从跟跑并跑到领跑:再论中国腹膜肿瘤学的建设发展与国际化历程

腹膜癌是癌症治疗历史上遗留的“老大难”问题,近40年来国际上致力于腹膜癌诊断治疗研究,取得了突破性进展,尤其是肿瘤细胞减灭术(cytoreductive surgery,CRS)加腹腔热灌注化疗(hyperthermic intraperitoneal chemotherapy,HIPEC)体系的形成和优化。近20年来,中国的腹膜癌研究进步迅速,在仪器设备研发、技术方案优化、人才队伍培养、学科组织建设等方面,均取得令人瞩目的成就,并快速融入腹膜肿瘤学国际联盟的国际化发展大格局。中国胃癌腹膜转移癌临床研究成果成为国际里程碑事件,C-HIPEC方案的推广实施,2021年国内主办第12届国际腹膜癌大会,都是该领域的突出成果,也使中国在腹膜癌诊治方面实现了从跟跑并跑到领跑的历史性转变。但是,与中国腹膜癌患者的巨大治疗需求相比,腹膜肿瘤学发展事业仍然任重而道远,需要全国肿瘤学家加倍努力,推动立足于国情的中国腹膜癌防治研究走向新高度。

Hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis:A multicenter propensity scorematched cohort study

Objective:Systemic chemotherapy has limited efficacy in the treatment of peritoneal metastasis(PM)in gastric cancer(GC).Hyperthermic intraperitoneal chemotherapy(HIPEC)combined with complete cytoreductive surgery(CRS)has shown promising outcomes but remains controversial.The present study aimed to evaluate the safety and efficacy of HIPEC without CRS in GC patients with PM.Methods:This retrospective propensity score-matched multicenter cohort study included GC patients with PM treated with either chemotherapy alone(Cx group)or with HIPEC combined with chemotherapy(HIPEC-Cx group)in four Chinese high-volume gastric medical centers between 2010 and 2017.The primary outcomes were median survival time(MST)and 3-year overall survival(OS).Propensity score matching was performed to compensate for controlling potential confounding effects and selection bias.Results:Of 663 eligible patients,498 were matched.The MST in the Cx and HIPEC-Cx groups was 10.8 and 15.9 months,respectively[hazard ratio(HR)=0.71,95%confidence interval(95%CI),0.58-0.88;P=0.002].The 3-year OS rate was 10.1%(95%CI,5.4%-14.8%)and 18.4%(95%CI,12.3%-24.5%)in the Cx and HIPEC-Cx groups,respectively(P=0.017).The complication rates were comparable.The time to first flatus and length of hospital stay for patients undergoing HIPEC combined with chemotherapy was longer than that of chemotherapy alone(4.6±2.4 d vs.2.7±1.8 d,P<0.001;14.2±5.8 d vs.11.4±7.7 d,P<0.001),respectively.The median follow-up period was 33.2 months.Conclusions:Compared with standard systemic chemotherapy,HIPEC combined with chemotherapy revealed a statistically significant survival benefit for GC patients with PM,without compromising patient safety.

A multi-institutional retrospective study of hyperthermic plus intravesical chemotherapy versus intravesical chemotherapy treatment alone in intermediate and high risk nonmuscle-invasive bladder cancer

Objective:To compare the efficacy and safety of hyperthermic intravesical chemotherapy(HIVEC)and intravesical chemotherapy(IVEC)in patients with intermediate and high risk nonmuscle-invasive bladder cancer(NMIBC)after transurethral resection.Methods:We included 560 patients diagnosed with primary or recurrent NMIBC between April 2009 and December 2015 at 1 of 6 tertiary centers.We matched 364 intermediate or high risk cases and divided them into 2 groups:the HIVEC+IVEC group[chemohyperthermia(CHT)composed of 3 consecutive sessions followed by intravesical instillation without hyperthermia]and the IVEC group(intravesical instillation without hyperthermia).The data were recorded in the database.The primary endpoint was 2-year recurrence-free survival(RFS)in all NMIBC patients(n=364),whereas the secondary endpoints were the assessment of radical cystectomy(RC)and 5-year overall survival(OS).Results:There was a significant difference in the 2-year RFS between the two groups in all patients(n=364;HIVEC+IVEC:82.42%vs.IVEC:74.18%,P=0.038).Compared with the IVEC group,the HIVEC+IVEC group had a lower incidence of RC(P=0.0274).However,the 5-year OS was the same between the 2 groups(P=0.1434).Adverse events(AEs)occurred in 32.7%of all patients,but none of the events was serious(grades 3–4).No difference in the incidence or severity of AEs between each treatment modality was observed.Conclusions:This retrospective study showed that HIVEC+IVEC had a higher 2-year RFS and a lower incidence of RC than IVEC therapy in intermediate and high risk NMIBC patients.Both treatments were well-tolerated in a similar manner.

Raltitrexed as a synergistic hyperthermia chemotherapy drug screened in patient-derived colorectal cancer organoids

Objective:Organoids have recently been used as in vitro models to screen chemotherapy drugs in combination with hyperthermia treatment in colorectal cancer.Our research aimed to establish a library of patient-derived colorectal cancer organoids to evaluate synergism between chemotherapy drugs and hyperthermia;validate an index of the hyperthermia chemotherapy sensitization enhancement ratio(HCSER)to identify the chemotherapeutics most enhanced by hyperthermia;and recommend chemotherapy drugs for hyperthermic intraperitoneal treatment.Methods:Organoids were grown from cells extracted from colorectal cancer patient samples or colorectal cancer cell lines.Cells from both sources were encapsulated in 3 D Matrigel droplets,which were formulated in microfluidics and phase-transferred into identical cell-laden Matrigel microspheres.The microspheres were seeded in 96-well plates,with each well containing a single microsphere that developed into an organoid after 7 days.The organoids were used to evaluate the efficacy of chemotherapy drugs at both 37℃ as a control and 43℃ for 90 min to examine hyperthermia synergism.Cell viability was counted with 10%CCK8.Results:We successfully established a library of colorectal cancer organoids from 22 patient parental tumors.We examined the hyperthermia synergism of 7 commonly used hyperthermic intraperitoneal chemotherapy drugs.In 11 of the 22 patient organoids,raltitrexed had significant hyperthermia synergism,which was indexed as the highest HCSER score within each patient group.Conclusions:Our results primarily demonstrated the use of patient-derived colorectal cancer organoids as in vitro models to evaluate hyperthermia synergistic chemotherapeutics.We found that hyperthermia enhanced the effect of raltitrexed the most among the common anti-colorectal cancer drugs.

Added Value of Quantitative Apparent Diffusion Coefficients for Identifying Small Hepatocellular Carcinoma from Benign Nodule Categorized as LI-RADS 3 and 4 in Cirrhosis

Background and Aims:Correct identification of small hepa-tocellular carcinomas(HCCs)and benign nodules in cirrhosis remains challenging,quantitative apparent diffusion coeffi-cients(ADCs)have shown potential value in characterization of benign and malignant liver lesions.We aimed to explore the added value of ADCs in the identification of small(≤3 cm)HCCs and benign nodules categorized as Liver Imag-ing Reporting and Data System(LI-RADS)3(LR-3)and 4(LR-4)in cirrhosis.Methods:Ninety-seven cirrhosis patients with 109 small nodules(70 HCCs,39 benign nodules)of LR-3 and 4 LR-4 based on major and ancillary magnetic resonance imaging features were included.Multiparametric quantitative ADCs of the lesions,including the mean ADC(ADCmean),min-imum ADC(ADCmin),maximal ADC(ADCmax),ADC standard deviation(ADCstd),and mean ADC value ratio of lesion-to-liv-er parenchyma(ADCratio)were calculated.Regarding the joint diagnosis,a nomogram model was plotted using multivariate logistic regression analysis.The performance was assessed using the area under the receiver operating characteristic curve(AUC).Results:The ADCmean,ADCmin,ADCratio,and ADCstd were significantly associated with the identification of small HCC and benign nodules(p<0.001).For the joint diagnosis,the LI-RADS category(odds ratio[OR]=12.50),ADCmin(OR=0.14),and ADCratio(OR=0.12)were identified as independent factors for distinguishing HCCs from benign nodules.The joint nomogram model showed good calibration and discrimination,with a C-index of 0.947.Compared with the LI-RADS category alone,this nomogram model demon-strated a significant improvement in diagnostic performance,with AUC increasing from 0.820 to 0.967(p=0.001).Con-clusions:The addition of quantitative ADCs could improve the identification of small HCC and benign nodules catego-rized as LR-3 and 4 LR-4 in patients with cirrhosis.

Tumor Necrosis Factor a Reduces SNAP29 Dependent Autolysosome Formation to Increase Prion Protein Level and Promote Tumor Cell Migration

Tumor Necrosis Factor α(TNFα) is best known as a mediator of inflammation and immunity, and also plays important roles in tumor biology. However, the role of TNFα in tumor biology is complex and not completely understood. In a human melanoma cell line, M2, and a lung carcinoma cell line, A549, TNFα up-regulates prion protein(PrP) level, and promotes tumor cell migration in a PrP dependent manner. Silencing PRNP abrogates TNFα induced tumor cell migration;this phenotype is reversed when PRNP is re-introduced. Treatment with TNFα activates nuclear factor kappa B(NF-κB)signaling, which then mitigates autophagy by reducing the expression of Forkhead Box P3(FOXP3). Down regulation of FOXP3 reduces the transcription of synaptosome associated protein 29(SNAP29), which is essential in the fusion of autophagosome and lysosome creating autolysosome. FOXP3 being a bona fide transcription factor for SNAP29 is confirmed in a promoter binding assay. Accordingly, silencing SNAP29 in these cell lines also up-regulates PrP, and promotes tumor cell migration without TNFα treatment. But, when SNAP29 or FOXP3 is silenced in these cells, they are no longer respond to TNFα. Thus, a reduction in autophagy is the underlying mechanism by which expression of PrP is up-regulated,and tumor cell migration is enhanced upon TNFα treatment. Disrupting the TNFα-NF-κB-FOXP3-SNAP29 signaling axis may provide a therapeutic approach to mitigate tumor cell migration.