efficacy and safety of paclitaxel liposome versus paclitaxel in combination with carboplatin in the first-line chemotherapy for ovarian cancer:a multicenter,open-label,non-inferiority,randomized controlled trial

Background:The paclitaxel liposome formulation,encapsulating paclitaxel within a phospholipid bilayer,ad-dresses the insolubility of traditional paclitaxel formulations,thereby reducing toxicity without compromising its antitumor efficacy.Methods:This multicenter,open-label,non-inferiority randomized controlled trial(ChiCTR2000038555)evalu-ates the efficacy and safety of paclitaxel liposome in comparison to the standard regimen of paclitaxel combined with carboplatin(PLC vs.PC)as first-line therapy in patients with epithelial ovarian cancer.Results:An analysis of median progression-free survival(PFS)revealed non-inferior outcomes between 263 pa-tients in the PLC group and 260 patients in the PC group(32.3 vs.29.9 months,hazard ratio[HR],0.89[95%CI,0.64−1.25]),using a non-inferior margin of 1.3.Although the overall incidence of treatment-related adverse events was comparable between groups,the PLC group experienced significantly fewer non-hematologic toxicities than those treated with the PC regimen.Conclusion:The findings affirm the non-inferiority of paclitaxel liposome compared to the combination of pa-clitaxel and carboplatin regarding therapeutic efficacy,with an enhanced safety profile marked by reduced non-hematologic toxicities.

Immunological features of EGFR-mutant non-small cell lung cancer and clinical practice:a narrative review

Immune checkpoint inhibitors(ICIs)have significantly improved outcomes for patients with advanced driver-negative non-small cell lung cancer(NSCLC).However,targeted therapy remains the preferred treatment for advanced driver-positive NSCLC,including cases with epidermal growth factor receptor(EGFR)mutations.Con-sidering the variability in EGFR-mutant NSCLC,including expression levels of programmed cell death ligand 1(PD-L1),tumor mutation burden(TMB),and other immunological features,the application of immunotherapy in this group is still a subject of investigation.Therefore,we have summarized and analyzed the immunological characteristics and regulatory mechanisms of different EGFR mutations in NSCLC,as well as the current clinical application of immunotherapy in the EGFR-mutant population,to provide a reference for future research.

Cancer survival analysis on population-based cancer registry data in Zhejiang Province,China(2018-2019)

Objective:This is a comprehensive overview of long-term cancer survival in Zhejiang Province,China.Hybrid analysis,a combination of cohort and period analysis,has been proposed to derive up-to-date cancer survival estimates.Using this approach,we aimed to timely and accurately analyze the 5-year relative survival(RS)and net survival(NS)in cancer registries of Zhejiang Province,China.Methods:A total of 255,725 new cancer cases diagnosed during 2013-2017 were included in 14 cancer registries in Zhejiang Province,China,with a follow-up on vital status until the end of 2019.The hybrid analysis was used to calculate the 5-year RS and 5-year NS during 2018-2019 for overall and stratifications by sex,cancer type,region,and age at diagnosis.Results:During 2018-2019,the age-standardized 5-year RS and NS for overall cancer in Zhejiang was 47.5%and 48.6%,respectively.The age-standardized 5-year RS for cancers of women(55.4%)was higher than that of men(40.0%),and the rate of urban areas(49.7%)was higher than that of rural areas(43.1%).The 5-year RS declined along with age,from 84.4%for ages<45 years to 23.7%for ages>74 years.Our results of the RS and NS showed the similar trend and no significant difference.The top five cancers with top age-standardized 5-year RS were thyroid cancer(96.0%),breast cancer(84.3%),testicular cancer(79.9%),prostate cancer(77.2%),and bladder cancer(70.6%),and the five cancers with the lowest age-standardized 5-year RS were pancreatic cancer(6.0%),liver cancer(15.6%),gallbladder cancer(17.1%),esophageal cancer(22.7%),and leukemia(31.0%).Conclusions:We reported the most up-to-date 5-year cancer RS and NS in Zhejiang Province,China for the first time,and found that the 5-year survival for cancer patients in Zhejiang during 2018-2019 was relatively high.The population-based cancer registries are recognized as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems.

