Genomic profiling of colorectal cancer in large-scale Chinese patients:amplification and somatic mutations in ERBB2

Objectives:Human epidermal growth factor receptor 2(HER2)-targeted therapies have demonstrated potential benefits for metastatic colorectal cancer(mCRC)patients with HER2 amplification,but are not satisfactory in cases of HER2 mutant CRCs.Methods:Consequently,further elucidation of amplifications and somatic mutations in erythroblastic oncogene B-2(ERBB2)is imperative.Comprehensive genomic profiling was conducted on 2454 Chinese CRC cases to evaluate genomic alterations in 733 cancer-related genes,tumor mutational burden,microsatellite instability,and programmed death ligand 1(PD-L1)expression.Results:Among 2454 CRC patients,85 cases(3.46%)exhibited ERBB2 amplification,and 55 cases(2.24%)carried ERBB2 mutation.p.R678Q(28%),p.V8421(24%),and p.S310F/Y(12%)were the most prevalent of the 16 detected mutation sites.In comparison to the ERBB2 altered(alt)group,KRAS/BRAF mutations were more prevalent in ERBB2 wild-type(wt)samples(ERBB2wt vs.ERBB2alt,KRAS:50.9%vs.25.6%,p<0.05;BRAF:8.5%vs.2.3%,p<0.05).32.7%(18/55)of CRCs with ERBB2 mutation exhibited microsatellite instability high(MSI-H),while no cases with HER2 amplification displayed MSI-H.Mutant genes varied between ERBB2 copy number variation(CNV)and ERBB2 single nucleotide variant(SNV);TP53 alterations tended to co-occur with ERBB2 amplification(92.3%)as opposed to ERBB2 mutation(58.3%).KRAS and PIK3CA alterations were more prevalent in ERBB2 SNV cases(KRAS/PIK3CA:45.8%/31.2%)compared to ERBB2 amplification cases(KRAS/PIK3CA:14.1%/7.7%).Conclusion:Our study delineates the landscape of HER2 alterations in a large-scale cohort of CRC patients from China.These findings enhance our understanding of the molecular features of Chinese CRC patients and offer valuable implications for further investigation.

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.

Bladder preservation in complicated invasive urothelial carcinoma following treatment with cisplatin/gemcitabine plus tislelizumab:A case report

BACKGROUND Invasive urothelial carcinoma(UC)with squamous and glandular differentiation is a highly malignant and complicated pathological subtype,and the standard care is radical cystectomy(RC).However,urinary diversion after RC significantly reduces patient quality of life,thus bladder-sparing therapy has become a research hotspot in this field.Recently,five immune checkpoint inhibitors have been approved for systemic therapy of locally advanced or metastatic bladder cancer by the Food and Drug Administration,but the efficacy of immunotherapy combined with chemotherapy for invasive UC is still unknown,especially for pathological subtypes with squamous and glandular differentiation.CASE SUMMARY We report the case of a 60-year-old male who complained of repetitive painless gross hematuria and was diagnosed with muscle-invasive bladder cancer with squamous and glandular differentiation,defined as cT3N1M0 according to the American Joint Committee on Cancer,who had a strong desire to preserve the bladder.Immunohistochemical staining revealed that programmed cell deathligand 1(PD-L1)expression in the tumor was positive.Thus,a transurethral resection to maximize removal of the bladder tumor was performed under cystoscopy,and the patient subsequently received a combination of chemotherapy(cisplatin/gemcitabine)and immunotherapy(tislelizumab)treatment.No tumor recurrence in the bladder was observed following pathological and imaging examination after 2 cycles and 4 cycles of treatment,respectively.The patient achieved bladder preservation and has been tumor-free for more than two years.CONCLUSION This case shows that the combination of chemotherapy and immunotherapy might be an effective and safe treatment strategy for PD-L1 expression positive UC with divergent histologic differentiation.

Response of BRCA1-mutated gallbladder cancer to olaparib: A case report

gallbladder cancer(gbc), although considered as a relatively rare malignancy, is the most common neoplasm of the biliary tract system. the late diagnosis and abysmal prognosis present challenges to treatment. the overall 5-year survival rate for metastatic gbc patients is extremely low. BRC A1 and BRCA2 are the breast cancer susceptibility genes and their mutation carriers are at a high risk for cancer development, both in men and women. Olaparib, an oral poly ADP-ribose polymerase inhibitor, has been approved by the Food and Drug Administration and the European commission for the treatment of ovarian cancer with any BRCA1/2 mutations. the first case of BRCA1-mutated gbc patient who responded to olaparib treatment is reported here.

