Correlation of human epidermal growth factor receptor 2 expression with clinicopathological characteristics and prognosis in gastric cancer

AIM:To investigate human epidermal growth factor receptor 2(HER2) gene amplification and protein expression in Chinese patients with resectable gastric cancer and the association with clinicopathological characteristics and survival.METHODS:One hundred and ninety-seven gastric cancer patients who underwent curative surgery procedures were enrolled into this study.HER2 gene amplification and protein expression were examined using fluorescence in-situ hybridization(FISH) and immunohistochemistry(IHC) analysis on formalin-fixed paraffinembedded gastric cancer samples from all patients.For scoring,Hofmann's HER2 gastric cancer scoring system was adopted.All cases showing IHC3+ or FISH positiv-ity were defined as HER2 positive.Patient clinicopathological data and survival information were collected.Finally,χ 2 statistical analysis was performed to analyze the HER2 positivity rate amongst the subgroups with different clinicopathological characteristics including;gender,age,tumor location,Lauren classification,differentiation,TNM staging,depth of invasion,lymph node metastases and distant metastasis.The probability of survival for different subgroups with different clinicopathological characteristics was calculated using the Kaplan-Meier method and survival curves plotted using log rank inspection.RESULTS:According to Hofmann's HER2 gastric cancer scoring criteria,31 cases(15.74%) were identified as HER2 gene amplified and 19 cases(9.64%) were scored as strongly positive for HER2 membrane staining(3+),25 cases(12.69%) were moderately positive(2+) and 153 cases(77.66%) were HER2 negative(0/1+).The concordance rate between IHC and FISH analyses was 88.83%(175/197).Thirty-six cases were defined as positive for HER2 gene amplification and/or protein expression,with 24 of these cases being eligible for Herceptin treatment according to United States recommendations,and 29 of these cases eligible according to EU recommendations.Highly consistent results were detected between IHC3+,IHC0/1 and FISH(73.68% and 95.42%),but low consistency was observed between IHC2+ and FISH(40.00%).The positivity rates in intestinal type and well-differentiated gastric cancer were higher than those in diffuse/mixed type and poorly-differentiated gastric cancer respectively(28.57% vs 13.43%,P = 0.0103;37.25% vs 11.64%,P < 0.0001),but were not correlated with gender,age,tumor location or TNM stage,depth of invasion,lymph node metastases and distant metastasis.In poorly-differentiated gastric cancer patients,those without lymph node metastasis showed a higher HER2 positivity rate than those with lymph node metastasis(26.47% vs 7.14%,P = 0.0021).This association was not present in thosepatients with well-differentiated gastric cancer(28.57% vs 43.33%,P = 0.2832).Within our patient cohort,26 cases were lost to follow-up.The median survival time for the remaining 171 patients was 18 mo.The median survival times of the HER2 positive and negative groups were 17 and 18.5 mo respectively.Overall survival was not significantly different between HER2-positive and negative groups(χ 2 = 0.9157,P = 0.3386),but in patients presenting well-differentiated tumors,the overall survival of the HER2-positive group was significantly worse than that of the HER2-negative group(P = 0.0123).In contrast,patients with poorly differentiated and diffuse/mixed subtype gastric cancers showed no significant differences in overall survival associated with HER2.Furthermore,the median survival time of the HER2 positive group did not show any statistically significant differences when compared to the subgroups of gender,age,tumor location,TNM classification,lymph node metastases and distant metastasis.CONCLUSION:Patients with intestinal type gastric cancer(GC),well-differentiated GC and poorly-differentiated GC without lymph node metastasis,may all represent suitable candidates for targeted therapy using Herceptin.

CLINICAL STUDY ON EFFECT OF TRIPTERYGIUM WILFORDII HOOK. F. GLYCOSIDES ON UTERINE LEIOMYOMA

Objective To observe the therapeutic effect and side reactions of Tripterygium wilfordii Hook,f. ( GTW) glycosides on patients with uterine leiomyomas. Methods 65 normally cycling women with symptomatic uterine leiomyomas received 40mg daily dose GTW for 3 to 6 months. Baseline ultrasound tests were obtained to evaluate the sizes of myomas and uterus, then repeated three and six months after treatment. Blood samples were collected to determine the hormonal levels of in the mid-follicular and mid-luteal phases of the menstrual cycles before GTW therapy and at 3~4 months and 5~6 months after treatment. Results Significant decrease in leiomy-oma volume was shown in 39 of 65 (60% ) and 28 of 40 ( 70% ) patients after 3~4 months and 5~6 months of treatment, respectively. The decrease of the volume of leiomyoma was time-dependent as while 27. 84% and 51.60% in 3~4 months and 5 ~ 6months, respectively. 25 of 65 patients had amenorrhea during the course of treatment. Tripterygium wilfordii glycosides treatment induced a significant increase in LH and FSH levels (P < 0. 01) as compared with pretreatment values. In contrary, a significant decrease in E2 and P levels (P <0. 05) was found, but no changes were observed in T and PRL levels after treatment. Conclusion Tripterygium wilfordii might serve as an effective therapeutic agent for leiomyomas with fewer side effects. A reversible inhibitory effect on the ovary by Tripterygium wilfordii glycosides may be one of the mechanisms of Tripterygium wilfordii in decreasing leiomyoma volume.

Berberine might block colorectal carcinogenesis by inhibiting the regulation of B-cell function by Veillonella parvula

Background:Colorectal carcinogenesis and progression are related to the gut microbiota and the tumor immune microenvironment.Our previous clinical trial demonstrated that berberine(BBR)hydrochloride might reduce the recurrence and canceration of colorectal adenoma(CRA).The present study aimed to further explore the mechanism of BBR in preventing colorectal cancer(CRC).Methods:We performed metagenomics sequencing on fecal specimens obtained from the BBR intervention trial,and the differential bacteria before and after medication were validated using quantitative polymerase chain reaction.We further performed Apc Min/+animal intervention tests,RNA sequencing,flow cytometry,immunohistochemistry,and enzyme-linked immunosorbent assays.Results:The abundance of fecal Veillonella parvula(V.parvula)decreased significantly after BBR administration(P=0.0016)and increased through the development from CRA to CRC.Patients with CRC with a higher V.parvula abundance had worse tumor staging and a higher lymph node metastasis rate.The intestinal immune pathway of Immunoglobulin A production was activated,and the expression of TNFSF13B(Tumor necrosis factor superfamily 13b,encoding B lymphocyte stimulator[BLyS]),the representative gene of this pathway,and the genes encoding its receptors(interleukin-10 and transforming growth factor beta)were significantly upregulated.Animal experiments revealed that V.parvula promoted colorectal carcinogenesis and increased BLyS levels,while BBR reversed this effect.Conclusion:BBR might inhibit V.parvula and further weaken the immunomodulatory effect of B cells induced by V.parvula,thereby blocking the development of colorectal tumors.Trial Registraion:ClinicalTrials.gov,No.NCT02226185.

CORRELATION BETWEEN LAMININ AND CATHEPSIN D EXPRESSIONS IN BREAST CARCINOMA

Objective： Laminin is a major glycoprotein component of basement membrance which is an important barrier to tumor cells which must be breeched before metastatic spread can occur. Proteolytic enzymes play an important role in mediating the passage of cancer cells through the basement membrane （BM） and extracellular matrix. We compared the patterns of laminin and cathepsin D （CD） expressions in a range of benign and malignant breast lesions to better understand the process of tumor progression. Methods： One hundred and sixty-two cases of breast samples comprising 18 fibroadeomas, 22 cases of fibrocystic disease, 96 cases of invasive ductal carcinoma and 26 carcinomas with intraductal components were evaluated for laminin and cathepsin D expressions by immunohistocbemical staining. Results： The prevalence of CD positivity in both neoplastic and stromal cell components were significantly higher in higher histological grade tumors compared to lower grades （P〈0.001）. Various severity of BM disruption correlated with histological grade of the carcinomas （P〈0.001）. There was a negative correlation between the laminin expression and CD presence. Conclusion： In the process of cancer cell invasion and metastasis, the basement membrane is disrupted by proteinase secreted by cancer cells, especially by stroma cells of cancer.

Mantle cell lymphoma with endobronchial involvement:A case report

BACKGROUND Mantle cell lymphoma(MCL)is a subtype of Non-Hodgkin’s lymphoma(NHL).MCL frequently affects extranodal sites while endobronchial involvement is uncommon.Only 5 cases of MCL with endobronchial involvement have been previously reported.CASE SUMMARY A 56-year-old male patient arrived at the hospital complaining of a dry cough.A mass in the right upper lobe of the lung was revealed in Chest computed tomography(CT).Right lung hilar and mediastinal lymphadenopathies were also found by CT scan.The patient was diagnosed with central-type lung cancer with multiple lymph node metastases after positron emission tomography(PET)CT scan examination.The fiber optic bronchoscope examination revealed diffuse neoplasm infiltration in the inlet of the right up lobar bronchus.The patient was finally diagnosed with MCL based on the bronchoscopy and mediastinoscopy biopsy results.CONCLUSION MCL could masquerade as central type lung cancer.An endobronchial biopsy examination is necessary for the early diagnosis of MCL.

Primary malignant melanoma of esophagus at esophagogastric junction: case report

Primary malignant melanoma of the esophagus is a raretumor that accounts for only 0.1％ of primary esophagealneoplasms. Although it was once thought that primarymelanoma could not arise in the esophagus hecause of thelack of precursor cells, it has since been shown inautopsy series that 4％-8％ of individuals havemelanoblasts in the esophageal mucosa.~2 To date,approximately 200 cases of primary esophageal malignantmelanoma have been reported in global literatures whileless than 20 cases of primary esophageal malignantmelanoma have been reported in China.2-4In this reportwe present a case of primary malignant melanoma of theesophagus in a Chinese man.

Guided chemotherapy based on patient-derived mini-xenograft models improves survival of gallbladder carcinoma patients

Background:Gallbladder carcinoma is highly aggressive and resistant to chemotherapy,with no consistent strategy to guide first line chemotherapy.However,patient-derived xenograft(PDX)model has been increasingly used as an effective model for in preclinical study of chemosensitivity.Methods:Mini-PDX model was established using freshly resected primary lesions from 12 patients with gallblad-der to examine the sensitivity with five of the most commonly used chemotherapeutic agents,namely gemcitabine,oxaliplatin,5-fluorouracil,nanoparticle albumin-bound(nab)-paclitaxel,and irinotecan.The results were used to guide the selection of chemotherapeutic agents for adjunctive treatment after the surgery.Kaplan-Meier method was used to compare overall survival(OS)and disease free survival(DFS)with 45 patients who received conventional chemo-therapy with gemcitabine and oxaliplatin.Results:Cell viability assays based on mini-PDX model revealed significant heterogeneities in drug responsiveness.Kaplan-Meier analysis showed that patients in the PDX-guided chemotherapy group had significantly longer median OS(18.6 months;95%CI 15.9-21.3 months)than patients in the conventional chemotherapy group(13.9 months;95%CI 11.7-16.2 months)(P=0.030;HR 3.18;95%CI 1.47-6.91).Patients in the PDX-guided chemotherapy group also had significantly longer median DFS(17.6 months;95%CI 14.5-20.6 months)than patients in the conventional chemotherapy group(12.0 months;95%CI 9.7-14.4 months)(P=0.014;HR 3.37;95%CI 1.67-6.79).Conclusion:The use of mini-PDX model to guide selection of chemotherapeutic regimens could improve the out-come in patients with gallbladder carcinoma.

Predictors of outcome in the surgical treatment for epilepsy

Background Knowledge about factors influencing the prognosis of resective epilepsy surgery can be used to identify which patients are most suitable for surgical treatment. The aim of this study was to identify preoperative prognostic factors associated with the chance of achieving long-term seizure freedom. Methods We retrospectively reviewed seizure outcomes and clinical, electroencephalography （EEG）, magnetic resonance imaging （MRI）, histopathology, and surgical variables from 99 epilepsy surgery patients with at least one year of postoperative follow-up. Seizure outcomes were categorized based on the modified classification by the International League Against Epilepsy. Results We found that the seizure-free rate was 27.9% after one year, and that it stabilized at about 20.0% between two and six years after surgery. Univariate analysis showed that medial temporal lobe epilepsy with hippocampal sclerosis, MRI with visible focal lesions concordant with EEG, and regional ictal EEG and electrocorticography patterns were associated with a favorable surgical outcome. On the other hand, seizure recurrence within six months, incomplete focus resection, and surgical complications were associated with a poor outcome. Multivariate analysis showed that medial temporal lobe epilepsy with hippocampal sclerosis and MRI with visible focal lesions were independent presurgical predictors of a favorable outcome （P 〈0.01）. Seizure recurrence within six months was the only significant independent predictor associated with a poor outcome （P〈0.01）. Conclusion Hippocampal sclerosis and abnormal MRI findings are strongly associated with a favorable surgical outcome, whereas seizure recurrence within six months is associated with a poor outcome.

Antibody-activated trans-endothelial delivery of mesoporous organosilica nanomedicine augments tumor extravasation and anti-cancer immunotherapy

Tumor vasculature constitutes a formidable hurdle for the efficient delivery of cancer nanomedicine into tumors.The leverage of passive pathway through inter-endothelial gaps in tumor blood vessels might account for limited extravasation of nanomedicine into tumor microenvironment(TME).Herein,Annexin A1 antibody-installed mesoporous organosilica nanoplatforms carrying immunotherapeutics of anti-PD-L1 antibody(aPD-L1)and Indoximod are developed to target at caveolar Annexin-A1 protein of luminal endothelial cells and to trigger the active trans-endothelial transcytosis of nanomedicine mediated by caveolae.Such strategy enables rapid nanomedicine extravasation across tumor endothelium and relatively extensive accumulation in tumor interstitium.aPD-L1 and Indoximod release from aPD/IND@MON-aANN in a reduction-responsive manner and synergistically facilitate the intratumoral infiltration of cytotoxic T lymphocytes and reverse the immunosuppressive TME,thus demonstrating substantial anti-tumor efficacy in subcutaneous 4T1 breast tumors and remarkable anti-metastatic capacity to extend the survival of 4T1 tumor metastasis model.Moreover,aPD/IND@MON-aANN nanomedicine also exhibits distinct superiority over the combination therapy of free drugs to potently attenuate the progression of urethane-induced orthotopic lung cancers.Collectively,aPD/IND@MON-aANN nanoplatforms with boosted delivery efficiency via antibody-activated trans-endothelial pathway and enhanced immunotherapeutic efficacy provides perspectives for the development of cancer nanomedicines.

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].

SUV39H1 deficiency suppresses clear cell renal cell carcinoma growth by inducing ferroptosis

Clear cell renal cell carcinoma(ccRCC)is a common kidney malignancy characterized by a poor prognosis.Suppressor of variegation 3-9 homolog 1(SUV39H1),which encodes a histone H3 lysine 9 methyltransferase,has been reported to act as an oncogene in many cancers.However,it is unclear whether SUV39H1 is involved in ccRCC.Here,we report that SUV39H1 expression is frequently upregulated in ccRCC tumors and is significantly correlated with ccRCC progression.SUV39H1 expression level is an independent risk factor for cancer prognosis,and integration with several known prognostic factors predicted ccRCC patient prognosis with improved accuracy than the conventional SSIGN(stage,size,grade and necrosis)prognostic model.Mechanistically,we discovered that siRNA knockdown or pharmacological inhibition of SUV39 H1 induced iron accumulation and lipid peroxidation,leading to ferroptosis that disrupted ccRCC cell growth in vitro and in vivo.We also show that SUV39H1 deficiency modulated the H3K9me3 status of the DPP4(dipeptidyl-peptidase-4)gene promoter,resulting in upregulation of its expression that contributes to ferroptosis.Taken together,our findings provide the mechanistic insight into SUV39H1-dependent epigenetic control of ccRCC tumor growth and indicate that SUV39H1 may serve as a potential therapeutic target for ccRCC treatment.

Peripheral monocyte count： an independent diagnostic and prognostic biomarker for prostate cancer - a large Chinese cohort study

Increasing evidence indicates that inflammation may play important roles in tumorigenesis and progression, and an elevated peripheral monocyte count predicts a poor prognosis in various types of malignancies. Here, we evaluate the roles of peripheral monocyte count in the diagnosis and prognosis for prostate cancer in Chinese patients. A total of 1107 consecutive patients who had undergone prostate biopsy and 290 prostate cancer patients receiving androgen deprivation therapy as first-line therapy were retrospectively analyzed. The parameters were measured at the time of diagnosis. Univariate and multivariate logistic regression analyses were performed to identify the independent predictors of a positive biopsy. Patients were categorized in two groups using a cutoff point of 0.425 x 109 1-1 as calculated by the receiver-operating curve analysis for prognosis. Univariate and multivariate Cox regression analyses were performed to determine the associations of monocyte count with progression-free survival, cancer-specific survival, and overall survival. Multivariate logistic regression analyses showed that monocyte count, age, prostate-specific antigen （PSA）, free/total PSA, and prostate volume were independent predictors for prostate cancer. Multivariate Cox regression analyses identified an elevated monocyte count as an independent prognostic factor for worse cancer-specific survival （hazard ratio = 2.244, P 〈 0.05） and overall survival （hazard ratio = 1.995, P 〈 0.05）, but not progression-free survival （P = 0.117）. Our results indicated that an elevated monocyte count was an independent diagnostic biomarker for prostate cancer, and pretreatment peripheral monocyte count might play a significant role in the prognosis of prostate cancer patients treated with androgen deprivation therapy.

Risk SNP-induced lncRNA-SLCCl drives colorectal cancer through activating glycolysis signaling

Long non-coding RNAs(lncRNAs)play key roles in colorectal carcinogenesis.Here,we aimed to identify the risk SNP-induced lncRNAs and to investigate their roles in colorectal carcinogenesis.First,we identified rs6695584 as the causative SNP in 1 q41 locus.The A>G mutation of rs6695584 created a protein-binding motif of BATF,altered the enhancer activity,and subsequently activated IncSLCCl expression.Further validation in two independent CRC cohorts confirmed the upregulation of IncSLCCl in CRC tissues,and revealed that increased IncSLCCl expression was associated with poor survival in CRC patients.Mechanistically,lncRNA-SLCCl interacted with AHR and transcriptionally activated HK2 expression,the crucial enzyme in glucose metabolism,thereby driving the glycolysis pathway and accelerating CRC tumor growth.The functional assays revealed that IncSLCCl induced glycolysis activation and tumor growth in CRC mediated by HK2.In addition,HK2 was upregulated in colorectal cancer tissues and positively correlated with IncSLCCl expression and patient survival.Taken together,our findings reveal a risk SNP-mediated oncogene lncRNA-SLCCl promotes CRC through activating the glycolysis pathway.

Patient-derived organoids potentiate precision medicine in advanced clear cell renal cell carcinoma

To investigate the role of patient-derived organoid(PDO)model in the precision medicine of advanced clear cell renal cell carcinoma(ccRCC),we retrospectively analyzed the clinical data of seven cases of ccRCC diagnosed by operation and pathology in Renji Hospital from September 2021 to September 2022.The seven patients were diagnosed with advanced ccRCC with or without remote metastasis.Cytoreductive and radical nephrectomy was performed respectively.To predict the response to immunotherapy and provide personalized medicine recommendation,a PDO model based on air-liquid interface system was established from the surgical resected tumor and subsequent drug screening was performed.Hematoxylin and eosin(H&E)staining and immunohistochemistry revealed that the PDO recapitulated the histological feature of parent tumor.Immunofluorescence staining identified that CD3^(+)T cells,SMA^(+)cancer associated fibroblasts,and CD31^(+)endothelial cells were preserved in PDO models.Fluorescence activated cell sorter(FACS)revealed an evidently increased ratio of CD8^(+)/CD4^(+)T cells and apoptotic tumor cells in PDO treated with toripalimab than those treated with IgG4.The results showed that toripalimab is able to rescue the excessive death of CD8^(+)T cells by critically reversing the immune exhaustion state of ccRCC in PDO model.This research validated that PDO is a promising and faithful preclinical model for prediction of immunotherapy response in patients with ccRCC.