Postoperative chemoradiotherapy with capecitabine and oxaliplatin vs.capecitabine for pathological stage N2 rectal cancer

Objective:Several studies have been conducted on the effects and toxicity of adding oxaliplatin to fluorouracilbased or capecitabine-based chemoradiotherapy(CRT)regimens as significantly increasing the toxic response without benefit to survival.In this study,we further explored the role of these two postoperative CRT regimens in patients with pathological stage N2 rectal cancer.Methods:This study was a subgroup analysis of a randomized clinical trial.A total of 180 patients with pathological stage N2 rectal cancer were eligible,85 received capecitabine with radiotherapy(RT),and 95 received capecitabine and oxaliplatin with RT.Patients in both groups received adjuvant chemotherapy[capecitabine and oxaliplatin(XELOX);or fluorouracil,leucovorin,and oxaliplatin(FOLFOX)]after CRT.Results:At a median follow-up of 59.2[interquartile range(IQR),34.0−96.8]months,the three-year diseasefree survival(DFS)was 53.3%and 64.9%in the control group and the experimental group,respectively[hazard ratio(HR),0.63;95%confidence interval(95%CI),0.41−0.98;P=0.04].There was no significant difference between the groups in overall survival(OS)(HR,0.62;95%CI,0.37−1.05;P=0.07),the incidence of locoregional recurrence(HR,0.62;95%CI,0.24−1.64;P=0.33),the incidence of distant metastasis(HR,0.67;95%CI,0.42−1.06;P=0.09)and grade 3−4 acute toxicities(P=0.78).For patients with survival longer than 3 years,the conditional overall survival(COS)was significantly better in the experimental group(HR,0.39;95%CI,0.16−0.96;P=0.03).Conclusions:Our results indicated that adding oxaliplatin to capecitabine-based postoperative CRT is safe and effective in patients with pathological stage N2 rectal cancer.

Association of overall survival benefit of radiotherapy with progression-free survival after chemotherapy for diffuse large B-cell lymphoma:A systematic review and meta-analysis

Objective:To evaluate whether improved progression-free survival(PFS)from radiotherapy(RT)translates into an overall survival(OS)benefit for diffuse large B-cell lymphoma(DLBCL).Methods:A systematic literature search identified randomized controlled trials(RCTs)and retrospective studies that compared combined-modality therapy(CMT)with chemotherapy(CT)alone.Weighted regression analyses were used to estimate the correlation between OS and PFS benefits.Cohen’s kappa statistic assessed the consis-tency between DLBCL risk-models and PFS patterns.Furthermore,the benefit trend of RT was analyzed by fitting a linear regression model to the pooled hazard ratio(HR)according to the PFS patterns.Results:For both 7 RCTs and 52 retrospective studies,correlations were found between PFS HR(HRPFS)and OS HR(HROS)at trial level(r=0.639-0.876),and between PFS and OS rates at treatment-arm level,regardless of CT regimens(r=0.882-0.964).Incorporating RT into CT increased about 18%of PFS,and revealed a different OS benefit profile.Patients were stratified into four CT-generated PFS patterns(>80%,>60-80%,>40-60%,and≤40%),which was consistent with risk-stratified subgroups(kappa>0.6).Absolute gain in OS from RT ranged from≤5%at PFS>80%to about 21%at PFS≤40%,with pooled HROS from 0.70(95%CI,0.51-0.97)to 0.48(95%CI,0.36-0.63)after rituximab-based CT.The OS benefit of RT was predominant in intermediate-and high-risk patients with PFS≤80%.Conclusion:We demonstrated a varied OS benefit profile of RT to inform treatment decisions and clinical trial design.