Blood exosomal micro ribonucleic acid profiling reveals the complexity of hepatocellular carcinoma and identifies potential biomarkers for differential diagnosis

BACKGROUND Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related deaths worldwide,but there is a shortage of effective biomarkers for its diagnosis.AIM To explore blood exosomal micro ribonucleic acids(miRNAs)as potential biomarkers for HCC diagnosis.RESULTS The principal component analysis suggested that daily alcohol consumption could alter the blood exosomal miRNA profiles of hepatitis B virus positive non-HCC patients through miR-3168 and miR-223-3p.The miRNA profiles also revealed the tumor stages of HCC patients.High expression of miR-455-5p and miR-30c-5p,which significantly correlated with better overall survival in tumor tissues,could also be detected in blood exosomes.Two pairs of miRNAs(miR-584-5p/miR-106-3p and miR-628-3p/miR-941)showed a 94.1%sensitivity and 68.4%specificity to differentiate HCC patients from non-HCC patients.The specificity of the combination was substantially influenced by alcohol consumption habits.CONCLUSION This study suggested that blood exosomal miRNAs can be used as new noninvasive diagnostic tools for HCC.However,their accuracy could be affected by tumor stage and alcohol consumption habits.

Treatment with sorafenib plus camrelizumab after splenectomy for primary splenic angiosarcoma with liver metastasis:A case report and literature review

BACKGROUND Primary splenic angiosarcoma(PSA)is an extremely rare and aggressive mesenchymal malignancy with high metastatic potential and a poor prognosis.There are no established treatment guidelines for PSA,even for adjuvant therapy.This rare case may provide a reliable therapeutic regime for a better prognosis.CASE SUMMARY A 49-year-old female who complained of right-upper quadrant abdominal pain was diagnosed as having PSA with splenic rupture and liver metastasis.After splenectomy and liver tumor resection,she received sorafenib and camrelizumab therapy.After 15 mo of follow-up,she is in good condition,without recurrence or any identified metastasis.CONCLUSION Immunotherapy combined with targeted therapy could be a potential option for the adjuvant therapy of PSA.

Siblings with coronavirus disease 2019 infection and opposite outcome—the hemodialysis’s better outcome paradox:Two case reports

BACKGROUND Coronavirus disease 2019(COVID-19)is a highly contagious infection caused by the severe acute respiratory syndrome coronavirus 2 virus and has a unique underlying pathogenesis.Hemodialysis(HD)patients experience high risk of contamination with COVID-19 and are considered to have higher mortality rates than the general population by most but not all clinical series.We aim to highlight the peculiarities in the immune state of HD patients,who seem to have both immune-activation and immune-depression affecting their outcome in COVID-19 infection.CASE SUMMARY We report the opposite clinical outcomes(nearly asymptomatic course vs death)of two diabetic elderly patients infected simultaneously by COVID-19,one being on chronic HD and the other with normal renal function.They were both admitted in our hospital with COVID-19 symptoms and received the same treatment by protocol.The non-HD sibling deteriorated rapidly and was intubated and transferred to the Intensive Care Unit,where he died despite all supportive care.The HD sibling,although considered more“high-risk”for adverse outcome,followed a benign course and left the hospital alive and well.CONCLUSION These cases may shed light on aspects of the immune responses to COVID-19 between HD and non-HD patients and stimulate further research in pathophysiology and treatment of this dreadful disease.

Response of human epidermal growth factor receptor 2-positive colorectal cancer to lapatinib monotherapy: A case report

BACKGROUND Human epidermal growth factor receptor 2(HER2)amplification is a molecular driver for a subset of colorectal cancers(CRCs)and one of the major causes of anti-epidermal growth factor receptor(EGFR)treatment failure.Compared to dual anti-HER2 treatments,which have been shown to be effective in HER2-positive metastatic CRC patients,single-agent anti-HER2 therapy is rarely used to treat CRC.CASE SUMMARY Herein,we report a case of RAS/BRAF-wild-type metastatic CRC that was identified as HER2-positive through circulating tumor DNA(ctDNA)testing by next-generation sequencing following the failure of two lines of therapy.Subsequently,the patient was given lapatinib monotherapy that led to a partial response with a progression-free survival of 7.9 mo.Moreover,serial ctDNA detection was used to monitor the efficacy of lapatinib.The aberration of HER2 copy number disappeared when radiographic assessment revealed a partial response.However,a high level of HER2 amplification was detected again at the time of disease progression.Finally,a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha mutation was identified at the time of tumor progression,which may explain the acquired resistance to lapatinib.CONCLUSION This is the first case report of HER2-positive RAS/BRAF wild-type metastatic CRC patient responding to lapatinib monotherapy.It highlights that ctDNA testing is an effective and feasible approach to evaluate the efficacy of anti-HER2 therapy.

FGFR2-TSC22D1,a novel FGFR2 fusion gene identified in a patient with colorectal cancer:A case report

BACKGROUND The FGFR signaling pathway is activated in multiple tumor types through gene amplifications,single base substitutions,or gene fusions.Novel FGFR gene fusions may represent candidate targets for the development of tyrosine kinase inhibitors.CASE SUMMARY Herein,we report a patient with colorectal cancer(CRC)harboring a novel FGFR2 fusion gene.A 59-year-old man felt discomfort in his right upper abdomen with loss of appetite for 6 mo.An abdominal computed tomography scan revealed the existence of a space-occupying lesion in the ascending colon.The pathological diagnosis was a poorly differentiated adenocarcinoma.Subsequent biopsy specimen was subjected to next-generation sequencing analysis,and a novel FGFR2-TSC22D1 fusion with complete kinase structure of FGFR2 protein was identified.CONCLUSION We report the first case of CRC harboring FGFR2-TSC22D1,which enriches the FGFR2 fusion spectrum.FGFR2 inhibitors might be effective in the later treatment for this patient.

Efficacy of afatinib in a patient with rare EGFR(G724S/R776H)mutations and amplification in lung adenocarcinoma:A case report

BACKGROUND The most common EGFR mutations are in-frame deletions in exon 19 and point mutations in exon 21.Cases with classical EGFR mutations show a good response to EGFR tyrosine kinase inhibitors(TKIs),the standard first-line treatment.With the development of next generation sequencing,some uncommon genomic mutations have been detected.However,the effect of TKIs on such uncommon EGFR mutations remains unclear.CASE SUMMARY Here,we report a case of rare EGFR co-mutation in non-small cell lung cancer and the efficacy of afatinib on this EGFR co-mutation.A 64-year-old woman was diagnosed with thoracolumbar and bilateral local rib bone metastases,bilateral pulmonary nodules,and pericardial and left pleural effusion.The pathological diagnosis was lung adenocarcinoma.To seek potential therapeutic regimens,rare co-mutation comprising rare EGFR G724S/R776H mutations and amplification were identified.The patient experienced a significant clinical response with a progression-free survival of 17 mo.CONCLUSION A case of non-small cell lung cancer with rare EGFR G724S/R776H mutations and EGFR amplification responds well to TKI treatment.

Genetic and immunologic characteristics of colorectal cancer patients with KRAS mutations and predictive significance of tumor immune microenvironment in adjuvant chemotherapy

Colorectal cancer(CRC)is one of the most common cancers around the world,and it is one of the leading causes of cancer-related death.1 Although anti-EGFR therapy and immune checkpoint inhibitor(ICl)therapy are becoming more and more important for colorectal therapy,however,clinical outcomes of current treatments for metastatic CRC,especially with ICls,have been shown to be affected by the status of KRAS.Therefore,KRAS mutation status detection has become a very important diagnostic factor for managing metastatic CRC patients.

First-line camrelizumab(a PD-1 inhibitor)plus apatinib(an VEGFR-2 inhibitor)and chemotherapy for advanced gastric cancer(SPACE):a phase 1 study

Patients with advanced gastric cancer typically face a grim prognosis.This phase 1a(dose escalation)and phase 1b(dose expansion)study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapyfor advanced gastric or gastroesophageal junction adenocarcinoma.The primary endpoints included maximum tolerated dose(MTD)in phase 1a and objective response rate(ORR)across phase 1a and 1b.Phase 1a tested three dose regimens of camrelizumab,apatinib,oxaliplatin,and S-1.Dose regimen 1:camrelizumab 200 mg on day 1,apatinib 250 mg every other day,oxaliplatin 100 mg/m^(2) on day 1,and S-140 mg twice a day on days 1-14.Dose regimen 2:same as dose regimen 1,but oxaliplatin 130mg/m.Dose regimen3:same as dose regimen 2,but apatinib 250 mg daily.Thirty-four patients were included(9 in phase 1a,25 in phase 1b).No dose-limiting toxicities occurred so no MTD was identified.Dose 3 was set for the recommended phase 2 doses and administered in phase 1b.The confrmed ORR was 76.5%(95%CI 58.8-89.3).The median progression-free survival was 8.4 months(95%CI 5.9-not evaluable[NE]),and the median overall survival(OS)was not mature(11.6-NE).Ten patients underwent surgery after treatment and the multidisciplinary team evaluation.Among 24 patients without surgery,the median OS was 19.6 months(7.8-NE).Eighteen patients(52.9%)developed grade≥3 treatment-emergent adverse events.Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer(ChiCTR2000034109).

Benefit of everolimus in treatment of an intrahepatic cholangiocarcinoma patient with a PIK3CA mutation

Intrahepatic cholangiocarcinoma(ICC) is a relatively rare form of liver cancer with a poor prognosis. The therapeutic options for patients with advanced ICC are limited and usually ineffective. There is currently no approved targeted therapy for ICC, although accumulating evidence supports inhibition of the PI3K/Akt/m TOR signaling pathway as a promising therapeutic strategy in the treatment of ICC. Here, we report a patient with stage IV ICC harboring a PIK3 CA mutation who responded well to the m TOR inhibitor everolimus. Computed tomography and magnetic resonance imaging demonstrated shrinkage of the tumor and maintenance of a partial response for 6.5 mo after everolimus treatment as the best response. To the best of our knowledge, this is the first clinical case report in the literature of clinical benefit from everolimus treatment in an ICC patient with PIK3 CA mutation.

Importance of Wolbachia-mediated biocontrol to reduce dengue in Bangladesh and other dengue-endemic developing countries

Mosquito-borne diseases,particularly dengue and chikungunya have become global threats,infecting millions of people worldwide,including developing countries of Southeast Asia and Latin America.Bangladesh,like many other developing countries,is experiencing frequent dengue outbreaks.This article,therefore,critically discussed the current status of dengue disease,vector control approaches,and the need for Wolbachia-mediated intervention in Bangladesh and other dengue-endemic developing countries.In this narrative review study,rel-evant literature was searched from major databases and search engines such as PubMed,BanglaJol,World Health Organization(WHO)/European Centre for Disease Prevention and Control(ECDC)and Google Scholar.Considering the selection criteria,our search strategies finally involved 55 related literature for further investigation.Findings showed that current vector control strategies could not render protection for an extended period,and the disease burden of arboviruses is increasing.The impoverished outbreak preparedness,urbanization,climate change,and less efficacy of existing control methods have made people susceptible to vector-borne diseases.Hence,Wolbachia,a naturally occurring endosymbiont of many mosquito species that can potentially limit virus transmission through several host genetic alterations,would be a potential alterna-tive for dengue prevention.We also critically discussed the challenges and prospects of Wolbachia-based den-gue control in developing countries.The evidence supporting the efficacy and safety of this intervention and its mechanism have also been elucidated.Empirical evidence suggests that this introgression method could be an eco-friendly and long-lasting dengue control method.This review would help the policymakers and health experts devise a scheme of Wolbachia-based dengue control that can control mosquito-borne diseases,partic-ularly dengue in Bangladesh and other developing countries.

The Potential Effects and Use of Chinese Herbal Medicine Pine Pollen(Pinus pollen):A Bibliometric Analysis of Pharmacological and Clinical Studies

The objectives of this study are to conduct a comprehensive literature search and bibliometric analysis to identify the breadth and volume of pharmacological and clinical studies on pine pollen(Pinus pollen)and to identify the potential effects and the use of pine pollen.Three Chinese electronic databases and two English electronic databases were searched for pharmacological and clinical studies on pine pollen.Data were extracted and analyzed and included publication year,authors,study type,pharmacological research topics or clinical diseases/conditions,usage and type of preparation,authors’conclusions,and adverse effects.Of 239 publications identified,180 were pharmacological studies,37 were clinical trials,and 22 were reviews.Numbers of publications increased particularly from 2004 onward.The top 10 most frequent topics in pharmacological studies were immune regulation,antisenility,antioxidation,liver protection,inhibiting prostate hyperplasia,inhibiting tumor cell proliferation,lowering blood glucose,lowering blood lipids,antifatigue,and improving intestinal function.The top 10 most frequent clinical diseases treated or where pine pollen was used as an adjuvant were bedsores,diaper dermatitis,hyperlipidemia,oral mucositis,eczema,hyperplasia of prostate,hypertension,prostatitis,type 2 diabetes mellitus,and radiodermatitis.Eight trials reported no adverse events associated with pine pollen,one reported mild gastrointestinal reactions,but symptoms disappeared without special management.There have been an increasing number of publications on pine pollen during the past 20 years.Pharmacological studies have shown many potential benefits,and clinical studies have indicated some positive effects when it is either used as a single herb or as an adjuvant to treat disease.Its use as a topical agent,especially for skin diseases,was notable.

