Prognostic value of PD-1 and PD-L1 expression in patients with metastatic clear cell renal cell carcinoma

Objective

In renal cell carcinoma (RCC), several prognostic biomarkers have been identified and are under investigation. Several reports have shown that the expression of programmed death 1 (PD-1) and its ligand PD-L1 is associated with poor outcome for patients with RCC. The present study is aimed at evaluating the expression of PD-1 and PD-L1 and to investigate their clinical and prognostic significance in patients with clear cell RCC (CCRCC) having received molecular targeted therapies. In addition, we also evaluated the relationship between the expression of PD-1 and PD-L1 and intratumoral tumor infiltrating lymphocytes (TILs).

Preparative cytoreductive surgery in patients with metastatic renal cell carcinoma treated with adoptive immunotherapy with interleukin-2 or interleukin-2 plus lymphokine activated killer cells

A total of 63 patients with metastatic renal cell carcinoma with the primary kidney tumor in place was accepted as candidates for immunotherapy at the Surgery Branch of the National Cancer Institute. Of the 63 patients 54 underwent nephrectomy and 9 were treated with the primary kidney tumor in place. Many of the patients underwent associated procedures, such as regional lymphadenectomy (11), venacavotomy with extraction of tumor thrombus (9), hepatic resection (2), pulmonary wedge resection (2), cholecystectomy (2), splenectomy (2), distal pancreatectomy (1), omentectomy (1) and contralateral adrenalectomy (1). Of the 54 patients 20 were not able to enter therapy because of tumor-related (17) or other medical (3) reasons that developed between the operation and therapy, while 34 were able to receive immunotherapy postoperatively. The 20 patients who were treated with either high dose interleukin-2 or interleukin-2 plus lymphokine activated killer cells soon postoperatively (mean 2.1 months) were able to tolerate roughly the same amount of interleukin-2 as the 74 who had undergone nephrectomy before referral to our institute and who were treated for a mean of 22 months after nephrectomy. Further studies, including a prospective, randomized trial, will be required to define the role of nephrectomy in patients with advanced renal cell carcinoma before treatment with interleukin-2 based immunotherapies.     

循环肿瘤细胞PD-L1表达在非小细胞肺癌免疫治疗中的应用

肺癌是全世界发病率及病死率最高的恶性肿瘤.近年来,针对程序性死亡受体1(programmedcell death 1,PD-1)及其配体(programmed cell death-ligand 1,PD-L1)的免疫检查点抑制剂治疗显著改善了非小细胞肺癌(non-small cell lung cancer,NSCL...     

Decreased PD-1 expression on circulating CD4+T cell and PD-L1 expression on myeloid dendritic cell correlate with clinical manifestations in systemic juvenile idiopathic arthritis

Objectives

Programmed cell death-1 (PD-1) and its ligand (PD-L1) mediate negative signal in autoimmune diseases. While little is known about its role in juvenile idiopathic arthritis (JIA). The study aimed to reveal the circulating cell profile and the relative PD-1/PD-L1 expression of JIA subsets, elucidating their underlying immunomodulatory mechanisms.

Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma

ObjectiveTo determine whether presurgical sunitinib reduces primary renal cell carcinoma (RCC) size and facilitates partial nephrectomy (PN).MethodsData from potential candidates for PN treated with sunitinib with primary RCC in situ were reviewed retrospectively. Primary outcome was reduction in tumor bidirectional area.ResultsIncluded were 72 potential candidates for PN who received sunitinib before definitive renal surgery on 78 kidneys. Median primary tumor size was 7.2 cm (interquartile range [IQR]: 5.3–8.7 cm) before and 5.3 cm (IQR: 4.1–7.5 cm) after sunitinib treatment (P<0.0001), resulting in 32% reduction in tumor bidirectional area (IQR: 14%–46%). Downsizing occurred in 65 tumors (83%), with 15 partial responses (19%). Tumor complexity per R.E.N.A.L. score was reduced in 59%, with median posttreatment score of 9 (IQR: 8–10). Predictors of lesser tumor downsizing included clinical evidence of lymph node metastases (P<0.0001), non–clear cell histology (P = 0.0017), and higher nuclear grade (P = 0.023). Surgery was performed for 68 tumors (87%) and was not delayed in any patient owing to sunitinib toxicity. Grade≥3 surgical complications occurred in 5 patients (7%). PN was performed for 49 kidneys (63%) after sunitinib, including 76% of patients without and 41% with metastatic disease (P = 0.0026). PN was completed in 100%, 86%, 65%, and 60% of localized cT1a, cT1b, cT2, and cT3 tumors, respectively.ConclusionPresurgical sunitinib leads to modest tumor reduction in most primary RCC, and many patients can be subsequently treated with PN with acceptable morbidity and preserved renal function. A randomized trial is required to definitively determine whether presurgical therapy enhances feasibility of PN.     

Alemtuzumab (Campath-1H) induction therapy and dendritic cells: Impact on peripheral dendritic cell repertoire in renal allograft recipients

Dendritic cells (DC) are the most potent antigen-presenting cells (APC) and are pivotal for initiating allograft immunity. Recently, particular DC subsets have been implicated also in allogeneic T cell hyporesponsiveness. Alemtuzumab (anti-CD52, Campath-1H) is a novel T cell depleting antibody that is currently under investigation for the use in allogeneic organ transplantation. While recent studies demonstrated a conspicuous effect of alemtuzumab on peripheral DC in clinical graft-versus-host disease, its efficiency in patients receiving allogeneic organ transplants is still undefined. In the present study we assessed the peripheral DC repertoire in kidney transplant recipients after either alemtuzumab induction therapy followed by FK506 monotherapy or after conventional immunosuppression (FK506, mycophenolate mofetil and steroids) without any induction agent. Induction with alemtuzumab caused a strong and sustained reduction of the total number of peripheral DC and a significant shift from myeloid to plasmacytoid DC subsets (mDC/pDC ratio) as early as 1 month post-transplantation. These data show that alemtuzumab induction targets the peripheral DC repertoire, which might add another mechanism allowing immunosuppressive drug minimization. Further studies are warranted to further elucidate the functional significance of these finding in the setting of allogeneic organ transplantation.     

仑伐替尼联合程序性死亡受体-1抗体治疗不可切除或进展期肝细胞癌的临床疗效

目的:探讨仑伐替尼联合程序性死亡受体-1（PD-1）抗体治疗不可切除或进展期肝细胞癌（以下简称肝癌）的临床疗效。方法:采用回顾性描述性研究方法。收集2018年9月至2020年1月复旦大学附属中山医院收治的59例不可切除或进展期肝癌病人的临床病理资料;男54例,女5例;中位年龄为52岁,年龄范围为25~73岁。59例病人...     

慢性乙型肝炎患者DC/CIK体外经HBsAg活化后自体回输的疗效和对机体免疫的影响

目的研究慢性乙型肝炎(CHB)患者外周血来源的树突状细胞(DC)和细胞因子诱导的杀伤细胞(CIK)自体回输治疗的疗效和对机体免疫的影响。方法 95例CHB患者随机分为3组,即A组(33例),行DC/CIK治疗;B组(22例),行核苷酸类抗病毒治疗;C组(20例),未进行抗病毒治疗。用CHB外周血培养和扩增DC和CIK,成熟前给予HBsAg刺激。自体静脉回输(DC/CIK细胞数量109/100 ml),1次/3 d,共3次。各组均于治疗前、治疗后第1、3、6、12个月分别检测肝功能、HBV DNA、IFN-γ、IL-4和IL-12水平。其中IFN-γ、IL-4和IL-12均采用双抗体夹心ELISA法进行检测。结果治疗前各组患者病毒载量无显著差异。治疗各阶段B组患者血清HBV DNA水平均低于A组和C组患者(P均<0.001);A组患者治疗后3、6个月时病毒载量显著下降(P均<0.05)。各组患者治疗前后ALT和TBil水平差异无统计学意义。治疗后1个月后,A组患者血清IL-12水平显著高于B组和C组(9.32±2.07 pg/ml vs6.96±2.17 pg/ml,9.32±2.07 pg/ml vs 7.32±2.36 pg/ml,P<0.05),其他时间阶段各组比较,IL-12水平差异无统计学意义。各组患者之间血清IFN-γ、IL-4水平差异均无统计学意义。结论 DC/CIK细胞治疗对HBV有一定的抑制作用;推测DC/CIK细胞治疗对辅助T细胞的失衡无显著影响。     

B7-H1及其受体PD-1在膀胱癌患者外周血免疫细胞中的表达及其临床意义

目的：研究膀胱癌患者外周血中树突状细胞（dendritic cells,DCs）表面B7-H1和CD8＋T淋巴细胞表面PD-1的表达情况及其临床意义。方法：分离30例膀胱癌患者外周血单个核细胞（peripheral blood mononuclear cell,PBMC）,联合培养后采用流式细胞术检测DCs表面B7-HI及CD8＋,T细胞表面PD-1的表达情况。结果：膀胱癌患者外周血DCs表面B7-H1表达水平及CD8＋T细胞表面PD-1表达水平均明显高于正常人,差异具有显著统计学意义（P〈0．01）,并且二者的表达水平随着病理分级和临床分期的增加均升高,差异有统计学意义（P〈0．05）。结论：在膀胱癌发生发展过程中存在着DCs表面B7-H1和CD8＋T细胞表面PD-1分子表达的上调,B7-H1／PD-1信号通路可能在T细胞免疫应答的初始阶段亦参与了膀胱癌免疫逃逸的发生。     

Association of RASSF1A genotype and haplotype with the progression of clear cell renal cell carcinoma in Japanese patients

What's known on the subject? and What does the study add? Ras association domain family 1A (RASSF1A) is a tumour suppressor and regulates cell cycle, apoptosis and microtubule stability. This is the first study to identify associations between RASSF1A polymorphisms and clinicopathological parameters and survival in patients with clear cell renal cell carcinoma (CCRCC). RASSF1A genotyping may be useful for predicting the prognosis of the clinical course of CCRCC, and this finding might provide a better understanding of the mechanism underlying the development and progression of CCRCC. However, functional and prospective studies with a larger number of patients are needed to confirm the results.

OBJECTIVE

• ? To compare Ras association domain family 1A (RASSF1A) genotypes or haplotypes with clinicopathological characteristics and survival rates of patients with clear cell renal cell carcinoma (CCRCC).

PATIENTS AND METHODS

• ? The study cohort comprised 224 Japanese patients who underwent radical nephrectomy and had CCRCC confirmed by histopathological analysis.
• ? Three common polymorphisms in the RASSF1A gene, 133Ala/Ser (G/T), ‐710C/T and ‐392C/T, were genotyped using TaqMan assays and haplotypes were analysed using appropriate software.

RESULTS

• ? Patients with CCRCC with RASSF1A ‐710TT genotype exhibited a significantly higher tumour stage and higher stage grouping than those with ‐710CC or ‐710CT (P = 0.005 and P = 0.032, respectively).
• ? There was no significant association between 133Ala/Ser or ‐392C/T genotype and clinicopathological characteristics.
• ? RASSF1A 133Ala‐710T‐392T haplotype and ‐710TT genotype were significantly associated with poorer recurrence‐free survival rates (P = 0.038 and P = 0.007, respectively).

CONCLUSIONS

• ? This is the first study to identify associations between RASSF1A polymorphisms and clinicopathological parameters and survival in patients with CCRCC.
• ? RASSF1A genotyping may be useful in predicting the prognosis of the clinical course of CCRCC, and this finding might provide a better understanding of the mechanism underlying the development and progression of CCRCC.
• ? Functional and prospective studies with a larger number of patients are needed to confirm the results.

     

Low-intensity pulsed ultrasound in combination with SonoVue induces cytotoxicity of human renal glomerular endothelial cells via repression of the ERK1/2 signaling pathway

Objectives: Low-intensity pulsed ultrasound (LIPUS) and SonoVue have been used widely for diagnosis and therapeutic treatment. The effects of LIPUS and SonoVue on the microvascular system and underlying molecular mechanisms have not been established.

Methods: Cultured human renal glomerular endothelial cells (HRGECs) were treated with 5-min ultrasonic irradiation, 20% SonoVue or the combination of both treatments. Cell proliferation, viablity, and apoptosis were measured by MTT assay, Trypan blue exclusion assay and flow cytometry, respectively. Activation of extracellular regulated protein kinases (ERK) were examined by Western blot.

Results: We found that LIPUS and SonoVue alone do not induce cytotoxicity of HRGECs; however, the combination of the two treatments reduces cell proliferation and increases cell death. In addition, the combination of LIPUS and SonoVue suppressed the activation of ERK 1/2 in HRGRCs. With pretreatment of the inhibitor of ERK1/2 signaling, PD98059, LIPUS, and SonoVue does not induce additional cell death and inhibition of proliferation.

Conclusions: LIPUS combined with SonoVue induces cytotoxicity of HRGECs via repression of the ERK1/2 signaling pathway.     

机体缺氧状态与肾透明细胞癌预后的关系

目的 初步探讨机体的慢性缺氧状态对肾透明细胞癌预后的影响. 方法 应用免疫组化方法半定量检测89例肾透明细胞癌标本缺氧诱导因子-lα(HIF-lα)的表达情况.回顾性分析89例患者的临床病理资料,其中男66例,女23例;平均年龄57岁;慢性肺疾病(CPD)组19例,无慢性肺疾病(NCPD)组70例;临床分期1期46例,11期15例,Ⅲ期26例,Ⅳ期2例.并对其预后情况进行随访.用Kaplan-Meier法对是否合并慢性肺部疾病、HIF-lα表达、Hb含量、吸烟史等变量与患者生存时间进行组间分析,同时建立Cox比例风险回归模型分析各变最l与生存时间的相关性.结果 89例随访6 ～84个月,中位随访时间19个月.死亡20例,存活69例.HIF-1α阴性表达15例(16.9％),阳性表达74例(83.1％).CPD组和NCPD组疾病临床分期、血红蛋白水平及HIF-1α表达程度等方面的差异有统计学意义(P＜0.05);两组患者中位总生存期分别为44、71个月,差异有统计学意义(P＜0.05);Hb≤1 10 g/L组和＞1l0g/L组患者中位总生存期分别为43、70个月,差异有统计学意义(P ＜0.05);HIF-1α的表达程度越强,总生存期越短,其差异有统计学意义(P＜0.05).合并CPD、Hb水平、HIF-1α表达是影响肿瘤患者总生存期的独立因素(P＜0.05).其中合并肺部疾病、HIF-1α表达与疾病生存时间呈正相关,Hb水平与疾病生存时间呈负相关. 结论 CPD导致的患者系统性缺氧可加重肾透明细胞癌患者的组织内缺氧状态.机体的缺氧状态与肾透明细胞癌预后存在负相关.     

慢性HBV感染者HBV特异性CD8＋ T细胞Tim-3和PD-1的表达水平及其与IFN-γ产生的相关性研究

目的：研究免疫球蛋白黏蛋白分子-3（Tim-3）和程序性死亡受体-1分子（PD-1）在慢性乙型肝炎病毒（HBV）感染患者外周血HBV特异性CD8＋ T细胞表面的表达模式,了解其与γ-干扰素（IFN-γ）产生的关系,并探讨其临床意义。方法采用流式细胞术检测主要组织相容性复合体-2（HLA-A2）阳性的78例临床类型不同的慢性HBV感染患者HBV特异性CD8＋ T细胞表面分子Tim-3和PD-1的表达,ELISA方法检测外周血单个核细胞（PBMC）培养上清液中IFN-γ的水平。结果慢性HBV感染者Tim-3＋/PD-1＋HBV特异性CD8＋ T细胞比例占总的HBV特异性CD8＋ T细胞的58%,Tim-3-/PD-1＋细胞比例为24%,Tim-3-/PD-1-比例16%,Tim-3＋/PD-1-比例最低为2%。临床病情越严重的临床类型中,Tim-3＋/PD-1＋HBV特异性CD8＋ T细胞比例越高,慢性乙型肝炎轻中度组为（52.05±18.68）%,重度肝炎组为（59.66±19.25）%,重型肝炎组最高为（68.72±17.21）%;各组与非活动性携带者组比较,P值分别为0.007、0.009、0.000。重型组与轻中度组比较,P =0.018。Tim-3＋/PD-1＋在HBV特异性CD8＋ T细胞的表达与细胞培养上清液IFN-γ的水平呈负相关性（r =-0.466,P ＜0.001）。结论在HBV特异性CD8＋ T细胞中,Tim-3和PD-1共同表达是其主要表达模式,Tim-3和PD-1的高表达可能负性调控IFN-γ的产生,从而影响慢性HBV感染的疾病进展和结局。