Clinical features and outcomes of diffuse large B-cell lymphoma based on nodal or extranodal primary sites of origin:Analysis of 1,085 WHO classified cases in a single institution in China

Objective: To explore the clinicobiologic features and outcomes of diffuse large B-cell lymphoma(DLBCL)patients in China according to the primary site.Methods: A total of 1,085 patients diagnosed with DLBCL in National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College during a 6-year period were enrolled. Their clinical characteristics and outcomes were analyzed according to the primary site.Results: In the 1,085 patients, 679(62.6%) cases were nodal DLBCL(N-DLBCL) and 406 cases(37.4%) were extranodal DLBCL(EN-DLBCL). The most common sites of N-DLBCL were lymphonodus(64.8%), Waldeyer's ring(19.7%), mediastinum(12.8%) and spleen(2.7%), while in EN-DLBCL, stomach(22.4%), intestine(16.0%),nose and sinuses(8.9%), testis(8.4%), skin(7.9%), thyroid(6.9%), central nervous system(CNS)(6.4%), breast(5.7%), bone(3.4%), and salivary gland(2.7%) were most common. N-DLBCL patients tend to present B symptoms, bulky disease, and elevated LDH more often, while age >60 years, extranodal sites >1, Ann Arbor stage I or II, bone marrow involvement, and Ki-67 index >90% were usually seen in EN-DLBCL. The 5-year overall survival(OS) rate and progression-free survival(PFS) rate for all patients were 62.5% and 54.2%. The 5-year OS rate for patients with N-DLBCL and EN-DLBCL were 65.5% and 56.9%(P=0.008), and the 5-year PFS were57.0% and 49.0%(P=0.020). Waldeyer's ring originated DLBCL possessed the highest 5-year OS rate(83.6%) and PFS rate(76.9%) in N-DLBCL. The top five EN-DLBCL subtypes with favorable prognosis were stomach,breast, nose and sinuses, lung, salivary gland, with 5-year OS rate: 70.3%, 69.6%, 69.4%, 66.7% and 63.6%,respectively. While CNS, testis, oral cavity and kidney originated EN-DLBCL faced miserable prognosis, with 5-year OS rate of 26.9%, 38.2%, and 42.9%.Conclusions: In our study, primary sites were associated with clinical characteristics and outcomes. Compared with EN-DLBCL, N-DLBCL had better prognosis.

Flotillin1 promotes EMT of human small cell lung cancer via TGF-β signaling pathway

Objective:Small cell lung carcinoma(SCLC)is considered one of the most aggressive types of lung cancer due to its rapid growth and early metastasis.No tumor markers or therapeutic targets have been demonstrated to be specific or effective in SCLC to date.This study aims to evaluate the potential of Flotillin1(Flot1)as a target of SCLC treatment.Methods:Flot1 expression level in the tissue of SCLC and other tissue of lung disease was detected using immunohistochemical staining.Transwell and Matrigel assays were employed to examine migration and invasion of cancer cells.Flow cytometry and xCELLigence system were used to evaluate cell apoptosis and cell viability,respectively.Expression levels of Flot1,epithelialmesenchymal transition(EMT)marker E-cadherin,vimentin,cyclinD1,TGF-β-Smad2/3,and p-AKT were examined using Western blot.Furthermore,xenograft tumor in nude mice was used to evaluate the growth and metastasis of NCI-H446 cells in vivo.Results:Our results demonstrated that Flot1 is highly expressed in SCLC samples and that its expression correlates strongly with clinical stage,distant metastasis,and poor survival.The knockdown of Flot1 decreased the growth,migration,and invasiveness of SCLC cells and reversed EMT phenotype in vitro and in vivo,while enhanced Flot1 expression exhibited the opposite behavior.Gene expression profile analysis demonstrated that Flot1-regulated genes frequently mapped to the AKT and TGF-β-Smad2/3pathways.Our results further revealed that Flot1 affected the progression of SCLC via regulation of EMT progression.Conclusions:These findings indicated an oncogenic role of Flot1 via promoting EMT in SCLC and suggested its potential as a tumor marker and prognostic indicator.

Down-staging depth score to predict outcomes in locally advanced rectal cancer achieving ypl stage after neoadjuvant chemo-radiotherapy versus de novo stage pl cohort:A propensity score-matched analysis

Objective：Prognosis of patients with locally advanced rectal cancer（LARC）but achieving yp T1–2N0 stage after neoadjuvant concurrent chemo-radiotherapy（CRT）has been shown to be favorable.This study aims to determine whether the long-term outcome of yp T1–2N0 cases can be comparable to that of p T1–2N0 cohort that received definitive surgery for early disease.Method：From January 2008 to December 2013,449 consecutive patients with rectal cancer were treated and their outcome maintained in a database.Patients with LARC underwent total mesorectal excision（TME）surgery at4–8 weeks after completion of CRT,and those achieving stage yp I were identified as a group.As a comparison,stage p I group pertains to patients whose initially limited disease was not upstaged after TME surgery alone.After propensity score matching（PSM）,comparisons of local regional control（LC）,distant metastasis-free survival（DMFS）,disease-free survival（DFS）and overall survival（OS）were performed using Kaplan-Meier analysis and log-rank test between yp I and p I groups.Down-staging depth score（DDS）,a novel method of evaluating CRT response,was used for subset analysis.Results：Of the 449 patients,168 matched cases were generated for analysis.Five-year LC,DMFS,DFS and OS for stage p I vs.yp I groups were 96.7%vs.96.4%（P=0.796）,92.7%vs.73.6%（P=0.025）,91.2%vs.73.6%（P=0.080）and 93.1%vs.72.3%（P=0.040）,respectively.In the DDS-favorable subset of the yp I group,LC,DMFS,DFS and OS resulted in no significant differences in comparison with the p I group（P=0.384,0.368,0.277 and0.458,respectively）.Conclusions：LC was comparable in both groups;however,distant metastasis developed more frequently in down-staged LARC than de novo early stage cases,reflecting the need to improve the efficacy of systemic treatment despite excellent pathologic response.DDS can be an indicator to identify a subset of the yp I group whose longterm oncologic outcomes are as good as those of stage p I cohort.

Genetic polymorphisms in genes regulating cell death and prognosis of patients with rectal cancer receiving postoperative chemoradiotherapy

Objective:The identification of biomarkers for predicting chemoradiotherapy efficacy is essential to optimize personalized treatment.This study determined the effects of genetic variations in genes involved in apoptosis,pyroptosis,and ferroptosis on the prognosis of patients with locally advanced rectal cancer receiving postoperative chemoradiotherapy(CRT).Methods:The Sequenom MassARRAY was used to detect 217 genetic variations in 40 genes from 300 patients with rectal cancer who received postoperative CRT.The associations between genetic variations and overall survival(OS)were evaluated using hazard ratios(HRs)and 95%confidence intervals(CIs)computed using a Cox proportional regression model.Functional experiments were performed to determine the functions of the arachidonate 5-lipoxygenase(ALOX5)gene and the ALOX5 rs702365 variant.Results:We detected 16 genetic polymorphisms in CASP3,CASP7,TRAILR2,GSDME,CASP4,HO-1,ALOX5,GPX4,and NRF2 that were significantly associated with OS in the additive model(P<0.05).There was a substantial cumulative effect of three genetic polymorphisms(CASP4 rs571407,ALOX5 rs2242332,and HO-1 rs17883419)on OS.Genetic variations in the CASP4 and ALOX5 gene haplotypes were associated with a higher OS.We demonstrated,for the first time,that rs702365[G]>[C]represses ALOX5 transcription and corollary experiments suggested that ALOX5 may promote colon cancer cell growth by mediating an inflammatory response.Conclusions:Polymorphisms in genes regulating cell death may play essential roles in the prognosis of patients with rectal cancer who are treated with postoperative CRT and may serve as potential genetic biomarkers for individualized treatment.

Down-staging depth score could be a survival predictor for locally advanced gastric cancer patients after preoperative chemoradiotherapy

Objective:The predictive effect of preoperative chemoradiotherapy(CRT)is low and difficult in guiding individualized treatment.We examined a surrogate endpoint for long-term outcomes in locally advanced gastric cancer patients after preoperative CRT.Methods:From April 2012 to April 2019,95 patients with locally advanced gastric cancer who received preoperative concurrent CRT and who were enrolled in three prospective studies were included.All patients were stage T_(3/4) N_(+).Local control,distant metastasis-free survival(DMFS),disease-free survival(DFS)and overall survival(OS)were evaluated.Clinicopathological factors related to long-term prognosis were analyzed using univariate and multivariate analyses.The down-staging depth score(DDS),which is a novel method of evaluating CRT response,was used to predict long-term outcomes.Results:The median follow-up period for survivors was 30 months.The area under the curve(AUC)of the receiver operating characteristic(ROC)curve predicted by the DDS was 0.728,which was better than the pathological complete response(pCR),histological response and ypN0.Decision curve analysis further affirmed that DDS had the largest net benefit.The DDS cut-off value was 4.pCR and ypN0 were associated with OS(P=0.026 and 0.049).Surgery and DDS are correlated with DMFS,DFS and OS(surgery:P=0.001,<0.001 and<0.001,respectively;and DDS:P=0.009,0.013 and 0.032,respectively).Multivariate analysis showed that DDS was an independent prognostic factor of DFS(P=0.021).Conclusions:DDS is a simple,short-term indicator that was a better surrogate endpoint than pCR,histological response and ypN0 for DFS.

Association Between Lipid Profiles and Left Ventricular Hypertrophy:New Evidence from a Retrospective Study

Objective To explore the association between lipid profiles and left ventricular hypertrophy in a Chinese general population.Methods We conducted a retrospective observational study to investigate the relationship between lipid markers[including triglycerides,total cholesterol,low-density lipoprotein cholesterol,high-density lipoprotein(HDL)cholesterol,non-HDL-cholesterol,apolipoprotein A-I,apolipoprotein B,lipoprotein[a],and composite lipid profiles]and left ventricular hypertrophy.A total of 309,400 participants of two populations(one from Beijing and another from nationwide)who underwent physical examinations at different health management centers between 2009 and 2018 in China were included in the cross-sectional study.7,475 participants who had multiple physical examinations and initially did not have left ventricular hypertrophy constituted a longitudinal cohort to analyze the association between lipid markers and the new-onset of left ventricular hypertrophy.Left ventricular hypertrophy was measured by echocardiography and defined as an end-diastolic thickness of the mterventricular septum or left ventricle posterior wall>11 mm.The Logistic regression model was used in the cross-sectional study.Cox model and Cox model with restricted cubic splines were used in the longitudinal cohort.Results In the cross-sectional study for participants in the highest tertile of each lipid marker compared to the respective lowest,triglycerides[odds ratio(OR):1.2S0,95%CI:1.060 to 1.474],HDL-cholesterol(OR:0.780,95%CI:0.662 to 0.918),and lipoprotein(a)(OR:1.311,95%C7:1.115 to 1.541)had an association with left ventricular hypertrophy.In the longitudinal cohort,for participants in the highest tertile of each lipid marker at the baseline compared to the respective lowest,triglycerides[hazard ratio(HR):3.277,95%C/:1.720 to 6.244],HDL-cholesterol(HR:0.516,95%C7:0.283 to 0.940),non-HDL-cholesterol(HR:2.309,95%C/:1.296 to 4.112),apolipoprotein B(HR:2.244,95%CI:1.251 to 4.032)showed an association with new-onset left ventricular hypertrophy.In the Cox model with forward stepwise selection,triglycerides were the only lipid markers entered into the final model.Conclusion Lipids levels,especially triglycerides,are associated with left ventricular hypertrophy.Controlling triglycerides level potentiate to be a strategy in harnessing cardiac remodeling but deserve to be furdier investigated.

Expressions of FEZ1 and Survivin, and their significance in small cell lung cancer and squamous cell lung carcinoma

Objective： To detect the expressions of FEZ1 and Survivin in small cell lung cancer （SOLO） and poorly differentiated squamous cell carcinoma （PDSCC）, and to approach a theoretical basis for clinical diagnosis and treatment. Methods： Immunohistochemical and flow cytometry method were used to detect the expressions of FEZ1 and Survivin. Apoptosis ratio and cell proliferation index in normal lung tissue, SCLC and PDSCC were analyzed. Results： The expressions of FEZ1 and Survivin were significantly different between SCLC and PDSCC （P 〈 0.05）. The apoptosis ratio and proliferation index of normal lung tissue were lower than those of PDSCC and SOLO, with a significant difference （P 〈 0.05）. Conclusion： The expressions of FEZ1 and Survivin are significantly different between SCLC and PDSCC, indicating that detecting the expressions of the two indexes may be helpful for clinical diagnosis.

