Clinical and molecular significance of homologous recombination deficiency positive non-small cell lung cancer in Chinese population:An integrated genomic and transcriptional analysis

Objective:The clinical significance of homologous recombination deficiency(HRD)in breast cancer,ovarian cancer,and prostate cancer has been established,but the value of HRD in non-small cell lung cancer(NSCLC)has not been fully investigated.This study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical care.Methods:A total of 355 treatment-naïve NSCLC patients were retrospectively enrolled.HRD status was assessed using the AmoyDx Genomic Scar Score(GSS),with a score of≥50 considered HRD-positive.Genomic,transcriptomic,tumor microenvironmental characteristics and prognosis between HRD-positive and HRDnegative patients were analyzed.Results:Of the patients,25.1%(89/355)were HRD-positive.Compared to HRD-negative patients,HRDpositive patients had more somatic pathogenic homologous recombination repair(HRR)mutations,higher tumor mutation burden(TMB)(P<0.001),and fewer driver gene mutations(P<0.001).Furthermore,HRD-positive NSCLC had more amplifications in PI3K pathway and cell cycle genes,MET and MYC in epidermal growth factor receptor(EGFR)/anaplastic lymphoma kinase(ALK)mutant NSCLC,and more PIK3CA and AURKA in EGFR/ALK wild-type NSCLC.HRD-positive NSCLC displayed higher tumor proliferation and immunosuppression activity.HRD-negative NSCLC showed activated signatures of major histocompatibility complex(MHC)-II,interferon(IFN)-γand effector memory CD8+T cells.HRD-positive patients had a worse prognosis and shorter progressionfree survival(PFS)to targeted therapy(first-and third-generation EGFR-TKIs)(P=0.042).Additionally,HRDpositive,EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy regimens.Conclusions:Unique genomic and transcriptional characteristics were found in HRD-positive NSCLC.Poor prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive NSCLC.This study highlights potential actionable alterations in HRD-positive NSCLC,suggesting possible combinational therapeutic strategies for these patients.

Low testing rates and high BRCA prevalence: Poly (ADP-ribose) polymerase inhibitor use in Middle East BRCA/homologous recombination deficiency-positive cancer patients

BACKGROUND Poly(ADP-ribose)polymerase inhibitors(PARPis)are approved as first-line therapies for breast cancer gene(BRCA)-positive,human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer.They are also effective for new and recurrent ovarian cancers that are BRCA-or homologous recombination deficiency(HRD)-positive.However,data on these mutations and PARPi use in the Middle East are limited.AIM To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer.METHODS This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations,and 25 of 65 ovarian cancer patients tested for HRD.These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023.Data were summarized using descriptive statistics and compared using counts and percentages.Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria.RESULTS Among the 472 breast cancer patients,12.1%underwent BRCA testing,and 38.5%of 65 ovarian cancer patients received HRD testing.Pathogenic mutations were found in 25.6%of the tested patients:26.3%breast cancers had germline BRCA(gBRCA)mutations and 24.0%ovarian cancers showed HRD.Notably,40.0%of gBRCA-positive breast cancers and 66.0%of HRD-positive ovarian cancers were Middle Eastern and Asian patients,respectively.PARPi treatment was used in 5(33.3%)gBRCA-positive breast cancer patients as first-line therapy(n=1;7-months progression-free),for maintenance(n=2;>15-months progression-free),or at later stages due to compliance issues(n=2).Four patients(66.6%)with HRD-positive ovarian cancer received PARPi and all remained progression-free.CONCLUSION Lower testing rates but higher BRCA mutations in breast cancer were found.Ethnicity reflected United Arab Emirates demographics,with breast cancer in Middle Eastern and ovarian cancer in Asian patients.