How to properly evaluate cardiac vagal tone in oncology studies:a state-of-the-art review

Heart rate variability(HRV)analysis provides an assessment of cardiac vagal tone and consequently global cardiac health as well as systemic condition.In systemic diseases such as cancer and during treatments that affect the whole body,like chemotherapy,the vagus nerve activity is low and deregulated.Some studies focus on using HRV to predict mortality in oncology.However,in cancer patients,systemic alterations substantially increase artifacts during HRV measurement,especially atrial ectopic beats.Moreover,HRV may be altered by various factors(duration and time of measurement,breathing,drugs,and other confounding factors)that alter each metric in different ways.The Standard Deviation of all Normal to Normal intervals(SDNN)is the most commonly used metric to evaluate HRV in oncology,but it does not appear to be specific to the cardiac vagal tone.Thus,cardiac vagal activity diagnosis and vital prognosis of cancer patients can be biased.Our review presents the main HRV metrics that can be currently used in oncology studies and their links with vagus nerve and cancer.We present the influence of external factors and the required duration and time of measurement.Considering all these parameters,this review proposes seven key points for an assessment of HRV and cardiac vagal tone in patients with cancer.

Risk assessment and triage strategy of cervical cancer primary screening on HPV integration status:5-year follow-up of a prospective cohort study

Objective:We investigated the relation between man papillomavirus(HPV)integration status and the immediate risk of cervical intraepithelial neoplasia(CIN),as well as the triage strategy based on HPV integration test.Methods:4086 women aged 20 to 65 years in China were enrolled in 2015 for a prospective,population-based,clinical observational study to evaluate the triage performance of HPV integration.Cervical exfoliated cells were collected for HPV testing and cytologic test.If high-risk HPV was positive,HPV integration test was performed at baseline,2-year and 5-year follow-up.Results:At baseline,HPV integration was positively correlated with the severity of cervical pathology,ranging from 5.0%(15/301)in normal diagnosis,6.9%(4/58)in CIN1,31.0%(9/29)in CIN2,70%(14/20)in CIN3,and 100%(2/2)in cervical cancer(P<0.001).Compared with cytology,HPV integration exhibits comparable sensitivity and negative predictive value for the diagnosis of CIN3+,higher specificity(92.8%[90.2%-95.4%]vs.75.5%[71.2%-79.8%],P<0.001)and higher positive predictive value(36.4%[22.1%-50.6%]vs.15.2%[8.5%-21.8%],P<0.001).HPV integration testing strategy yielded a significantly lower colposcopy referral rate than cytology strategy(10.7%[44/410]vs.27.3%[112/410],P<0.001).The HPV integration-negative group exhibited the lowest immediate risk for CIN3+(1.6%)and accounted for the largest proportion of the total population(89.3%),when compared with the normal cytology group(risk,1.7%;proportion,72.7%).Conclusion:As a key molecular basis for the development of cervical cancer,HPV integration might be a promising triage strategy for HPV-positive patients.

Associations between blood glucose and early- and late-onset colorectal cancer: evidence from two prospective cohorts and Mendelian randomization analyses

Background: The incidence of early-onset colorectal cancer (EOCRC), which exhibits differential clinical, patho- logical, and molecular features compared to late-onset CRC (LOCRC), is rising globally. The potential differential effects of blood glucose on EOCRC compared to LOCRC have not been investigated. Methods: This study analyzed 374,568 participants from the UK Biobank cohort and 172,809 participants from the Kailuan cohort. The linear associations between blood glucose and EOCRC/LOCRC were estimated using Cox regression models. Restricted cubic spline (RCS) analysis and non-linear Mendelian randomization (MR) analysis using a 70-SNPs genetic instrument for fasting glucose were used to explore the potential non-linear associations. Results: Participants in the highest quintile of blood glucose had higher overall CRC risk compared to the lowest quintile (HR = 1.10 in the UK Biobank cohort, 95% CI: 1.01-1.21, P -trend = 0.012;HR = 1.23 in the Kailuan cohort, 95% CI: 1.01-1.51, P -trend = 0.036). Elevated glucose ( > 7.0 mmol/L) was more strongly associated with increased risk of EOCRC (HR = 1.61, 95% CI: 1.07-2.44) than with LOCRC (HR = 1.14, 95% CI: 1.02-1.27) in the UK Biobank cohort ( P- heterogeneity = 0.014). Elevated glucose ( > 7.0 mmol/L) was associated with increased risk of LOCRC (HR = 1.25, 95% CI: 1.04-1.65) in the Kailuan cohort as well. There was no evidence for non-linear associations between blood glucose and risks of EOCRC/LOCRC. Conclusions: This study showed a positive association between blood glucose and CRC risk in a dose-response manner, particularly for EOCRC, suggesting that tighter glucose control should be a priority for younger age groups.

