Association of an anaplastic lymphoma kinase pathway signature with cell de-differentiation, neoadjuvant chemotherapy response, and recurrence risk in breast cancer

Background:Aberrant activation of anaplastic lymphoma kinase(ALK)signaling has been found to be involved in the tumorigenesis of multiple types of cancer.The aim of this study was to determine the role of this pathway in the pathogenesis of breast cancer.Methods:An ALK pathway signature that we generated previously was used to compute the ALK pathway activity in 6381 breast cancer samples from 42 microarray datasets,and the associations between ALK pathway signature score and clinical variables were examined using logistic regression and survival analyses.Results:Our results indicated that high ALK pathway activity was a significant risk factor for hormone receptor-negative,high-grade breast cancer in the 42 datasets.ALK pathway activity was positively associated with pathological complete response(pCR)in 15 datasets annotated with patient’s neoadjuvant chemotherapy response information(overall odds ratio=1.67,P<0.01),and this association was more significant in HER2-negative and grade 1&2 tumors than in HER2-positive and grade 3 tumors.ALK pathway activity was also positively associated with recurrence risk in breast cancer patients from 30 datasets annotated with survival information(overall hazard ratio=1.21,P<0.01),particularly in patients with age>50 years old,with positive lymph nodes,or with residual disease after neoadjuvant chemotherapy.Conclusions:ALK may be involved in breast cancer tumorigenesis,and ALK pathway signature score may serve as a prognostic biomarker for breast cancer.

Multi-cohort comprehensive analysis unveiling the clinical value and therapeutic effect of GNAL in glioma

Clinical data indicates that glioma patients have poor treatment outcomes and clinical prognosis.The role of olfactory signaling pathway-related genes(OSPRGs)in glioma has not been fully elucidated.In this study,we aimed to investigate the role and relationship between OSPRGs and glioma.Univariate and multivariate Cox regression analyses were performed to assess the relationship between OSPRGs and the overall survival of glioma based on public cohorts,and the target gene(G Protein Subunit Alpha L,GNAL)was screened.The association of GNAL expression with clinicopathological characteristics,gene mutation landscape,tumor immune microenvironment(TIME),deoxyribonucleic acid(DNA)methylation,and naris-occlusion controlled genes(NOCGs)was performed.Immunohistochemistry was used to evaluate GNAL level in glioma.Further analysis was conducted to evaluate the drug sensitivity,immunotherapy response,and functional enrichment of GNAL.GNAL was an independent prognostic factor,and patients with low GNAL expression have a poor prognosis.Expression of GNAL was closely associated with clinicopathological characteristics,DNA methylation,and several immune-related pathways.Immune infiltration analysis indicated that GNAL levels were negatively correlated with immune scores.GNAL low-expression group showed efficacy with anti-PD-1 therapy.Ten compounds with significantly different half-maximal inhibitory concentration(IC50)values between the GNAL high and low-expression groups were identified.Furthermore,its expression was associated with several immune cells,immune-related genes,and NOCGs.The expression of GNAL is closely associated with clinicopathological characteristics,TIME,and the response to therapeutic interventions,highlighting its potential as a prognostic biomarker for glioma.

Targeting methyltransferase-like 5-mediated sphingomyelin metabolism:A novel therapeutic approach in gastric cancer

Gastric cancer(GC)is a global health problem and a leading cause of cancerrelated deaths,with its mortality rate ranking third among all cancers.The etiology and progression of GC are characterized by a complex interplay of genetic and epigenetic changes,which present challenges for its early diagnosis and effective treatment.Elucidating the mechanisms underlying the occurrence and development of GC and identifying novel biomarkers for early detection and prognosis are crucial to improving patient outcomes.This editorial examines the role of methyltransferase-like 5(METTL5)in the progression of GC through sphingomyelin metabolism by considering an article published by Zhang et al in the World Journal of Gastrointestinal Oncology in 2024,which is entitled“METTL5 promotes GC progression via sphingomyelin metabolism”.These authors investigated the biological behavior of METTL5 in GC by examining its expression patterns,clinical relevance,functional effect,and potential mechanisms,as well as its response to chemotherapy.This editorial provides valuable insights into the role of METTL5 in the progression of GC and its potential as a therapeutic target.