Differential Proteomic Analysis of Wheat Roots under Different Levels of Potassium

[ Objective ] This study aimed to investigate the regulatory role of potassium levels in plant gene expression. [ Method ] By using wheat （ Triticum aesti- vum L. Beinong 9549） as experimental material, the protein expression in wheat roots under different levels of potassium was determined by two-dimensional elec- trophoresis （2-DE）. [ Result] Compared with the plants supplied with normal level of potassium, 152 protein spots in wheat roots under potassium deficiency con- dition showed significant differences （P 〈 0.05 ）, including 76 protein spots significantly up-regulated by more than twice and 76 protein spots significantly down- regulated by more than twice. After potassium deficiency treatment, the wheat plants were supplied with normal level of potassium for two weeks, which showed sig- nificant differences in 73 protein spots compared with the plants continuously supplied with normal level of potassium （ P 〈 0. 05 ）, including 36 protein spots signif- icantly up-regulated by more than twice and 37 protein spots significantly down-regulated by more than twice. [ Conclusion] This study indicates that potassium de- ficiency stress would lead to induction of a large number of specific proteins in wheat roots.

Adaptive ultra-hypofractionated whole-pelvic radiotherapy in high-risk and very high-risk prostate cancer on 1.5-Tesla MR-Linac:Estimated delivered dose and early toxicity results

Background: Magnetic resonance(MR)-guided ultra-hypofractionated radiotherapy with whole-pelvic irradiation(UHF-WPRT)is a novel approach to radiotherapy for patients with high-risk(HR)and very high-risk(VHR)prostate cancer(PCa).However,the inherent complexity of adaptive UHF-WPRT might inevitably result in longer on-couch time.We aimed to estimate the delivered dose,study the feasibility and safety of adaptive UHF-WPRT on a 1.5-Tesla MR-Linac.Methods: Ten patients with clinical stage T3a-4N0-1M0-1c PCa,who consecutively received UHF-WPRT,were enrolled prospectively.The contours of the target and organ-at-risks on the position verification-MR(PV-MR),beam-on 3D-MR(Bn-MR),and post-MR(after radiotherapy delivery)were derived from the pre-MR data by deformable image registration.The physician then manually adjusted them,and dose recalculation was performed accordingly.GraphPad Prism 9(GraphPad Prism Software Inc.)was utilized for conducting statistical analyses.Results: In total,we collected 188 MR scans(50 pre-MR,50 PV-MR,44 Bn-MR,and 44 post-MR scans).With median 59 min,the mean prostate clinical target volume(CTV)-V_(100%)was 98.59%±2.74%,and the mean pelvic CTVp-V_(100%)relative percentages of all scans was 99.60%±1.18%.The median V29 Gy change in the rectal wall was−2%(−18%to 20%).With a median follow-up of 9 months,no patient had acute Common Terminology Criteria for Adverse Events(CTCAE)grade 2 or more severe genitourinary(GU)or gastrointestinal(GI)toxicities(0%).Conclusion: UHF-RT to the prostate and the whole pelvis with concomitant boost to positive nodes using an Adapt-To-Shape(ATS)workflow was technically feasible for patients with HR and VHR PCa,presenting only mild GU and GI toxicities.The estimated target dose during the beam-on phase was clinically acceptable based on the 3D-MR-based dosimetry analysis.Clinical trial registration Chinese Clinical Trial Registry ChiCTR2000033382.

Real-world data on ALK rearrangement test in Chinese advanced non-small cell lung cancer(RATICAL):a nationwide multicenter retrospective study

Background:Anaplastic lymphoma kinase(ALK)test in advanced non-small cell lung cancer(NSCLC)can help physicians provide target therapies for patients harboring ALK gene rearrangement.This study aimed to investigate the real-world test patterns and positive rates of ALK gene rearrangements in advanced NSCLC.Methods:In this real-world study(ChiCTR2000030266),patientswith advanced NSCLC who underwent an ALK rearrangement test in 30 medical centers in China between October 1,2018 and December 31,2019 were retrospectively analyzed.Interpretation training was conducted before the study was initiated.Quality controls were performed at participating centers using immunohistochemistry(IHC)-VENTANA-D5F3.The positive ALK gene rearrangement rate and consistency rate were calculated.The associated clinicopathological characteristics of ALK gene rearrangement were investigated as well.Results:The overall ALK gene rearrangement rate was 6.7%in 23,689 patients with advanced NSCLC and 8.2%in 17,436 patients with advanced lung adenocarcinoma.The quality control analysis of IHC-VENTANA-D5F3 revealed an intrahospital consistency rate of 98.2%(879/895)and an inter-hospital consistency rate of 99.2%(646/651).IHC-VENTANA-D5F3 was used in 53.6%,real-time polymerase chain reaction(RT-PCR)in 25.4%,next-generation sequencing(NGS)in 18.3%,and fluorescence in-situ hybridization(FISH)in 15.9%in the adenocarcinoma subgroup.For specimens tested with multiple methods,the consistency rates confirmed by IHC-VENTANA-D5F3 were 98.0%(822/839)for FISH,98.7%(1,222/1,238)forNGS,and 91.3%(146/160)for RT-PCR.The overall ALK gene rearrangement rateswere higher in females,patients of≤35 years old,never smokers,tumor cellularity of>50,and metastatic specimens used for testing in the total NSCLC population and adenocarcinoma subgroup(all P<0.05).Conclusions:This study highlights the real-world variability and challenges of ALK test in advanced NSCLC,demonstrating a predominant use of IHCVENTANA-D5F3 with high consistency and distinct clinicopathological features in ALK-positive patients.These findings underscore the need for a consensus on optimal test practices and support the development of refined ALK test strategies to enhance diagnostic accuracy and therapeutic decision-making in NSCLC.

Establishment and validation of a multigene model to predict the risk of relapse in hormone receptor-positive early-stage Chinese breast cancer patients

Background: Breast cancer patients who are positive for hormone receptor typically exhibit a favorable prognosis. It is controversial whether chemotherapy is necessary for them after surgery. Our study aimed to establish a multigene model to predict the relapse of hormone receptor-positive early-stage Chinese breast cancer after surgery and direct individualized application of chemotherapy in breast cancer patients after surgery. Methods: In this study, differentially expressed genes (DEGs) were identified between relapse and nonrelapse breast cancer groups based on RNA sequencing. Gene set enrichment analysis (GSEA) was performed to identify potential relapse-relevant pathways. CIBERSORT and Microenvironment Cell Populations-counter algorithms were used to analyze immune infiltration. The least absolute shrinkage and selection operator (LASSO) regression, log-rank tests, and multiple Cox regression were performed to identify prognostic signatures. A predictive model was developed and validated based on Kaplan-Meier analysis, receiver operating characteristic curve (ROC). Results: A total of 234 out of 487 patients were enrolled in this study, and 1588 DEGs were identified between the relapse and nonrelapse groups. GSEA results showed that immune-related pathways were enriched in the nonrelapse group, whereas cell cycle- and metabolism-relevant pathways were enriched in the relapse group. A predictive model was developed using three genes ( CKMT1B , SMR3B , and OR11M1P ) generated from the LASSO regression. The model stratified breast cancer patients into high- and low-risk subgroups with significantly different prognostic statuses, and our model was independent of other clinical factors. Time-dependent ROC showed high predictive performance of the model. Conclusions: A multigene model was established from RNA-sequencing data to direct risk classification and predict relapse of hormone receptor-positive breast cancer in Chinese patients. Utilization of the model could provide individualized evaluation of chemotherapy after surgery for breast cancer patients.

Clinical characteristics and treatment outcomes of Chinese diffuse large B-cell lymphoma patients in the era of rituximab(2005–2018)

Background Rituximab combined with cyclophosphamide,doxorubicin hydrochloride,vincristine,and prednisone(R-CHOP)regimen has improved the survival of diffuse large B-cell lymphoma(DLBCL)patients worldwide,compared with CHOP alone.Several limitations were seen in previous studies of Chinese DLBCL patients treated with R-CHOP or R-CHOP-like regimens.This study aimed to investigate the clinical characteristics and treatment outcomes of Chinese DLBCL patients treated with the standard first-line treatment.Methods Clinical data were collected from DLBCL patients who received frontline R-CHOP or R-CHOP-like regimens at the Cancer Hospital Chinese Academy of Medical Sciences&Peking Union Medical College(CHCAMS)between January 1,2005,and December 31,2018.The treatment outcomes were compared with those of patients diagnosed with DLBCL between 2004 and 2017 and who received immunochemotherapy from the United States Surveillance,Epidemiology,and End Results(SEER)database.Survival rates were estimated using the Kaplan-Meier method and compared using the log-rank test.Multivariate analysis of progression-free survival(PFS)and overall survival(OS)was performed using Cox proportional hazard regression.Results Overall,1084 patients from the CHCAMS and 4013 patients from the SEER database were included in the study.As of April 30,2022,the median follow-up period for the CHCAMS group was 87.3(range:0.5-195.4)months.For the CHCAMS group,the 5-year PFS and OS rates were 61.7%(95%confidence interval[CI]:58.8-64.7%)and 70.6%(95%CI:67.8-73.4%),respectively.For the SEER group,the 5-year OS rate was 66.5%(95%CI:65.0-68.0%),which was inferior to that of the CHCAMS group(P<0.001).After adjusting for clinical factors and treatment,no significant difference was observed in the OS between the CHCAMS and SEER groups(P=0.867).In the CHCAMS group,multivariate analysis showed that an Eastern Cooperative Oncology Group performance status score≥2,presence of B symptoms,Ann Arbor stage III-IV,elevated serumβ2-microglobulin levels,and bulky mass were independent adverse prognostic factors affecting PFS and OS(P<0.05).Additionally,patients aged over 60 years,elevated lactate dehydrogenase levels,and more than two extranodal sites were independent adverse prognostic factors for OS(P<0.05).Local radiotherapy was significantly associated with better PFS(P<0.001)and OS(P=0.001).Conclusion After adjusting for clinical and treatment-related factors,no significant difference was observed in the 5-year OS rate between Chinese DLBCL patients treated with standard first-line treatment and those from the SEER database.

Genomic characterization reveals distinctmutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract

Background:Neuroendocrine carcinomas of the gastrointestinal tract(GINECs)remain a disease of grim prognosis with limited therapeutic options.Their molecular characteristics are still undefined.This study aimed to explore the underlying genetic basis and heterogeneity of GI-NECs.Methods:Comprehensive genomic analysis using whole-exome sequencing was performed on 143 formalin-fixed,paraffin-embedded samples of surgically resected GI-NEC with a thorough histological evaluation.Mutational signatures,somatic mutations,and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes.Survival analysis was conducted to identify the independent factors.Results:In total,143GI-NECswere examined:the stomach,87 cases(60.8%);the esophagus,29 cases(20.3%);the colorectum,20 cases(14.0%);and the small intestine,7 cases(4.9%).Eighty-three(58.0%)and 60(42.0%)cases were subclassified into small cell and large cell subtypes,respectively.GI-NECs showed distinct genetic alterations from their lung counterparts and non-neuroendocrine carcinomas in the same locations.Obvious heterogeneity of mutational signatures,somatic mutations,and copy number variations was revealed across anatomic locations rather than histological subtypes.Except for tumor protein p53(TP53)and retinoblastoma 1(RB1),the most frequently mutated genes in the stomach,esophagus,colorectum,and small intestine were low-density lipoprotein receptor-related protein 1B(LRP1B),notch receptor 1(NOTCH1),adenomatosis polyposis coli(APC),catenin beta 1(CTNNB1),respectively.Mutations in the WNT-β-catenin,NOTCH and erythroblastic leukemia viral oncogene B(ERBB)pathwayswere prevalently identified in gastric,esophageal,and colorectalNECs,respectively.Importantly,104(72.7%)GI-NECs harbored putative clinically relevant alterations,and non-gastric location and RB1 bi-allelic inactivation with copy number alterations were identified as two independent poor prognostic factors.Furthermore,we found that tumor cells in GI-NECs first gain clonal mutations in TP53,RB1,NOTCH1 and APC,followed by subsequent wholegenome doubling(WGD)and post-WGD clonal mutations in LRP1B,CUB and Sushi multiple domains 3(CSMD3),FAT tumor suppressor homolog 4(FAT4)and erb-b2 receptor tyrosine kinase 4(ERBB4),and finally develop subclonal mutations.Conclusions:GI-NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations.Moreover,potentially actionable alterations and prognostic factors were revealed for GI-NECs.