Therapeutic effect and apoptosis mechanism of lung-tonifying and expectorant decoction on lung cancer rats with Qi deficiency and blood stasis

Objective:To explore the effect and specific mechanism of lung-tonifying and expectorant decoction on lung cancer rats with Qi deficiency and blood stasis,and aim to provide a new idea on treating the disease with traditional Chinese medicine based on syndrome differentiation.Methods:A total of 60 C57BL/6J male rats were included in the study.The model of Qi deficiency and blood stasis was established in 60 rats by using multiple-factor stimulation.About 10 rats were randomly taken to verify whether the model establishment was successful and the rest of 50 rats were divided into 5 groups with 10 rats each:blank control group,cisplatin group,low dose group,medium dose group and high dose group.The blank control group was treated with normal saline,and cisplatin group was treated with cisplatin while the other three groups were treated with lung-tonifying and expectorant decoction at different doses.The volume change in transplanted tumor,tumor inhibition rate,apoptosis rate,and expression of Bc1-2,Bax.cleaved caspase-3 and cleaved caspase-9 in 5 groups were compared.Results:The rapidest growth rate of transplanted tumor volume was observed in blank control group and the slowest in cisplatin group.The growth rate was gradually decreased with the increasing dose of lung-tonifying and expectorant decoction,and the difference in growth of tumor volume among groups was statistically significant(P<0.05).The cisplatin group showed the highest tumor inhibition rate,with dose-dependent increase(P<0.05).The apoptosis rate in low dose group was higher than blank control group but lower than high dose group(P<0.05).The apoptosis rate in medium dose group was significantly higher man blank control group(P).05).The apoptosis rate in high dose group was significantly higher than control group(P<0.05).The positive expression rates of Bel-2 and Bax in all groups showed statistically significant difference(P<0.05),while expression of cleaved caspase-3 and cleaved caspase-9 in 5 groups was significantly different,with dose-dependent increase(P<0.05).Conclusions:The lung-tonifying and expectorant decoction inhibits the proliferation of tumor cells by inducing and activating the cell apoptosis in treatment of lung cancer with Qi deficiency and blood stasis,probably with good clinical therapeutic effect.

Effect of Yiqi Jianpi plus anticancer herbs on spleen deficiency in colorectal cancer and its anti-tumor role

Objective:To observe the effect of Yiqi Jianpi plus anticancer herbs on spleen deficiency in colorectal cancer and its anti-tumor role.Methods:Human intestinal cancer cell HT29 xenograft of nude mice model was established.The expression of ECF,VEGF,gastric cancer tumor growth in mice were observed.Results:Protein kinase C expression in in the Yiqi Jianpi group and Yiqi Jianpi anti-tumor group was significantly better than the model group(P<0.01,P<0.05).There was significantly more apoptotic cells in Yiqi Jianpi anti-tumor group than Yiqi Jianpi group and model group(P<0.01).Epidermal growth factor and vascular endothelial growth factor expression in Yiqi Jianpi group was significantly lower than Yiqi Jianpi group and model group(P<0.05).Conclusions:Tumor can inhibit the expression of PKC inhibition.Yiqi Jianpi and anticancer treatment can reduce this inhibition.Besides this treatment can also inhibit expression of tumor related genes such as epidermal growth factor and vascular endothelial growth factor.

Association between homologous recombination deficiency and outcomes with platinum and platinum-free chemotherapy in patients with triple-negative breast cancer

Objective:The choice of chemotherapeutic regimen for triple-negative breast cancer(TNBC)remains controversial.Homologous recombination deficiency(HRD)has attracted increasing attention in informing chemotherapy treatment.This study was aimed at investigating the feasibility of HRD as a clinically actionable biomarker for platinum-containing and platinum-free therapy.Methods:Chinese patients with TNBC who received chemotherapy between May 1,2008 and March 31,2020 were retrospectively analyzed with a customized 3D-HRD panel.HRD positivity was defined by an HRD score≥30 or deleterious BRCA1/2 mutation.A total of 386 chemotherapy-treated patients with TNBC were screened from a surgical cohort(NCT01150513)and a metastatic cohort,and 189 patients with available clinical and tumor sequencing data were included.Results:In the entire cohort,49.2%(93/189)of patients were identified as HRD positive(40 with deleterious BRCA1/2 mutations and 53 with BRCA1/2 intact with an HRD score of≥30).In the first-line metastatic setting,platinum therapy was associated with longer median progression-free survival(mPFS)than platinum-free therapy[9.1 vs.3.0 months;hazard ratio(HR),0.43;95%confidence interval 0.22–0.84;P=0.01].Among HRD-positive patients,the mPFS was significantly longer in those treated with platinum rather than platinum-free therapy(13.6 vs.2.0 months;HR,0.11;P=0.001).Among patients administered a platinum-free regimen,HRD-negative patients showed a PFS significantly superior to that of HRD-positive patients(P=0.02;treatment-biomarker P-interaction=0.001).Similar results were observed in the BRCA1/2-intact subset.In the adjuvant setting,HRD-positive patients tended to benefit more from platinum chemotherapy than from platinum-free chemotherapy(P=0.05,P-interaction=0.02).Conclusions:HRD characterization may guide decision-making regarding the use of platinum treatment in patients with TNBC in both adjuvant and metastatic settings.