Characterization of DNA damage response deficiency in pancreatic cancer patients from China

To the editor,Pancreatic ductal adenocarcinoma(PDAC)has the worst prognosis among all common malignant solid tumors,with a 5-year overall survival(OS)rate of less than 10%[1].Few effective targets for anticancer ther-apy have been confirmed in pancreatic cancer.Recently,it was substantiated that pancreatic cancer patients carry-ing deleterious mutations of the DNA damage response(DDR)genes are more likely to benefit from platinum-based chemotherapy[2]and poly(adenosine diphosphate-ribose)polymerase(PARP)inhibitor[3].

A case report of response to crizotinib in chemotherapy-refractory metastatic gallbladder cancer with met amplification and acquired resistance resulting from the loss of MET amplification

Gallbladder cancer(GBC)is a highly invasive disease and the most prevalent malignancy of the biliary system.Patients with GBC are commonly diagnosed at a late stage and have an unfavorable prognosis.Palliative chemotherapy has been the standard care for recurrent or metastatic disease in the past decades.Recently,several targeted therapies have been investigated in advanced biliary tract cancer(BTC)including inhibitors of genes or pathways such as FGFR2 fusions or rearrangements,IDH1 mutations,and NTRK gene fusions.Also,several clinical studies involving molecular stratification have been performed in defined patient groups,for example,BRAF V600E and HER2.Mesenchymal epithelial transition(MET)encodes a tyrosine kinase receptor and its ligand hepatocyte growth factor is a proto-oncogene.Targeting the MET signaling pathway is an effective strategy in numerous cancer types.However,the poor efficacy of MET inhibitors has been demonstrated in several phase II studies,but currently no reports have explained the potential mechanisms of resistance to MET inhibitors in BTC.In this article,we report a case of metastatic GBC with MET amplification that exhibited a rapid response to crizotinib after the failure of two lines of chemotherapy.After the patient had progressed and discontinued crizotinib,cabozantinib was introduced.Analysis of circulating tumor DNA(ctDNA)by nextgeneration sequencing(NGS)indicated a loss of MET amplification status.To our knowledge,this is the first case study demonstrating the use of NGS in ctDNA to monitor the development of acquired resistance during anti-MET treatment in GBC.

Clinical Study on Therapeutic Effect of Shuwei Decoction (舒胃汤) on Functional Dyspepsia

Objective: To explore the clinical effectiveness and therapeutic mechanism of Shuwei Decoction (舒胃汤) in treating functional dyspepsia (FD). Methods: A total of 124 FD patients were randomly divided into two groups: Shuwei Decoction group (60 cases) and the control group (64 cases) treated with cisapride. After one month treatment, all patients were examined with motilin and electrogastrography (EGG). Results: The therapeutic effectiveness of Shuwei Decoction group was much better than that of the control group ( P <0.05), while the changes on motilin and EGG in the two groups were relatively similar ( P <0.05). Conclusion: Shuwei Decoction could effectively raise motilin level, promote gastric movement and improve the clinical symptoms in FD patients.

用于结直肠癌预后评估和精准免疫治疗的肿瘤免疫微环境转录组学分型

背景:基于免疫环境的生物学标志物或许可以指导预后评估。T细胞失活、T细胞排斥以及T细胞功能障碍均会损害肿瘤微环境进而影响免疫治疗的效果及预后。然而,截至目前尚未见利用免疫相关生物标记物来对结直肠癌患者进行分类的报道。因此,本研究旨在根据肿瘤微环境中的T细胞失活、T细胞排斥和T细胞功能障碍的程度来对结直肠癌患者进行分类。方法:通过肿瘤免疫功能障碍和排斥(TIDE)算法,对TCGA数据库中的618例结直肠癌患者的RNAseq数据和GEO数据库中的316例结直肠癌患者的基因芯片数据进行分析。采用无监督聚类法对患者进行分类。结果:基于骨髓来源抑制细胞、癌相关成纤维细胞、M2型肿瘤相关巨噬细胞、细胞毒性T细胞和PD-L1的表达,将患者聚类分为4型:1型为高度免疫功能障碍,2型为低度免疫激活,3型为强烈免疫排斥,4型为高度免疫激活、中度免疫功能障碍及中度免疫排斥。多因素Cox分析结果显示,与1型相比,2、3、4型患者总体生存的风险比(95%可信区间)分别为0.63(0.35-1.13)、0.55(0.29-1.03)和0.30(0.14-0.64)。利用GSE39582队列进行验证,也得到了相似的聚类分型和预后模式。亚组分析中,在I/II期、微卫星稳定和未接受辅助治疗的患者中,免疫聚类分型与总体生存显著相关。结论:本研究结果表明,免疫分型可作为结直肠癌患者一项可靠的预后指标,且有助于个体化免疫治疗的病例选择。