Clinical,pathological,and adjuvant chemotherapy use differences among microsatellite unstable and microsatellite stable colon cancers

Background:Colon cancers are categorized into mismatch repair deficient/microsatellite unstable(MSI-H)and mismatch repair proficient/microsatellite stable(MSS)cancers.This study aims to compare the disease char-acteristics and trends in the utilization of cancer therapies across different age groups and stages in these two groups.Methods:MSI-H and MSS colon adenocarcinomas from 2010 to 2016 were identified using the National Can-cer Database.We compared patient and disease characteristics between the two groups and evaluated the use of adjuvant chemotherapy across age groups and cancer stages.Within MSI-H and MSS groups,we conducted a land-mark analysis after propensity score matching for adjuvant chemotherapy versus no chemotherapy to determine its effect on survival.Results:Of the 542,368 patients that met inclusion criteria,120,751(22%)had mismatch repair results avail-able-out of these 96,928(80%)had MSS colon cancers while 23,823(19.7%)had MSI-H cancers.MSI-H disease had a bimodal age distribution(<40 years=22%;≥75 years=26%)and was frequent among females(22%)and non-Hispanic Whites(20%).Among those<65 years,15%of low-risk stage 2 MSI-H patients and 40%of high-risk stage 2 MSI-H patients received adjuvant chemotherapy.More than two-thirds of stage 3 patients<65 years received adjuvant chemotherapy in both groups.After conducting propensity-score matching for age,gender,and co-morbidities,we found that adjuvant chemotherapy use had a trend towards lower overall survival(OS)in low-risk stage 2 MSI-H(HR=1.8[95%CI,0.8-4.02])and high-risk stage 2 MSI-H(HR=1.42[95%CI,0.96-2.12])groups.Adjuvant chemotherapy significantly improved OS in stage 3 colon cancer patients irrespective of microsatellite status or risk category of disease.Conclusions:MSI-H colon cancer had bimodal age distribution.Among stage 2 MSI-H patients<65 years,a notable proportion received adjuvant chemotherapy.Among MSI-H stage 2 patients,adjuvant chemotherapy use was associated with lower survival while it significantly improved survival for stage 3 patients,irrespective of MSI status.

The development and implementation of pathological parameters and molecular testing impact prognosis of colorectal adenocarcinoma

Objective:This study aims to analyze how changes in pathological diagnosis practice and molecular detection technology have affected clinical outcomes for colorectal cancer(CRC)patients in Fudan University Shanghai Cancer Center(FUSCC).Methods:This retrospective cohort study analyzed 21,141 pathologically confirmed CRC cases diagnosed at FUSCC from 2008 to 2020.Patients were divided into five groups for different analytical purposes:(1)the before vs.since 2014 groups to analyze the influence of the changes in the classification criteria of pT3 and pT4 staging on the survival of patients;(2)the partial vs.total mesorectal excision(TME)groups to analyze whether evaluation of completeness of the mesorectum have impact on the survival of patients;(3)the tumor deposit(TD)(+)N0 vs.TD(+)N1c groups to analyze the influence of the changes in the pN staging on the survival of patients with positive TD and negative regional lymph node metastasis(LNM);(4)the before vs.since 2013 groups to analyze the influence of the changes in the testing process of deficient mismatch repair on the survival of patients;and(5)the groups with vs.without RAS/BRAF gene mutation testing to analyze the influence of these testing on the survival of patients.Patients’clinicopathological parameters,including age at diagnosis,sex,tumor size,location,differentiation,mucinous subtype,TD,lymphovascular invasion,perineural invasion,tumor depth,LNM and distant metastasis,and tumor-node-metastasis(TNM)stage,were compared between groups.Kaplan-Meier analysis with log rank method was performed for patients’overall survival(OS)and disease-free survival(DFS)analyses.Results:In pathological reports,there were three parameter changes that impacted patient outcomes.Firstly,changes in the pT staging criteria led to a shift of the ratio of patients with stage pT3 to stage pT4 from 1:110.9 to 1:0.26.In comparison to patients admitted before 2014(n=4,754),a significant difference in prognosis between pT3 and pT4 stages was observed since 2014(n=9,965).Secondly,we began to evaluate the completeness of the mesorectum since 2016.As a result,91.0%of patients with low rectal cancer underwent TME(n=4,111)surgery,and patients with TME had significantly better OS compared with partial mesorectal excision(PME,n=409).Thirdly,we began to stage TD(+)LNM(-)as N1c since 2017.The results showed that N1c(n=127)but not N0(n=39)can improve the prognosis of patients without LNM and distal metastasis.In molecular testing,there have been three and five iterations of updates regarding mismatch repair(MMR)/microsatellite instability(MSI)status and RAS/BRAF gene mutation detection,respectively.The standardization of MMR status testing has sharply decreased the proportion of deficient MMR(dMMR)patients(from 32.5%to 7.4%)since 2013.The prognosis of patients underwent MMR status testing since 2013(n=867)were significantly better than patients before 2013(n=1,313).In addition,detection of RAS/BRAF gene mutation status(n=5,041)resulted in better DFS but not OS,for patients with stage I-III disease(n=16,557).Conclusion:Over the past few decades,updates in elements in pathological reports,as well as the development of standardized tests for MMR/MSI status and RAS/BRAF gene mutations have significantly improved patient outcomes.