Dynamic monitoring of carcinoembryonic antigen,CA19-9 and inflammation-based indices in patients with advanced colorectal cancer undergoing chemotherapy

BACKGROUND The roles of carcinoembryonic antigen(CEA)and carbohydrate antigen(CA19-9)in monitoring the patient response to chemotherapy for metastatic colorectal cancer(mCRC)are not clearly defined,and inflammatory indices,including the neutrophil-to-lymphocyte ratio(NLR),lymphocyte-to-monocyte ratio(LMR),platelet-to-lymphocyte ratio(PLR)and systemic immune-inflammation index(SII),have been sparsely investigated for this purpose.AIM To aim of this study was to evaluate the relationship between the kinetics of CEA,CA19-9,NLR,LMR,PLR and SII in serum and patient response to chemotherapy estimated by computed tomography(CT)in patients with unresectable mCRC.METHODS Patients with mCRC treated with a 1st-line and 2nd-line chemotherapy underwent at least 3 whole-body spiral CT scans during response monitoring according to the Response Evaluation Criteria in Solid Tumour 1.1(RECIST 1.1),and simultaneous determination of CEA,CA19-9,neutrophil,lymphocyte,platelet and monocyte levels was performed.The kinetics of changes in the tumour markers and inflammatory indices were calculated as the percentage change from baseline or nadir,while receiver operating characteristic curves were drawn to select the thresholds to define patients with progressive or responsive disease with the highest sensitivity(Se)and specificity(Sp).The correlation of tumour marker kinetics with inflammatory index changes and RECIST response was determined by univariate and multivariate logistic regression analysis and the clinical utility index(CUI).RESULTS A total of 102 patients with mCRC treated with chemotherapy were included.Progressive disease(PD),defined as a CEA increase of 25.52%,resulted in an Se of 80.3%,an Sp of 84%,a good CUI negative[CUI(Ve-)]value of 0.75 and a good fraction correct(FC)value of 81.2;at a CEA cut-off of-60.85%with an Se of 100%and an Sp of 35.7%for PD,CT could be avoided in 25.49%of patients.The 21.49%CA19-9 cut-off for PD had an Se of 66.5%,an Sp of 87.4%,an acceptable CUI(Ve-)value of 0.65 and an acceptable FC value of 75.An NLR increase of 11.5%for PD had an Se of 67%and an Sp of 66%;a PLR increase of 5.9%had an Se of 53%and an Sp of 69%;an SII increase above-6.04%had an Se of 72%and an Sp of 63%;and all had acceptable CUI(Ve-)values at 0.55.In the univariate logistic regression analysis,CEA(P<0.001),CA19-9(P<0.05),NLR(P<0.05),PLR(P<0.05)and SII(P<0.05)were important predictors of tumour progression,but in the multivariate logistic regression analysis,CEA was the only independent predictor of PD(P<0.05).CONCLUSION CEA is a useful marker for monitoring the chemotherapy response of patients with unresectable mCRC and could replace a quarter of CT examinations.CA19-9 has poorer diagnostic characteristics than CEA but could be useful in some clinical circumstances,particularly when CEA is not increased.Dynamic changes in the inflammatory indices NLR,PLR and SII could be promising for further investigation as markers of the chemotherapy response.

Clinical meaning of BRAF mutation in Korean patients with advanced colorectal cancer

AIM: To evaluate the clinicopathological features of colorectal cancer (CRC) with a v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation and its molecular interaction with microsatellite instability (MSI) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) in patients with advanced CRCs.

Pancreatic head vs pancreatic body/tail cancer:Are they different?

BACKGROUND The impact of pancreatic tumor location on patient survival has been studied in large national data-based analyses which yielded controversial results.AIM To explore if pancreatic head cancer(PHC)and pancreatic body/tail cancer(PBTC)have different overall survival(OS),molecular signature and response to chemotherapy.METHODS We retrospectively queried patient records from July 2016 to June 2020 in our institution.Patient demographics,cancer stage on diagnosis,tumor location,somatic mutations,treatment,and survival are recorded and analyzed.A test is considered statistically significant if the P value was<0.05.RESULTS We reviewed 101 patients with complete records,among which 67(66.34%)were PHC and 34(33.66%)were PBTC.More PHC were diagnosed at younger age[61.49 vs 68.97,P=0.010],earlier stages(P=0.006)and underwent surgical resection(P=0.025).There were no significant differences among all mutations and pathways studied except for TP53 mutations(37.0%in PHC vs 70.0%in PBTC,P=0.03).OS was not statistically different between PHC and PBTC(P=0.636)in the overall population and in subgroups according to surgical resection status or stages.In terms of response to chemotherapy,chemotherapy regimens(FOLFIRINOX-based vs gemcitabine-based)didn’t impact disease free interval in those who had surgical resection in either PHC(P=0.546)or PBTC(P=0.654),or the duration of response to first line palliative treatment in those with advanced disease in PHC(P=0.915)or PBTC(P=0.524).CONCLUSION Even though PHC and PBTC have similar poor OS and response to chemotherapy,the different presentations and molecular profiles indicate they are different diseases.Utilization of molecular profiling to develop targeted therapy for individualization of treatment is needed.

Proteomic Stratification of Prognosis and Treatment Options for Small Cell Lung Cancer

Small cell lung cancer(SCLC)is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models.Here,we analyzed formalin-fixed,paraffin-embedded(FFPE)samples of surgical resections by proteomic profiling,and stratified SCLC into three proteomic subtypes(S-I,S-II,and S-III)with distinct clinical outcomes and chemotherapy responses.The proteomic subtyping was an independent prognostic factor and performed better than current tumor–node–metastasis or Veterans Administration Lung Study Group staging methods.The subtyping results could be further validated using FFPE biopsy samples from an independent cohort,extending the analysis to both surgical and biopsy samples.The signatures of the S-II subtype in particular suggested potential benefits from immunotherapy.Differentially overexpressed proteins in S-III,the worst prognostic subtype,allowed us to nominate potential therapeutic targets,indicating that patient selection may bring new hope for previously failed clinical trials.Finally,analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better progression-free survival and overall survival after first-line immunotherapy.Collectively,our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.

Genetic alterations and tumor mutation burden predict chemosensitivity of pancreatic cancer: a retrospective study

Background:Chemotherapy stands as a recommended approach for all stages of pancreatic cancer.However,its efficacy stratification remains obscure.Genomic sequencing is extensively applied across diverse diseases.This study aims to explore the potential genomic markers in relation to the decision-making of chemotherapy.Methods:A total of 140 patients with pancreatic cancer were categorized into chemotherapy-first group and adjuvant chemo-therapy group.The genomic alterations were detected from the next-generation sequencing using surgical or fine-needle-biopsy specimens.Chemotherapy response was defined according to objective response based on the RECIST criteria(version 1.1).Results:In the chemotherapy-first group,the patients who harbored higher tumor mutation burden(TMB)levels had significant shorter progress-free survival(PFS)than that with low TMB levels(hazard ratio[HR]=30.362,P=.002).No independent risk factors were found to be correlated with chemoresistance in patients receiving chemotherapy at first(all P>.05).In the adjuvant chemotherapy group,the increased carbohydrate antigen 125(CA125)level of more than 35 U/mL potentially elucidated a shorter period of DFS(HR=3.695,P=.020).Conclusion:Our study indicated that a high level of TMB may predict earlier tumor progression in pancreatic cancer patients received chemotherapy at first.The elevation of CA125 presents itself as a predictive indicator for postoperative chemotherapy patients’tumor recurrence,whereas gene mutations remain unrelated to this phenomenon.