The Continuous Relative Deficiency of Intracellular Potassium Is a Core Mechanism for the Occurrence and Metastasis of Tumor Cancer Cells

The core mechanism for occurrence of tumor cancer cells is related to the continuous relative deficiency of potassium ions in the cells of organs and tissues, which results in embryonic like proliferation and differentiation in the affected cells. The purpose of the metastasis of cancer cells is to obtain and utilize the potassium resources in other organs in body. However, if the overall potassium storage in body is obviously insufficient, the metastatic cancer cells still fail to achieve the purpose of obtaining enough potassium and turn into normal cells, further proliferation and differentiation of cancer cells will continue, and finally will lead to functional decline in the organs and tissues affected or death. Therefore, the key means to prevent and treat tumors and cancers is to ensure the normal and balanced potassium ions in cells in various organs and tissues, so as to avoid the formation of tumors and cancer cells caused by obvious deficiency of potassium ions.

Growth Hormone Replacement Therapy in Adult Growth Hormone Deficiency and Risk of Cancer: A Meta-Analysis

The growth hormone (GH) replacement therapy in adult growth hormone deficiency (AGHD) is now well developed, nevertheless, the safety of GH replacement, especially the incidence of cancer in these patients remains to be further clarified. To summarize the evidence on the safety of using GH in AGHD, we conduct this meta-analysis to assess the relationship between the risk of cancer and GH replacement therapy. Randomized controlled trials and cohort studies involved in GH therapy for AGHD were selected. Meta-analysis was performed and risk ratio (RR) was pooled with 95% confidence interval (CI) to investigate the relationship between GH replacement and the risk of cancer. The result indicated that there was no evidence to draw a conclusion that GH replacement therapy will increase the risk of cancer (P = 0.001, RR = 0.77, 95% CI [0.65, 0.90]). Meanwhile, according to the calculated analysis, the replacement therapy might even reduce the risk of cancer. Furthermore, subgroup analysis demonstrated that there was no correlation between replacement therapy of GH and the risk of cancer both in prospective and retrospective cohort design research, and in prospective group, the risk of cancer even decreased (P = 0.0002, RR = 0.71, 95%CI [0.59, 0.85]). In conclusion, our study corroborates evidence from previous studies showing that GH replacement therapy in AGHD patients would not increase the risk of cancer;instead, it might be even decrease cancer risk. The results suggested that GH replacement therapy in AGHD patients was safe.

Effects of dietary zinc deficiency on esophageal squamous cell proliferation and the mechanisms involved

BACKGROUND Dietary zinc deficiency has been shown to be associated with the development of esophageal cancer in humans,but the exact mechanism of action is not known AIM To observe the effects of dietary zinc deficiency on esophageal squamous cell proliferation.METHODS Thirty C57BL/6 mice were randomly divided into three groups:A zinc-sufficient(ZS)group,zinc-deficient(ZD)group,and zinc-replenished(ZR)group.For weeks 1–10,zinc levels in the mice diets were 30.66–30.89 mg/kg in the ZS group and 0.66–0.89 mg/kg in the ZD and ZR groups.During weeks 10–12,the ZR group was switched to the ZS diet;the other two groups had no changes in their diets.Changes in body weight,serum,and esophageal tissue zinc concentrations were assessed as well as differences in the expression of proliferating cell nuclear antigen(PCNA),mitogen-activated protein kinase p38(p38MAPK),nuclear factor kappa B(NF-κB)p105,NF-κB p65,and cyclooxygenase(COX)-2 proteins in the esophageal mucosa.RESULTS The body weight and zinc concentration in the serum and esophageal mucosa were significantly lower in the ZD and ZR groups than in the ZS group(P<0.05).In ZD mice,there was a marked proliferation of basal cells in the esophageal mucosa,resulting in a disturbance in the arrangement of basal cells in layers 2–4,a thickening of the squamous layer,and a significant increase in the expression of the above-mentioned five proteins involved in proliferation and inflammation in the esophageal mucosa.Two weeks after switching to the ZS diet,the serum zinc concentration in the ZR group increased,and the expression of PCNA,NF-κB p105,and COX-2 decreased,but the concentration of zinc in the esophageal mucosa and the structure of the esophageal mucosa did not display any significant changes CONCLUSION The ZD diet decreased the growth rate and promoted the proliferation of esophageal squamous cells in mice.The mechanism of proliferation was related to the induced overexpression of COX-2,P38,PCNA,and NF-κB(p105 and p65),and the ZR diet reduced the expression of PCNA,NF-κB p105,and COX-2,thereby reversing this process.

