肝细胞癌的靶向治疗

近年来,随着肝细胞癌(HCC)分子机制研究深入,靶向治疗也得到了迅猛发展,在延缓和改善患者疾病进展和预后方面作出了巨大贡献。由于HCC的发病机制错综复杂,单一的分子靶向治疗总体临床收益并不理想。因此,近年来靶向联合其他治疗方式的新方案不断出新,并取得了令人鼓舞的成果。就HCC分子靶向治疗药物、研究现状及临床联合应用治疗进展予以简要总结。     

分子靶向药物与免疫抑制剂联合治疗及其他联合治疗在肝细胞癌中的应用

肝细胞癌(HCC)是最常见的恶性肿瘤之一,发病隐匿,发展迅速,高复发的特点导致HCC患者长期生存面临巨大挑战。分子靶向药物与免疫抑制剂在HCC治疗中成为研究的热点,大量临床试验发现,联合治疗取得了不错的疗效。主要介绍了分子靶向药物与免疫抑制剂联合治疗及其他联合治疗在HCC中的应用,指出当前HCC治疗的最新研究热点在于系统治疗或局部治疗相关的联合治疗。     

本期导读

肝细胞癌(HCC)分子靶向药物及免疫检查点抑制剂(ICIs)治疗已成为不可切除HCC一线治疗方案及根治性治疗高复发风险患者抗复发治疗的选择之一。本期执行主编南月敏教授为本刊组织了HCC靶向及免疫治疗肝损伤应对策略的重点号专题。南月敏教授等从HCC分子靶向药物、ICIs及其联合治疗方案的适应证, 与靶向药物、ICIs单用和联合用药相关肝损伤的管理策略方面进行了评述(南月敏等, 第1121 ～ 1124页)。HCC一线治疗的ICIs均需靶免联合或双免联合治疗, 这增加了免疫相关不良事件的风险, 如ICIs肝毒性。茅益民教授等总结了ICIs相关肝毒性的流行病学、风险因素、临床特征及管理策略(支阳等, 第1125 ～ 1128页) 。分子靶向药物已成为晚期HCC患者的重要治疗手段, 肝损伤是靶向药物常见的不良反应之一。赵素贤教授等总结了HCC靶向药物导致肝损伤的发生情况、机制、危险因素、诊断和治疗策略(赵素贤等, 第1129 ～ 1132页)。大多数HCC患者发现时已为中晚期, 靶免联合治疗成为主要的治疗方案。然而, 不少患者由于存在肝脏基础病变肝功能不能满足靶免治疗的要求, 影响疗效。张缭云...     

肝细胞癌的分子靶向治疗

肝细胞癌(hepatocellular carcinoma, HCC)死亡率居所有肿瘤的第二位,且近年在我国有上升趋势.因其发病隐匿、进展快、预后差,一直是研究的热点和难点.近10年来, HCC的治疗方法有了显著性进展,尤其是分子靶向药物的使用和研究,开启了HCC治疗方法的新阶段.本文就目前HCC发生发展相关信号通路及潜在分子靶点的研究现状、分子靶向治疗药物临床使用状况以及新药研发进展做了比较详细地叙述.     

肝细胞癌的免疫治疗

在过去的10年里,肝细胞癌(HCC)系统治疗的进步归功于分子靶向治疗的应用及免疫治疗的提高。HCC所处的免疫抑制微环境使肝癌细胞逃逸免疫系统的攻击,这亦为肝癌发展的重要原因,通过提高针对HCC的免疫杀伤能力,纠正免疫抑制状态是HCC免疫治疗的策略。HCC特异性抗原为基础的肿瘤疫苗治疗、基因工程改造的T淋巴细胞治疗、免疫检查点抑制剂的基础研究及临床转化使免疫治疗效果较过去有了显著提高。免疫治疗联合其他抗肿瘤治疗方法如局部消融、分子靶向治疗或肿瘤疫苗等综合治疗模式值得进一步探索。     

肝细胞癌的分子靶向治疗

分子靶向治疗是近10年来肿瘤治疗领域的重大突破,在肺癌、恶性胃肠间质细胞瘤、恶性淋巴瘤、肠癌、乳腺癌等肿瘤的治疗中已获得很大的成功,尤其HCC的分子靶向治疗在小分子靶向治疗上取得了令人瞩目的新进展,特别是多靶点药物索拉非尼在HCC的靶向治疗中取得的成功,使HCC分子靶向全身治疗有了新的标准。     

重视肝细胞癌靶向及免疫治疗的肝损伤

肝细胞癌(HCC)分子靶向药物及免疫检查点抑制剂(ICIs)治疗已成为不可切除HCC一线治疗方案及根治性治疗高复发风险患者抗复发治疗的选择之一。一线分子靶向药物联合ICIs治疗或双免治疗的中位总生存期、客观缓解率均较单一靶向药物显著改善。HCC靶向及免疫治疗适用于Child-Pugh A～B级患者, 靶向药物所致肝损伤包括转氨酶、胆红素异常, 严重者可发生低蛋白血症、腹水等。ICIs相关性肝炎多发生于1～3个疗程(4～12周), 其治疗可应用糖皮质激素, 必要时加用吗替麦考酚酯等免疫抑制剂治疗, 肝功能复常后可根据全身状况及肿瘤治疗需求选择不同作用机制靶向药物及ICIs治疗。     

肝细胞癌分子靶向治疗进展

目前肝细胞癌(HCC)的主要治疗手段包括手术、化疗和放疗等。随着分子生物学技术的不断发展,分子靶向治疗迅速崛起。针对HCC发生发展相关的信号通路中某些特定位点设计靶向药物,成为HCC治疗研究的新热点。就近年来HCC的相关信号通路和对应的靶向治疗药物进行简要阐述。     

肝癌的免疫治疗进展

近年来,随着生物治疗技术的发展,免疫治疗成为了目前肿瘤治疗研究的热点。肝细胞癌(hepatocellular carcinoma,HCC)是最常见的肝脏恶性肿瘤,其治疗以手术、介入治疗、分子靶向治疗以及全身系统化疗等多种治疗手段联合应用,但效果不理想,无进展生存期及中位生存时间仍不尽人意。该文应用Pub Med数据库及中国期刊全文数据库(CNKI)检索系统,以"肝细胞癌、免疫治疗、免疫耐受"为关键词进行检索分析,总结了最近几年免疫疗法在肝癌治疗方面中的进展。重点是肝脏免疫系统的特殊性、HCC的免疫耐受性和HCC的免疫治疗策略,包括疫苗适应性治疗、免疫检查点抑制剂和细胞因子,以及靶向治疗联合免疫治疗在肝癌治疗中的应用等方面。希望能为临床医师了解肝癌免疫耐受的机制和HCC免疫治疗的进展和临床疗效提供参考。     

肝细胞癌的分子靶向治疗

肝细胞癌(hepatocellular carcinoma,HCC)是人类第5大恶性肿瘤,死亡率极高.在我国,HCC的治疗已取得显著进展,但总体发病率和死亡率尚无明显改观,对于不适宜手术切除的晚期HCC,现有的药物治疗并不能改善患者预后,进一步提高疗效仍面临严峻挑战.所以,发现新的靶向治疗药物或新的靶点对HCC的早期诊断、化学预防以及治疗显得尤为重要.目前从对HCC发生、发展的分子机制的研究中,人类已发现了多个潜在分子靶点.这些靶点大部分为酪氨酸激酶受体激活的信号传导通路,包括:Raf/MEK/ERK,PI-3K/Akt/mTOR和Jak/Stat等.以索拉菲尼、舒尼替尼等为药物代表的多靶点、多激酶抑制剂治疗HCC更是受到高度关注.本文主要介绍HCC潜在的分子靶点以及常用靶向药物的临床进展.     

Three layer functional model and energy exchange concept of aging process

Relying on a certain degree of abstraction, we can propose that no particular distinction exists between animate or living matter and inanimate matter. While focusing attention on some specifics, the dividing line between the two can be drawn. The most apparent distinction is in the level of structural and functional organization with the dissimilar streams of ‘energy flow’ between the observed entity and the surrounding environment. In essence, living matter is created from inanimate matter which is organized to contain internal intense energy processes and maintain lower intensity energy exchange processes with the environment. Taking internal and external energy processes into account, we contend in this paper that living matter can be referred to as matter of dissipative structure, with this structure assumed to be a common quality of all living creatures and living matter in general. Interruption of internal energy conversion processes and terminating the controlled energy exchange with the environment leads to degeneration of dissipative structure and reduction of the same to inanimate matter, (gas, liquid and/or solid inanimate substances), and ultimately what can be called ‘death.’ This concept of what we call dissipative nature can be extended from living organisms to social groups of animals, to mankind. An analogy based on the organization of matter provides a basis for a functional model of living entities. The models relies on the parallels among the three central structures of any cell (nucleus, cytoplasm and outer membrane) and the human body (central organs, body fluids along with the connective tissues, and external skin integument). This three-part structural organization may be observed almost universally in nature. It can be observed from the atomic structure to the planetary and intergalactic organizations. This similarity is corroborated by the membrane theory applied to living organisms. According to the energy nature of living matter and the proposed functional model, the decreased integrity of a human body's external envelope membrane is a first cause of the structural degradation and aging of the entire organism. The aging process than progresses externally to internally, as in single cell organisms, suggesting that much of the efforts towards the restoration and maintenance of the mechanisms responsible for structural development should be focused accordingly, on the membrane, i.e., the skin. Numerous reports indicate that all parts of the human body, like: bones, blood with blood vessels, muscles, skin, and so on, have some ability for restoration. Therefore, actual revival of not only aging tissue of the human body's membrane, but the entire human body enclosed within, with all internal organs, might be expected. We assess several aging theories within the context of our model and provide suggestions on how to activate the body's own anti-aging mechanisms and increase longevity. This paper presents some analogies and some distinctions that exist between the living dissipative structure matter and inanimate matter, discusses the aging process and proposes certain aging reversal solutions.     

Unusual responses of nocturnal pineal melatonin synthesis and secretion to swimming: Attempts to define mechanisms

Abstract: The effect of swimming at night on rat pineal melatonin synthesis was compared with that of light exposure at night. Rats were forced to swim at 0030 hr (lights out at 2000 hr) and sacrificed by decapitation 15 and 30 min later, immediately after swimming. Other groups of animals were exposed to white light (650μW/cm²) for 15 and 30 min at same time. Swimming caused a rapid and highly significant drop in the melatonin content in the pineal gland; however, the activity of N-acetyltransferase (NAT), the supposed rate limiting enzyme in the melatonin production, was not changed. Despite the drop in pineal melatonin levels, serum concentrations of the indole remained elevated in the rats that swam. In contrast, melatonin levels in the pineal and serum of light exposed rats fell precipitously, accompanied by a significant suppression of NAT activity. Since we anticipated that the strenuous exercise associated with swimming may induce release of artrial natriuretic peptide (ANP) from the heart, which in turn could cause the release of pineal melatonin, in a second study we injected physiological saline intravenously to stretch the cardiac muscle and release ANP. Three milliliters of normal saline was injected during the day into the jugular vein of anesthetized rats that were pretreated with isoproterenol to stimulate pineal melatonin production. Animals were killed 15 min after the saline injection, and pineal NAT activity and pineal melatonin levels were measured. The saline injections caused no alteration in the elevated levels of either NAT or melatonin. These data suggest that the disparity in pineal NAT activity (which was high) and pineal melatonin (which was low), in animals swum at night, may not be caused by ANP which is released during strenuous exercise such as swimming.     

Melatonin and photoperiodic time measurement: Seasonal breeding in the sheep

Abstract: Well-established circadian physiology supports the view that photoperiodic time measurement utilizes the coincidence between the presence of light and a photosensitive phase of a 'biological clock' to alter reproductive status—the so-called external coincidence model of seasonal breeding. In this review, we examine the mechanism whereby photoperiod interacts with presumed suprachiasmatic nuclei activity to allow endogenous melatonin to normally synchronize reproductive activity to the optimal time of year. The Romney Marsh sheep is particularly explored as an experimental model. It is suggested that the on/off activity of seasonal reproduction may be a robust mechanism able to be predictably manipulated by the judicious use of the light/dark cycle and exogenous melatonin, but firmly based on circadian principles.     

The immunoneuroendocrine role of melatonin

Abstract: A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MHO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as -γ-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.     

Serological survey of HIV and syphilis in pregnant women in Madagascar

Objectives Peripartal transmission of human immunodeficiency virus (HIV) and Treponema pallidum, the causative agent of syphilis, leads to severe consequences for newborns. Preventive measures require awareness of the maternal infection. Although HIV and syphilis testing in Madagascar could be theoretically carried out within the framework of the national pregnancy follow‐up scheme, the required test kits are rarely available at peripheral health centres. In this study, we screened blood samples of pregnant Madagascan women for HIV and syphilis seroprevalence to estimate the demand for systemic screening in pregnancy. Methods Retrospective anonymous serological analysis for HIV and syphilis was performed in plasma samples from 1232 pregnant women that were taken between May and July 2010 in Ambositra, Ifanadiana, Manakara, Mananjary, Moramanga and Tsiroanomandidy (Madagascar) during pregnancy follow‐up. Screening was based on Treponema pallidum haemagglutination tests for syphilis and rapid tests for HIV, with confirmation of positive screening results on line assays. Results Out of 1232 pregnant women, none were seropositive for HIV and 37 (3%) were seropositive for Treponema pallidum. Conclusions Our findings are in line with previous studies that describe considerable syphilis prevalence in the rural Madagascan population. The results suggest a need for screening to prevent peripartal Treponema pallidum transmission, while HIV is still rare. If they are known, Treponema pallidum infections can be easily, safely and inexpensively treated even in pregnancy to reduce the risk of transmission.     

Response of rat pineal melatonin to calcium, magnesium, and lithium is circadian stage dependent

Abstract: Herein we documented the response of pineal melatonin production to electrolytes known to be effective on pineal function in view of a possible circadian stage dependence. We studied the release of melatonin by perifused rat pineal glands at 2 different circadian stages corresponding to the middle of the light and dark periods, i.e., respectively, 7 and 19 HALO (Hours After Light Onset, L:D = 12:12). The initial efflux rates were, as expected, much higher in the perifusates of glands removed from rats sacrificed during the dark phase than of those removed during the light phase. After 3 hr of perifusion, melatonin release reached similar levels which were found constant up to the 8th hr of perifusion, whatever the circadian stage. Perifusion of the glands with physiological concentrations for the rat of calcium (5.2 mmol/1) and magnesium (1.34 mmol/1) resulted in a stimulatory effect on the pineal glands removed from rats sacrificed in the middle of the dark period (19 HALO), whereas no effects were observed on the pineal glands removed from rats sacrificed during the light (7 HALO). Lithium (0.28 and 0.55 mmol/1) was ineffective on melatonin release in pineal glands removed 7 and 19 HALO. Our results show differences in the initial efflux rates of melatonin and in the response of perifused pineal glands to calcium and magnesium according to the circadian stage.     

Conservative management of perforated duodenal diverticulum： A case report and review of the literature

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs.