A nomogram to predict Gleason sum upgrading of clinically diagnosed localized prostate cancer among Chinese patients

Although several models have been developed to predict the probability of Gleason sum upgrading between biopsy and radical prostatectomy specimens,most of these models are restricted to prostatespecific antigen screening-detected prostate cancer.This study aimed to build a nomogram for the prediction of Gleason sum upgrading in clinically diagnosed prostate cancer.The study cohort comprised 269 Chinese prostate cancer patients who underwent prostate biopsy with a minimum of 10 cores and were subsequently treated with radical prostatectomy.Of all included patients,220(81.8%) were referred with clinical symptoms.The prostate-specific antigen level,primary and secondary biopsy Gleason scores,and clinical T category were used in a multivariate logistic regression model to predict the probability of Gleason sum upgrading.The developed nomogram was validated internally.Gleason sum upgrading was observed in 90(33.5%) patients.Our nomogram showed a bootstrap-corrected concordance index of 0.789 and good calibration using 4 readily available variables.The nomogram also demonstrated satisfactory statistical performance for predicting significant upgrading.External validation of the nomogram published by Chun et al.in our cohort showed a marked discordance between the observed and predicted probabilities of Gleason sum upgrading.In summary,a new nomogram to predict Gleason sum upgrading in clinically diagnosed prostate cancer was developed,and it demonstrated good statistical performance upon internal validation.

Two novel germline mutations of MLH1 and investigation of their pathobiology in hereditary non-polyposis colorectal cancer families in China

AIM： To detect germline mutations of MLH1, and investigate microsatellite instability and expression of MLH1 in tumor tissues of hereditary non-polyposis colorectal cancer （HNPCC） with two novel germline mutations, and further investigate the pathobiology of the two novel mutations of MLH1. METHODS： RNA was extracted from the peripheral blood of 12 patients from 12 different families that fulfilled the Amsterdam 11 Criteria for HNPCC. Germline mutations of MLH1 were determined by RT-PCR, followed by cDNA sequencing analysis. PCR-GeneScan analysis was used to investigate microsatellite instability with a panel of five microsatellite markers （BAT26, BAT25, D5S346, D2S123 and mfd15）, along with immunohistochemical staining to detect the expression of MLH1 protein in two patients＇ tumor tissues with novel mutations. RESULTS： Three germline mutations were found in four patients, one of the mutations has previously been reported, but the other two, CGC→TGC at codon 217 of exon 8 and CCG→CTG at codon 581 of exon 16, have not been reported. The two patients＇ tumor tissues with novel mutations had high-frequency microsatellite instability that showed more than two unstable loci, and both tumors lost their MLH1 protein expression. CONCLUSION： The two novel germline mutations of MLH1 in HNPCC families i.e. CGC→TGC at codon 217 of exon 8 and CCG→CTG at codon 581 of exon 16, are very likely to have pathological significance.

A Combined Clinicopathologic Analysis of 658 Urothelial Carcinoma Cases of Urinary Bladder

Objective To study the clinicopathological features of patients with urothelial carcinoma of the urinary bladder (UCB), and analyze the association of clinicopathological characteristics with tumor recurrence and progression. Methods Altogether 658 UCB cases in Fudan University Shanghai Cancer Center were collected from January 2006 to December 2010. The histopathologic materials and the clinical records were reviewed. Univariate and multivariate analyses were preformed to detect the association. Results The mean age of the patients was 61.97±12.97 years (range, 20-90 years). Male to female ratio was about 5:1. A total of 517 cases (78.6%) were superficial at the time of diagnosis (stage Ta/T1). The mean follow-up period was 22.36±24.92 months. Twenty-five patients lacking follow-up information were excluded in calculating recurrence and progression rates, the recurrence rate was about 37.0% (234/633), and progression rate about 6.2% (39/633). Three variables (grade, tumor growth pattern, and pathological stage) were found to be significant risk factors for tumor progression in univariate and multivariate analyses (P<0.05). Conclusions Most of the newly diagnosed UCB cases may be superficial diseases. Grade, tumor growth pattern, and pathological stage are associated with tumor progression of UCB.

Anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab for first-line treatment in advanced natural killer T cell lymphoma

Natural killer T cell lymphoma(NKTCL)is highly aggressive,with advanced stage patients poorly responding to intensive chemotherapy.To explore effective and safe treatment for newly diagnosed advanced stage NKTCL,we conducted a phase ll study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab(NCT04096690).Twenty-two patients with a median age of 51 years(range,24-74)were enrolled and treated with induction treatment of pegaspargase 2500 IU/m2 intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days,followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days.The complete response and overall response rate after induction treatment were 59%(95%Cl,43-79%)and 68%(95%Cl,47-84%),respectively.With a median follow-up of 30 months,the 2 year progression-free and overall survival rates were 68%(95%Cl,45-83%)and 86%(95%Cl,63-95%),respectively.The most frequently grade 3/4 adverse events were neutropenia(32%,n=7)and hypofibrinogenemia(18%,n=4),which were manageable and led to no discontinuation of treatment.Tumor proportion score of PD-L1,peripheral blood high-density lipoprotein cholesterol,and apolipoprotein A-l correlated with good response,while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment.In conclusion,the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed,advanced stage NKTCL.Dysregulated lipid profle and immunosuppressive signature contributed to treatment resistance,providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.

GPCR信号通路调控微环境的免疫特征和介导EB病毒相关淋巴瘤的发生

EB病毒(EBV)是多种肿瘤的致癌驱动因素.然而,肿瘤发生过程中病毒与肿瘤免疫相互作用的潜在机制仍不清楚.自然杀伤T细胞淋巴瘤(NKTCL)是研究EBV相关淋巴瘤发生的代表性疾病模型.本文整合基因组、转录组和蛋白质组数据,全面报道了NKTCL的蛋白质基因组特征.多组学分析发现EBV基因模式与免疫介导的致癌信号相关.单细胞转录组分析进一步描绘肿瘤微环境的免疫炎症、缺陷和沙漠三种表型特征,与肿瘤-免疫循环的不同设定点相关.EBV与转录因子相互作用引起GPCRome重编程,肿瘤细胞和免疫抑制细胞上CCR1的高表达,从而调控微环境中病毒与肿瘤的相互作用.在NKTCL类器官中,靶向CCR1可清除EBV、激活T细胞和杀伤淋巴瘤细胞,具有潜在的靶向治疗作用.综上,本研究首次发现了一种GPCR介导的肿瘤发生发展机制,将病毒分子的感知效应转化为针对EBV的特异性抗肿瘤疗法.