The prognostic role of circulating tumor DNA across breast cancer molecular subtypes:A systematic review and meta-analysis

Objective:Circulating tumor DNA(ctDNA)is increasingly being used as a potential prognostic biomarker in cancer patients.We aimed to assess the prognostic value of ctDNA in different subtypes of breast cancer patients throughout the whole treatment cycle.Materials and methods:PubMed,Web of Science,Embase,Cochrane Library,Scopus,and clinical trials.gov databases were searched from January 2016 to May 2022.The following search terms were used:ctDNA OR circulating tumor DNA AND breast cancer OR breast carcinoma.Only studies written in English were included.The following pre-specified criteria should be met for inclusion:(i)original articles,conference abstracts,etc.;(ii)patients with breast cancer;(iii)ctDNA measurement;and(iv)clinical outcome data such as recurrence-free survival(RFS)and overall survival(OS).The random-effects model was preferred considering the potential het-erogeneity across studies.The main outcomes are ctDNA detection rate and postoperative long-term outcomes(RFS and OS).Results:A total of 24 studies were screened.At every measurement time,the ctDNA detection rate of the HR+subgroup was similar to that of the HR-subgroup(P=0.075;P=0.458;P=0.744;and P=0.578),and the ctDNA detection rate of the HER2+subgroup was similar to that of the HER2-subgroup(P=0.805;P=0.271;P=0.807;and P=0.703).In the HR+subgroup,RFS and OS of ctDNA positive patients were similar to those of ctDNA negative patients(P=0.589 and P=0.110),while RFS and OS of the ctDNA positive group was significantly shorter than those of the ctDNA negative patients in the HR-subgroup(HR=4.03,P<0.001;HR=3.21,P<0.001).According to HER grouping,the results were the same as above.In the triple negative breast cancer(TNBC)subgroup,the RFS and OS of ctDNA-positive patients was significantly shorter than of the ctDNA negative patients before and after surgery.Conclusions:ctDNA was more predictive of recurrence-free survival and overall survival in the HR-subgroup than in the HR+subgroup,and the same result was showed in the HER2-subgroup vs.HER2+subgroup.The prognosis of the TNBC subtype is closely related to ctDNA before and after surgery.

Application of Survival Quilts for prognosis prediction of gastrectomy patients based on the Surveillance,Epidemiology,and End Results database and China National Cancer Center Gastric Cancer database

Objective:Accurate prognosis prediction is critical for individualized-therapy making of gastric cancer patients.We aimed to develop and test 6-month,1-,2-,3-,5-,and 10-year overall survival(OS)and cancer-specific survival(CSS)prediction models for gastric cancer patients following gastrectomy.Methods:We derived and tested Survival Quilts,a machine learning-based model,to develop 6-month,1-,2-,3-,5-,and 10-year OS and CSS prediction models.Gastrectomy patients in the development set(n=20,583)and the internal validation set(n=5,106)were recruited from the Surveillance,Epidemiology,and End Re-sults(SEER)database,while those in the external validation set(n=6,352)were recruited from the China National Cancer Center Gastric Cancer(NCCGC)database.Furthermore,we selected gastrectomy patients with-out neoadjuvant therapy as a subgroup to train and test the prognostic models in order to keep the accuracy of tumor-node-metastasis(TNM)stage.Prognostic performances of these OS and CSS models were assessed using the Concordance Index(C-index)and area under the curve(AUC)values.Results:The machine learning model had a consistently high accuracy in predicting 6-month,1-,2-,3-,5-,and 10-year OS in the SEER development set(C-index=0.861,0.832,0.789,0.766,0.740,and 0.709;AUC=0.784,0.828,0.840,0.849,0.869,and 0.902,respectively),SEER validation set(C-index=0.782,0.739,0.712,0.698,0.681,and 0.660;AUC=0.751,0.772,0.767,0.762,0.766,and 0.787,respectively),and NCCGC set(C-index=0.691,0.756,0.751,0.737,0.722,and 0.701;AUC=0.769,0.788,0.790,0.790,0.787,and 0.788,respectively).The model was able to predict 6-month,1-,2-,3-,5-,and 10-year CSS in the SEER development set(C-index=0.879,0.858,0.820,0.802,0.784,and 0.774;AUC=0.756,0.827,0.852,0.863,0.874,and 0.884,respectively)and SEER validation set(C-index=0.790,0.763,0.741,0.729,0.718,and 0.708;AUC=0.706,0.758,0.767,0.766,0.766,and 0.764,respectively).In multivariate analysis,the high-risk group with risk score output by 5-year OS model was proved to be a strong survival predictor both in the SEER development set(hazard ratio[HR]=14.59,95%confidence interval[CI]:1.872-2.774,P<0.001),SEER validation set(HR=2.28,95%CI:13.089-16.293,P<0.001),and NCCGC set(HR=1.98,95%CI:1.617-2.437,P<0.001).We further explored the prognostic value of risk score resulted 5-year CSS model of gastrectomy patients,and found that high-risk group remained as an independent CSS factor in the SEER development set(HR=12.81,95%CI:11.568-14.194,P<0.001)and SEER validation set(HR=1.61,95%CI:1.338-1.935,P<0.001).Conclusion:Survival Quilts could allow accurate prediction of 6-month,1-,2-,3-,5-,and 10-year OS and CSS in gastric cancer patients following gastrectomy.

Editorial note to“Tumor microenvironment-based signatures distinguish intratumoral heterogeneity,prognosis,and immunogenomic features of clear cell renal cell carcinoma”[J Natl Cancer Cent.2023;3(3):236-249]

The Editorial Office regrets that an article with editors in their au-thorship were published without a statement of fair and rigorous peer-review process.The below statement should be published on the first page of the article as footnote.

DCS, a novel classifier system based on disulfidptosis reveals tumor microenvironment heterogeneity and guides frontline therapy for clear cell renal carcinoma

Background: Emerging evidence suggests that cell deaths are involved in tumorigenesis and progression, which may be treated as a novel direction of cancers. Recently, a novel type of programmed cell death, disulfidptosis, was discovered. However, the detailed biological and clinical impact of disulfidptosis and related regulators remains largely unknown. Methods: In this work, we first enrolled pancancer datasets and performed multi-omics analysis, including gene expression, DNA methylation, copy number variation and single nucleic variation profiles. Then we deciphered the biological implication of disulfidptosis in clear cell renal cell carcinoma (ccRCC) by machine learning. Finally, a novel agent targeting at disulfidptosis in ccRCC was identified and verified. Results: We found that disulfidptosis regulators were dysregulated among cancers, which could be explained by aberrant DNA methylation and genomic mutation events. Disulfidptosis scores were depressed among cancers and negatively correlated with epithelial mesenchymal transition. Disulfidptosis regulators could satisfactorily stratify risk subgroups in ccRCC, and a novel subtype, DCS3, owning with disulfidptosis depression, insensitivity to immune therapy and aberrant genome instability were identified and verified. Moreover, treating DCS3 with NU1025 could significantly inhibit ccRCC malignancy. Conclusion: This work provided a better understanding of disulfidptosis in cancers and new insights into individual management based on disulfidptosis.