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.

Comprehensive analysis of gene mutations and mismatch repair in Chinese colorectal cancer patients

BACKGROUND RAS,BRAF,and mismatch repair(MMR)/microsatellite instability(MSI)are crucial biomarkers recommended by clinical practice guidelines for colorectal cancer(CRC).However,their characteristics and influencing factors in Chinese patients have not been thoroughly described.AIM To analyze the clinicopathological features of KRAS,NRAS,BRAF,and PIK3CA mutations and the DNA MMR status in CRC.METHODS We enrolled 2271 Chinese CRC patients at the China-Japan Friendship Hospital.MMR proteins were tested using immunohistochemical analysis,and the KRAS/NRAS/BRAF/PIK3CA mutations were determined using quantitative polymerase chain reaction.Microsatellite status was determined using an MSI detection kit.Statistical analyses were conducted using SPSS software and logistic regression.RESULTS The KRAS,NRAS,BRAF,and PIK3CA mutations were detected in 44.6%,3.4%,3.7%,and 3.9% of CRC patients,respectively.KRAS mutations were more likely to occur in patients with moderate-to-high differentiation.BRAF mutations were more likely to occur in patients with right-sided CRC,poorly differentiated,or no perineural invasion.Deficient MMR(dMMR)was detected in 7.9% of all patients and 16.8% of those with mucinous adenocarcinomas.KRAS,NRAS,BRAF,and PIK3CA mutations were detected in 29.6%,1.1%,8.1%,and 22.3% of patients with dMMR,respectively.The dMMR was more likely to occur in patients with a family history of CRC,aged<50 years,right-sided CRC,poorly differentiated histology,no perineural invasion,and with carcinoma in situ,stage I,or stage II tumors.CONCLUSION This study analyzed the molecular profiles of KRAS,NRAS,BRAF,PIK3CA,and MMR/MSI in CRC,identifying key influencing factors,with implications for clinical management of CRC.

Identify Non-mutational p53 Functional Deficiency in Human Cancers

An accurate assessment of p53's functional statuses is critical for cancer genomic medicine.However,there is a significant challenge in identifying tumors with non-mutational p53 inactivation which is not detectable through DNA sequencing.These undetected cases are often misclassified as p53-normal,leading to inaccurate prognosis and downstream association analyses.To address this issue,we built the support vector machine(SVM)models to systematically reassess p53's functional statuses in TP53 wild-type(TP53^(WT))tumors from multiple The Cancer Genome Atlas(TCGA)cohorts.Cross-validation demonstrated the good performance of the SVM models with a mean area under the receiver operating characteristic curve(AUROC)of 0.9822,precision of 0.9747,and recall of 0.9784.Our study revealed that a significant proportion(87%-99%)of TP53^(WT) tumors actually had compromised p53 function.Additional analyses uncovered that these genetically intact but functionally impaired(termed as predictively reduced function of p53 or TP53^(WT)-pRF)tumors exhibited genomic and pathophysiologic features akin to TP53-mutant tumors:heightened genomic instability and elevated levels of hypoxia.Clinically,patients with TP53^(WT)-pRF tumors experienced significantly shortened overall survival or progression-free survival compared to those with predictively normal function of p53(TP53^(WT)-pN)tumors,and these patients also displayed increased sensitivity to platinum-based chemotherapy and radiation therapy.

基于肿瘤微环境糖代谢低氧诱导因子-1α基因探讨气阴两虚型胃癌病机的研究进展

在过去的十几年中,肿瘤在中国已上升为致死率最高的疾病,胃肠道肿瘤在所有恶性肿瘤中发病率及致死率均位居第二,其中气阴两虚证是胃癌患者常见基本证候之一。中医认为脾为后天之本,气血生化之源,脾胃气虚,脾主运化失司,则胃阴生津无源,损及阴液,不能濡养,形成气阴两虚状态,是胃癌常见病机理论之一。在胃癌发生和发展过程中,肿瘤微环境的改变和糖代谢的重编程与气阴两虚型胃癌病机理论相契合。本文以中医理论与现代分子生物学角度相结合,聚焦基于肿瘤微环境糖代谢理论对气阴两虚型胃癌病机的探讨,旨在为中西医结合治疗胃癌的理论及临床提供价值参考。

TP53-specific mutations serve as a potential biomarker for homologous recombination deficiency in breast cancer:a clinical next-generation sequencing study

Background:TP53 mutations and homologous recombination deficiency(HRD)occur frequently in breast cancer.However,the characteristics of TP53 pathogenic mutations in breast cancer patients with/without HRD are not clear.Methods:Clinical next-generation sequencing(NGS)of both tumor and paired blood DNA from 119 breast cancer patients(BRCA-119 cohort)was performed with a 520-gene panel.Mutations,tumor mutation burden(TMB),and genomic HRD scores were assessed from NGS data.NGS data from 47 breast cancer patients in the HRD test cohort were analyzed for further verification.Results:All TP53 pathogenic mutations in patients had somatic origin,which was associated with the protein expression of estrogen receptor and progestogen receptor.Compared to patients without TP53 pathologic mutations,patients with TP53 pathologic mutations had higher levels of HRD scores and different genomic alterations.The frequency of TP53 pathologic mutation was higher in the HRDhigh group(HRD score≥42)relative to that in the HRD-low group(HRD score<42).TP53 has different mutational characteristics between the HRD-low and HRD-high groups.TP53-specific mutation subgroups had diverse genomic features and TMB.Notably,TP53 pathogenic mutations predicted the HRD status of breast cancer patients with an area under the curve(AUC)of 0.61.TP53-specific mutations,namely HRD-low mutation,HRD-high mutation,and HRD common mutation,predicted the HRD status of breast cancer patients with AUC values of 0.32,0.72,and 0.58,respectively.Interestingly,TP53 HRD-high mutation and HRD common mutation combinations showed the highest AUC values(0.80)in predicting HRD status.Conclusions:TP53-specific mutation combinations predict the HRD status of patients,indicating that TP53 pathogenic mutations could serve as a potential biomarker for poly-ADP-ribose polymerase(PARP)inhibitors in breast cancer patients.

加味逍遥散治疗乳腺癌术后情绪改变肝郁脾虚证临床观察

目的观察加味逍遥散对乳腺癌术后情绪改变肝郁脾虚证患者的临床疗效。方法将上犹县人民医院64例乳腺癌术后患者作为研究对象,各32例。对照组予心理干预,观察组加用加味逍遥散,两组均连续治疗8周。观察疗效、中医症状积分、免疫功能指标、炎症指标以及负性情绪、生活质量评分情况。结果观察组总有效率为78.12%(25/32),高于对照组的50.00%(16/32)(P<0.05)。与对照组比较,观察组炎症指标水平、负性情绪评分、中医症状积分更低,免疫功能指标、生存质量评分改善更显著(P<0.05)。两组均未出现明显不良反应(P>0.05)。结论加味逍遥散可以帮助乳腺癌术后患者提高免疫功能、缓解炎症、改善负性情绪、提高生活质量,且安全性好。

晚期非小细胞肺癌患者免疫治疗所致甲状腺功能减退症的中医证候、证素特点研究

【目的】探索晚期非小细胞肺癌(NSCLC)患者接受免疫检查点抑制剂(ICIs)治疗后出现甲状腺功能减退症(以下简称“甲减”)的中医证候特点、证素分布与组合情况以及中医证型的分布规律。【方法】选择2020年1月至2023年6月就诊于广州中医药大学附属中山中医院,经病理确诊为ⅢB-ⅣB期、表皮生长因子受体/间变性淋巴瘤激酶(EGFR/ALK)阴性、并使用ICIs治疗后出现甲减的NSCLC患者,共168例。收集患者的四诊信息,运用聚类分析总结出晚期NSCLC免疫治疗后出现甲减的中医证候特点和证型分布规律,并对不同性别、年龄段和甲减分级的中医证型分布规律进行分析。【结果】(1)168例晚期NSCLC患者接受免疫治疗后出现甲减的中医证候以虚为主,表现为咳嗽、倦怠乏力、健忘、面色少华、自汗、皮肤干燥、痰色白、懒言、头晕、夜尿多、视物模糊、形体消瘦、皮肤弹性差、纳呆恶食、嗜睡、长期食少、水肿、失眠、声低、隐痛、指甲淡白、吐痰、经常畏冷、口渴、面色?白、喜温恶凉、渴欲热饮、气喘、经常便秘、大便干结、面睑浮肿、多梦、腹胀、腰痛、排便无力等;舌脉象主要包括:舌苔薄白、舌淡红、舌边齿印、舌淡胖、舌淡、脉沉、脉滑、脉虚、尺脉弱、脉细。(2)总体病位证素以肺、脾、肾多见,病性证素以气虚、阳虚、血虚、水停多见。(3)经聚类分析,得出以下3种证型,分布频次由高到低依次为肺脾气虚证、肾阳亏虚证和气虚水停证。(4)不同年龄段的中医证型分布比较,差异有统计学意义(P<0.01)。其中,60~69岁患者以肺脾气虚为主要证型,≥70岁患者以肾阳亏虚为主要证型,<50岁患者以气虚水停证为主要证型。而不同性别、甲减等级的中医证型分布比较,差异均无统计学意义(P>0.05)。【结论】晚期NSCLC免疫治疗所致甲减患者的中医证型以肺脾气虚、肾阳亏虚、气虚水停为主,正气亏虚是其变化、发展的主要病机。临床医师应及时关注患者的症状变化,监测患者甲状腺功能指标,避免发生严重免疫治疗相关不良反应。

免疫治疗对晚期胃癌中医证型演变规律的影响

目的:观察免疫治疗对晚期胃癌(gastric cancer, GC)患者中医证型演变规律的影响。方法:共纳入58例晚期GC患者,其中腹膜转移组38例,无腹膜转移组20例,收集患者的一般资料、临床病理学特征及治疗前后中医证型。运用χ~2检验评估各项指标间的相关性,运用Kaplan-Meier法评估各种证型无进展生存期(progression-free survival, PFS)。结果:58例GC患者治疗前中医证型以痰湿凝结证、肝胃不和证为主,两种证型PFS比较,差异无统计学意义(P>0.05);治疗后以气阴两虚证、脾胃虚寒证为主,两种证型PFS比较,差异无统计学意义(P>0.05)。腹膜转移组治疗前主要证型为肝胃不和证、痰湿凝结证、气滞血瘀证;治疗后主要证型为脾胃虚寒证、气阴两虚证、气血亏虚证。无腹膜转移组治疗前主要证型为气阴两虚证、痰湿凝结证、脾胃虚寒证;治疗后主要证型为气阴两虚证、脾胃虚寒证、气血亏虚证。腹膜转移组治疗前肝胃不和证与痰湿凝结证肿瘤原发部位、分化程度、组织学、分期比较,差异并无统计学意义(P>0.05)。58例晚期GC患者PFS为(5.19±2.95)个月,其中腹膜转移组PFS为(4.22±2.77)个月,无腹膜转移组PFS为(7.02±2.40)个月,两组PFS比较,差异具有统计学意义(P<0.05)。将58例GC患者肝胃不和证、痰湿凝结证、气滞血瘀证归为实证,气阴两虚证、脾胃虚寒证、气血亏虚证归为虚证。实证与虚证PFS比较,差异无统计学意义(P>0.05)。结论:肝胃不和证和痰湿凝结证在晚期腹膜转移患者中多见,且生存期更短,免疫治疗可改善晚期GC患者中医证型的分布规律,加强对晚期GC患者中医证型的关注,并进行及早干预,有助于提高患者的生存期。

Ataxic gait following total gastrectomy for gastric cancer

A 58-year-old woman, who had undergone total gastrectomy for early gastric cancer 9 years previously, visited the outpatient clinic complaining of progressive difficulty in walking for 15 d. Laboratory examinations showed macrocytic anemia and a decreased serum vitamin B12 concentration and increased serum concentrations of folate, vitamin E and copper. Magnetic resonance imaging showed multifocal high signal intensities along the posterior column of the cervical and thoracic spinal cord. Treatment consisted of intramuscular injections of vitamin B12 for 7 d, which increased her serum level of vitamin B12 to normal. This was followed by weekly intramuscular injections of vitamin B12 for another 2 wk and oral administration of vitamin B12 three times per day. After comprehensive rehabilitation for 4 wk, she showed sufficient improvements in strength and ataxic gait, enabling her to return to her normal daily activities.

The mutational pattern of homologous recombination(HR)-associated genes and its relevance to the immunotherapeutic response in gastric cancer

Objective:Currently,there is an urgent need to identify immunotherapeutic biomarkers to increase the benefit of immune checkpoint inhibitors(ICIs)for patients with gastric cancer(GC).Homologous recombination deficiency(HRD)can modify the tumor immune microenvironment by increasing the presence of tumor-infiltrating lymphocytes and therefore might serve as a biomarker of immunotherapeutic response.We aimed to analyze the mutational pattern of HR-associated genes in Chinese patients with GC and its relevance to the tumor immune profile and clinical immunotherapeutic response.Methods:A panel of 543 cancer-associated genes was used to analyze genomic profiles in a cohort comprising 484 Chinese patients with GC.Correlations between HR gene mutations and tumor immunity or clinical outcomes were identified via bioinformatic analysis using 2 GC genomic datasets(TCGA and MSK-IMPACT).Results:Fifty-one of the 484(10.54%)patients carried at least one somatic mutation in an HR gene;ATM(16/484,3.31%)was among the most frequently mutated HR genes in the Chinese cohort.Mutations in HR genes were associated with elevated tumor mutational burden,enhanced immune activity,and microsatellite instability status.In the MSK-IMPACT cohort comprising 49 patients with stomach adenocarcinoma or gastroesophageal junction adenocarcinoma treated with ICIs,patients with HR-mut GC(n=12)had significantly better overall survival than those with HR-wt GC(n=37)(log-rank test,P<0.05).Conclusions:Our data suggest that detection of somatic mutations in HR genes might aid in identifying patients who might benefit from immune checkpoint blockade therapy.

Epigenetic reduction of DNA repair in progression to gastrointestinal cancer

Deficiencies in DNA repair due to inherited germ-line mutations in DNA repair genes cause increased risk of gastrointestinal(GI) cancer. In sporadic GI cancers, mutations in DNA repair genes are relatively rare. However, epigenetic alterations that reduce expression of DNA repair genes are frequent in sporadic GI cancers. These epigenetic reductions are also found in field defects that give rise to cancers. Reduced DNA repair likely allows excessive DNA damages to accumulate in somatic cells. Then either inaccurate translesion synthesis past the un-repaired DNA damages or error-prone DNA repair can cause mutations. Erroneous DNA repair can also cause epigenetic alterations(i.e., epimutations, transmitted through multiple replication cycles). Some of these mutations and epimutations may cause progression to cancer. Thus, deficient or absent DNA repair is likely an important underlying cause of cancer. Whole genome sequencing of GI cancers show that between thousands to hundreds of thousands of mutations occur in these cancers. Epimutations that reduce DNA repair gene expression and occur early in progression to GI cancers are a likely source of this high genomic instability. Cancer cells deficient in DNA repair are more vulnerable than normal cells to inactivation by DNA damaging agents. Thus, some of the most clinically effective chemotherapeutic agents in cancer treatment are DNA damaging agents, and their effectiveness often depends on deficient DNA repair in cancer cells. Recently, at least 18 DNA repair proteins, each active in one of six DNA repair pathways, were found to be subject to epigenetic reduction of expression in GI cancers. Different DNA repair pathways repair different types of DNA damage. Evaluation of which DNA repair pathway(s) are deficient in particular types of GI cancer and/or particular patients may prove useful in guiding choice of therapeutic agents in cancer therapy.

Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein

Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer(CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase(PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients(Check2 for the first patient and RAD51 C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency.