肿瘤的微进化及其临床意义

肿瘤作为体内产生的新生物可在有限的时空内发生微进化.肿瘤细胞克隆在遗传变异和表观遗传学机制改变的调控下呈线性或分枝进化,多数临床患者的肿瘤呈嵌合式分枝进化,导致肿瘤的异质性,影响其发展,是临床难治和易于复发的生物学基础,已引起研究者的关注.文章以急性髓系白血病（AML）和骨髓增生异常综合征（MDS）等为例介绍肿瘤微进化的历程和线性/分枝进化的概念,并对肿瘤微进化研究的一些问题和方向进行了讨论.     

癌症进化发育学的新证据：结直肠癌和肝细胞癌的研究发现

本文主要阐述慢性炎症促进癌症进化发育过程中“变异-选择-适应”的主要分子机制,其中重点阐述慢性炎症促进结直肠癌（colorectal cancer,CRC）和肝细胞癌（hepatocellular carcinoma,HCC）发生的早期共性和特性分子事件。总结了高危癌前病变和侵袭的关键分子事件及可阻遏癌症发生和侵袭的信号通路的主要分子靶标,进一步夯实了“癌症进化发育学”理论体系,体现 “癌症进化发育学”在癌症特异性防治中的重要作用。未来通过“癌症进化发育学”理论和技术方法可能有助于确定何种癌前病变更易恶化以及何种癌症更易发生早期侵袭,从而实现癌症特异性预防和治疗“关口前移”的目标。     

“癌症进化发育学”理论的关键功能分子及其在恶性肿瘤防治中的作用

恶性肿瘤的发生和发展遵循“变异-选择-适应”的进化轨迹,外源性和内源性促癌因素直接或通过慢性非可控性炎症促进染色体变异以及主要功能基因变异。在癌前病变阶段,慢性炎症促进了变异驱动力量的积累,其中在50%以上的癌症病变中肿瘤抑制基因脆弱组蛋白三联体（fragile histidine triad,FHIT）的转录和翻译被严重抑制。外源性致癌因素通过对启动子CpG岛甲基化、复制应激导致杂合性缺失,使FHIT表达受损,导致染色体非整数倍扩增,形成染色体不稳定为特征的大变异;同时产生单链DNA促进了APOBEC3B致突变作用,形成以单碱基替换为特征的显微变异。炎症分子如IL-6反式激活APOBEC3B表达,反式抑制UNG表达,造成APOBEC3B/UNG平衡失调,促进体细胞变异和病毒变异,加速癌症进化。变异细胞在炎症条件下通过改造周围纤维母细胞为癌症相关纤维母细胞,招引抑制性免疫细胞,在缺氧环境下形成肿瘤微环境,通过选择和适应,促进变异细胞逆向进化为肿瘤起始细胞,从而促进癌症细胞逆向发育。据此认为,FHIT与APOBEC3B/UNG可能是肿瘤防控的新靶标。解除抑制FHIT和增强AID/APOB...     

2012—2019年中国未知HAdV病毒株分型及基因特征分析

目的 分析11株来自中国尚未明确分型的HAdV病毒株完整基因组的基因特征并分型。方法 从GenBank数据库中下载到67条已明确基因型的HAdV基因组序列和7条HAdV参照基因组序列，将这74条参照序列与11株未明确分型的HAdV病毒株基因组序列进行基因结构、基因同源性以及系统进化等分析，从而确定其分型。结果 从系统进化分析结果预测出6株HAdV可能的分型，再由多序列比对分析进行验证。其中两株HAdV通过多序列比对结果发现与HAdV-B参照基因组序列之间的同源性为97.8%，属于B型HAdV；两株HAdV与HAdV-D参照基因组序列之间的同源性为92.8%，属于D型HAdV；还有两株HAdV的多序列比对结果与系统进化分析预测结果不一致，无法推断其分型。剩余5株未能预测的HAdV通过与7条HAdV参照序列进行多序列比对分析，发现与B型HAdV基因组序列的同源性达到了97.9%，推测这5株HAdV基因组可能属于B型HAdV。结论 从基因角度来对11株未知的HAdV基因组进行分型，预测有7株可能属于B型HAdV，有两株可能属于D型HAdV，还有两株无法判断其分型。其中7株B型HAdV可能适合作为溶瘤腺病毒进行骨肉瘤的治疗。     

进化理论在癌症治疗中的探索

肿瘤的发生、发展本质上是进化过程发生的疾病，包括肿瘤细胞相互竞争及其对环境的适应。进化理论的探索研究，为肿瘤治疗提供更多新的思路及理论依据。本文从进化要素、生态理念、微环境3个方面分别综述治疗策略、疗效及可能存在的问题，为肿瘤精准治疗提供新视角。      

肿瘤进化异质性研究现状及进展

肿瘤进化是肿瘤异质性、肿瘤转移及药物靶向治疗的研究基础。近年来,肿瘤原发灶与转移灶进化关系的研究取得快速进展。肿瘤进化研究涉及基因组学、转录组学、表观遗传学等多种组学研究方法,通过不同的研究方法构建了多种肿瘤进化模型。本文通过文献回顾,对肿瘤进化的基因组学基础、肿瘤进化的基因组学研究方法及肿瘤进化的不同模式的研究现状及进展进行综述,并对肿瘤进化研究的新方法进行展望。     

过氧化物酶4与NF-κB在外阴硬化性苔藓及外阴鳞癌中的表达及意义

目的:探讨过氧化物酶4（peroxiredoxin 4，Prx4）和NF-κB在外阴硬化性苔藓（vulvar lichen sclerosis，VLS）和外阴鳞癌（vulvar squarnous cell carcinoma，VSCC）中的表达及意义。方法:采用免疫组化方法检测Prx4和NF-κB在VLS和VSCC及外阴正常组织中的表达情况，并结合临床病理资料进行分析。结果:Prx4在VLS的表达明显高于外阴正常皮肤，两者有统计学差异（P<0.05）；在VSCC中的表达明显高于外阴正常皮肤（P<0.05）。在VSCC Ⅲ-Ⅳ期中表达高于Ⅰ-Ⅱ期（P<0.05）；有淋巴结转移的表达高于无淋巴结转移（P<0.05），中分化的表达高于高分化（P<0.05）。NF-κB在VLS中的表达明显低于外阴正常皮肤，两者有统计学差异（P<0.05）；NF-κB在VSCC中的表达明显高于外阴正常皮肤（P<0.05），在VSCC Ⅲ-Ⅳ 期中表达高于Ⅰ-Ⅱ期（P<0.05）；有淋巴结转移的表达高于无淋巴结转移（P<0.05），中分化的表达高于高分化（P<0.05）。Spearman相关性分析结果表明:在VLS中Prx4和NF-κB的表达呈负相关；在VSCC中，两者表达呈正相关。结论:Prx4和NF-κB在VSCC中高表达；NF-κB在VLS中低表达。     

VATS解剖性肺段切除术与肺叶切除术治疗Ⅰa期NSCLC患者的手术情 况及对肺功能影响的比较

目的:探讨电视胸腔镜（VATS）解剖性肺段切除术与肺叶切除术治疗Ia 期非小细胞肺癌（NSCLC）患者的手术情况及对患者肺功能的影响。方法:选取我院手术治疗的Ⅰa期NSCLC患者，收集时间2014年1月至2016年12月，根据术式不同分为两组，均采用VATS手术治疗，A组（54例）患者采用解剖性肺段切除术、B组（60例）采用肺叶切除术治疗，对比两组患者的手术效果及术后肺功能变化。结果:A组患者的手术时间、清扫淋巴结数目与B组比较差异无统计学意义（P>0.05）；A组患者的手术出血量、术后胸腔引流量、术后拔管时间、术后住院时间均显著的低于B组患者（P<0.05）；术前，A组和B组患者的FEV1%、FVC%、MVV%测定值差异无统计学意义（P>0.05），术后3个月复查，A组患者的FEV1%、FVC%、MVV%测定值均显著高于B组患者（P<0.05）；手术后，A组患者的并发症发生率（7.41%）低于B组患者（13.33%），但是差异无统计学意义（P>0.05）。结论:VATS解剖性肺段切除术治疗Ⅰa期NSCLC患者具有手术创伤小、术后恢复快、对患者肺功能影响更小的优势。     

全量或半量索拉非尼联合卡培他滨治疗肝细胞肝癌的临床观察

目的:比较全量或半量索拉非尼（Sor）联合卡培他滨(CAP)治疗肝细胞肝癌的疗效和不良反应。方法:收集2012年2月至2016年6月肝细胞肝癌患者38例，随机分为A组（全量Sor联合CAP，n=19）和B组（半量Sor联合CAP，n=19）。A组:Sor 400 mg/次，B组:Sor 200 mg/次，每天2次口服，连续服用，直到疾病进展或不能耐受不良反应为止。A、B组均联用CAP 850 mg/m2每次，每天2次口服，连用14天，休息1周，每21天重复。结果:A组部分缓解（PR）3例，稳定（SD）11例，进展（PD）5例，总有效率（ORR）为15.8%，疾病控制率（DCR）为73.7%，中位肿瘤进展时间（mTTP）为（4.5±0.3）个月，中位总生存期（mOS）为7.2个月［95%可信区间（95%CI）:7.1~7.3］。B组PR 2例，SD 11例，PD 6例，ORR为10.5%,DCR为68.4%，mTTP为（4.4±0.4）个月，mOS为7.3个月（95%CI:7.2~7.4）。 两组的ORR比较，P=1.000；DCR比较，P=0.721；TTP比较,P=0.549；OS比较，P=0.265，差异均无统计学意义（P＞0.05）。不良反应:A组除手足综合征和高血压发生率明显高于B组外，其它不良反应发生率无统计学差异。结论:半量Sor联合CAP治疗晚期肝细胞肝癌疗效与全量Sor联合CAP无显著差异，半量Sor联合CAP组的手足综合征和高血压的发生率显著低于全量Sor联合CAP组。     

肿瘤进化的表现

肿瘤进化是肿瘤细胞选择、竞争和扩增的过程，表现为肿瘤的印记、异质、抵抗、转化和适应等方面。肿瘤进化使肿瘤在各种压力下能够存活。理解肿瘤进化史将为精准治疗的实现提供理论指导。     

Karyotypic Evolution: Cytogenetics Follow-Up Study In Childhood Acute Lymphoblastic Leukemia

Forty seven children affected with acute lymphoblastic leukemia (ALL) were cytogenetically investigated ‍at diagnosis and all through different stages of the disease (remission and relapse). A clonal karyotypic abnormality ‍was found in 32% at diagnosis (mainly comprised of cALLa+). A hyperdiploid mode with chromosome counts ‍ranging from 47-58, was found to be most prominent among cALLa+ patients. The most common numerical ‍aberrations were gain of chromosomes 2, 5, and 21. The structural aberrations at diagnosis were found to be ‍del(9)(p22), inv(9)(p11q13) and del(19)(p12). None of the children showed ph+ chromosome. A good prognosis ‍was found in cALLa+ children with an abnormal karyotype at diagnosis and of these children, those who ‍showed karyotypic instability , had a significantly longer first remission time. The karyotypic evolution ‍through remission(s) and relapse(s) revealed the occurrence of structural alterations , including changes in ‍chromosomes 3, 6, 9, 21 and 22. However, irrespective of the karyotypic clonal nature at diagnosis, ‍chromosome 9 was the most commonly involved chromosome through the course of disease. ‍     

细胞减灭术加腹腔热灌注化疗治疗卵巢癌腹膜转移癌的临床研究

目的 研究细胞减灭术（CRS）加腹腔热灌注化疗（HIPEC）治疗卵巢癌腹膜转移癌的疗效及安全性。方法 46例晚期（A组,FIGO Ⅲc/Ⅳ期,n=16和复发性,B组,n=30）卵巢癌腹膜癌患者接受了CRS+HIPEC治疗,分析其临床资料,主要终点指标为总生存期,次要指标为安全性。结果 A、B两组患者的中位总生存期（OS）分别为74.0月和57.5月（P=0.68）。腹膜癌指数（PCI）≤20（n=24）和＞20（n=22）的中位OS分别为76.6和38.5月（P=0.01）。CC 0~1分和CC 2~3分的中位OS分别为79.5和24.3月（P=0.00）。对复发性卵巢癌腹膜癌患者来说,铂类敏感型和耐药型患者的中位OS分别为6 5 . 3 和2 0 . 0 月（P=0.05）。无围手术期死亡病例,5例患者出现术后并发症。多因素分析显示,CC 0~1分、术后化疗≥6周期为改善生存的独立预后因素。结论 CRS+HIPEC可延长卵巢癌腹膜癌患者的总生存期,安全可行。     

开普拓联合奥沙利铂及5-氟尿嘧啶治疗晚期胃肠道癌疗效观察

目的:观察开普拓(CPT-11),奥沙利铂(L-OHP),亚叶酸钙(CF),5-氟尿嘧啶(5-FU)联合治疗晚期胃肠道癌的疗效和毒副反应。方法:采用CPT-11 120mg/m2静滴,第1、15天;L-OHP 65mg/m2静滴,第2、16天;CF100mg静滴,第1天~3天;5-FU 300mg/m2静注,第1天~3天,(静脉微泵推注72小时)。28天一周期,3~6周期判定疗效。结果:36例患者中完全缓解(CR)2例(5.5%),部分缓解(PR)8例(22.2%),稳定(SD)22例(61.1%),进展(PD)2例(11.1%),总有效率27.8%。临床受益率88.9%,中位疾病进展6个月,中位生存期17个月。毒副反应主要以骨髓抑制,胃肠道反应,脱发为主,其中白细胞减少77.8%,胃肠道反应72.2%,脱发100%,无化疗相关死亡。结论:开普拓联合奥沙利铂及5-氟尿嘧啶治疗晚期胃肠道癌疗效肯定,临床受益明显,毒副反应能耐受,值得进一步试用。     

Impaired Liver Function Implied Shorter Progression Free Survival for EGFR Tyrosine Kinase Inhibitors

Background: Epithelial growth factor receptor tyrosine kinase inhibitor (EGFR TKI) revolutionize the standardof care for advanced non-small cell lung cancer (NSCLC) harboring sensitive EGFR mutation. Liver toxicity is thedose-limiting factor for TKI but its importance is largely overlooked. Here the relationship between the elevationof transaminase and progression-free survival (PFS) was explored. Methods: This was a retrospective study wherepatients with advanced NSCLC were screened. And those treatment-naïve and with sensitive EGFR mutation whowere prescribed with EGFR TKI were enrolled. The highest level of transaminase (alanine aminotransferase, ALT, andaspartate transaminase, AST) during the treatment course was recorded. Results: Totally 208 patients were recruited,and most of them (48.6%) took gefitinib. The whole cohort achieved a median PFS of 11.2 months (95%CI: 10.0-12.3m). 73 (35.1%) patients had elevated transaminase and most was attributed to gefitinib (n=43, 42.5%). Specifically,ALT was elevated in 65 patients (31.3%) while AST in 24 patients (11.5%). Again, gefitinib was associated with morecases of ALT (40.6%) and AST (17.8%) elevation. The elevation of AST was not related to PFS (P=0.259, HR=0.751,95%CI: 0.464-1.214). Interestingly, those with normal ALT level had a longer PFS (12.6m, 95%CI: 10.6-14.5 m) thanthose with elevated ALT (9.5m 95%CI: 7.9-11.0 m, P=0.025, HR=0.682, 95%CI: 0.488-0.953). The inverse relationshipwas confirmed in the COX regression analysis (P=0.047). Conclusion: This study revealed the side effects of elevatedALT was inversely related to the PFS of EGFR TKI treatment. The liver impairment by TKI should not be overlooked.     

CLINICAL SIGNIFICANCES OF THE EXPRESSION OF METALLOTHIONEIN IN FIVE TYPES EPITHELIUM CELL CANCER

Objective： To study the expressions of （CSC）, bladder transitional cell cancer metallothionein and the significances in cervical squamous cell cancer （BTC）, esophageal squamous cell cancer （ESC）, gastral tubular adenocarcinoma （GC） and large intestinal tubular adenocarcinoma （LIC）. Methods： lmmunohistochemical method was used to examine the expression rates of MT in five types of cancer tissue. Results： The expression rates of MT were 75.00% （24/32） in ESC, 52.27% （46/88） in GTC, 59.46% （44/74） in LIC, 64.86% （48/74） in BTC and 58.57% （41/70） in CSC respectively. The positive rates of MT expression were higher in low differentiation and deep muscular group than those in medium or high differentiation and superficial muscular invasion group （P〈0.05）. Conclusion： The expression of MT is related to differentiation degree and invasion degree.     

HMVP、MVP和 HVP方案治疗晚期NSCLC的前瞻性随机研究

背景与目的非小细胞肺癌( non-small cell lung cancer,NSCLC)对常用的一、二线化疗方案敏感性较低,在化疗中联用喜树碱类衍生物已引起国内外的研究兴趣.本研究旨在观察羟基喜树碱( hydroxycamptothecin,HCPT)联合丝裂霉素( mitomycin,MMC)、长春花碱酰胺( vindesine,VDS)和顺铂( cisplatin,DDP)组成的 HMVP、 MVP和 HVP方案治疗晚期 NSCLC的近期、远期疗效和不良反应.方法 134例晚期 NSCLC患者随机分为 HMVP组( 46例)、 MVP组( 44例)和 HVP组( 44例),接受相应方案的化疗,观察各组的近期及远期疗效、不良反应和生存情况.结果 HMVP、 MVP和 HVP三组的有效率分别为 39.54%、 36.59%和 26.19%,三组之间无显著性差异( P >0.05);三组的中位缓解期、中位生存期、 1年及 2年生存率亦无明显差别.三组之间的Ⅲ～Ⅳ度白细胞减少、Ⅲ～Ⅳ度血小板减少、Ⅲ～Ⅳ度恶心 / 呕吐及Ⅲ～Ⅳ度便秘发生率均无显著性差异( P >0.05).结论 MVP方案治疗晚期 NSCLC的疗效略低于 HMVP方案,但后者未显示出明显的疗效优势,且可能增加白细胞抑制、恶心 /呕吐和便秘的发生率. MVP方案疗效略高于 HVP方案.     

LP和TP方案治疗晚期非小细胞肺癌的临床研究(英文)

Objective:The aim of the study was to evaluate the responses and toxicities of liposome encapsulated paclitaxel (LEP) plus cisplatin (DDP) (LP regimen) and paclitaxel (TAX) plus DDP (TP regimen) in the treatment of advanced non-small cell lung cancer (NSCLC). Methods: A total of 89 cases with advanced NSCLC was randomized into two groups: the LP group (57 patients) and the TP group (32 patients). The responses, toxicities and survivals of the two groups were compared. Results: The response rates were 40.00%...     

HPV感染对口咽癌无病生存期影响的Meta分析

目的 综合评价人乳头状瘤病毒（HPV）感染与口咽癌无病生存期（disease-free survival,DFS）的关联。方法 检索中国知网、维普、万方、PubMed等数据库,全面收集研究HPV感染与口咽癌无病生存期关系的文献,设定纳入和排除标准,评价文献质量,检验异质性,计算合并风险比（HR）及其95%可信区间（95%CI）,评估发表偏倚。结果 纳入文献16篇,口咽癌病例共2 512例,其中HPV阳性1 210例,HPV阳性率48.17%,HPV阴性1 302例。与HPV阴性相比,HPV感染的口咽癌病例复发或转移风险较低（合并HR: 0.371, 95%CI: 0.231~0.511）,其中HPV-16型感染对口咽癌DFS的合并HR为0.248, 95%CI: 0.132~0.365;HPV阳性且p16蛋白表达对口咽癌DFS有保护作用（合并HR:0.281, 95%CI: 0.137~0.424)。结论 HPV感染对口咽癌无病生存期可能有保护作用。     

Bortezomib-related neuropathy may mask CNS relapse in multiple myeloma: A call for diligence

Background: Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system (CNS) relapse in MM remains exceedingly rare and carries a dismal prognosis. We present an unusual case of bortezomib related neuropathy masking a CNS relapse of MM. Case presentation: A 57-year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement. She was treated with 4 cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a VGPR, after which she underwent an autologous stem cell transplant (ASCT) followed by bortezomib maintenance. Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse. Discussion: CNS involvement in MM (CNS-MM) is uncommon and is considered an aggressive disease. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis. Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib-based therapy. The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement. Conclusion: In the era of proteasome inhibitor (PtdIns)/immunomodulator (IMID)-based therapy for MM which carries neurologic adverse effects, it is prudent to consider CNS relapse early. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration.     

Marked radiosensitization of cells in culture to X ray by 5-chlorodeoxycytidine coadministered with tetrahydrouridine, and inhibitors of pyrimidine biosynthesis

Our approach to overcome the problem of rapid catabolism and general toxicity encountered with 5-halogenated analogues of deoxyuridine (5-bromo, chloro or iododeoxyuridine), which has limited their use as tumor radiosensitizers, is to utilize 5-chlorodeoxycytidine (CldC) with tetrahydrouridine (H4U). We propose that CldC, coadministered with H4U, is metabolized in the following manner: CldC----CldCMP----CldUMP---- ----CldUTP----DNA. All the enzymes of this pathway are elevated in many human malignant tumors and in HEp-2 cells. In X irradiation studies with HEp-2 cells, limited to 1 or 2 radiation doses, we have obtained 3.0 to 3.8 apparent dose enhancement ratios (these represent upper limits) when cells are preincubated with inhibitors of pyrimidine biosynthesis: N-(Phosphonacetyl)-L-aspartate (PALA) and 5-fluorodeoxyuridine (FdU) or 5-fluorodeoxycytidine (FdC) + H4U. Optimum conditions for radiosensitization are: PALA (0.1 mg/ml) 18-20 hr prior to FdU (0.1 microM) or FdC (0.02 microM) + H4U (0.1 mM) followed 6 hr later by CldC (0.1-0.2 mM) + H4U (0.1 mM) for 56-68 hr. Viabilities of 10 +/- 4% to 15 +/- 1% (+/- S.E.) were obtained for drug-treated unirradiated cells. Enzymatic studies indicate that this toxicity may be tumor selective. CldC + H4U alone (at these concentrations) results in 20% substitution of CldU for thymidine in DNA (determined by HPLC analysis). Preliminary toxicity studies indicate that mice will tolerate treatment protocols involving a single dose of PALA (200 mg/kg) followed by a dose of FdU (50 mg/kg) and 3 cycles of CldC (500 mg/kg) + H4U (100 mg/kg) at 10 hour intervals, with marginal weight loss (4%). In this approach we seek to obtain preferential conversion of CldC to CldUTP at the tumor site by taking advantage of quantitative differences in enzyme levels between tumors and normal tissues.