@Tivens 2017-05-09 22:04:37
巨噬细胞，作为固有免疫的重要组成部分，通常扮演抵御病原体入侵的“排头兵”和激活适应性免疫的“通信兵”。但是，在肿瘤环境中，它却禁不住肿瘤细胞释放的一些信号分子的“诱惑”，变成了“叛军”：它不仅阻止T细胞等攻击肿瘤细胞，还会分泌生长因子滋养肿瘤细胞，促进肿瘤血管的生成，导致肿瘤细胞转移扩散[1]。据统计，巨噬细胞可占肿瘤总重量的一半[2]！面对如此众多的 “叛变”巨噬细胞，有没有方法改变肿瘤环境，对巨......
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媒体报道总是和现实相差很远，正好我知道，就说点现实的不会报道的事实吧。
Weissman实验室在Stanford是大牛，但是他们实验室做动物试验最牛的老师是我们实验室出去的。后来在那里做了一年不顾挽留自愿降低待遇回到了我们实验室。我估计她宁愿安安静静听我聊探论怎么治病也不愿意看那些自以为是的博士后和进修医生是怎么创造出一篇篇的nature和science 文章的吧。当然，还是那句老话，这些所谓的医学“突破”再过5-10年还会有人记起吗？但是探论还会在这里，只是更加灿烂。

@Auferstehung1 2017-05-21 23:00:15
（6）好像临床上上述（2）靶点易变（CD19抗原选择性缺失）？这倒也容易理解，因为选择性杀伤太精准。那么是不是单一靶点易变和其他靶点因特异性不强易造成严重的自体免疫攻击所以难找到可临床的其他靶点可能是CART技术最终用途可能会仅局限于给患者多一次传统治疗机会的原因？而如果（5）为真，那么多一次的传统治疗可能并不能得到最后的更优结果？另一方面，如果单疗程或多疗程CD19抗原选择性缺失中位时间较晚，那么CART因......
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对你的推测，我简单回答我的看法：
1）CART在血液肿瘤的阿疗效不是其本身特有的性质：任何通过血液实施的减负治疗（化疗，靶向，抗体，免疫）都会有远比实体瘤要高的疗效。这也是为什么我们一半看不到在这里救助的血液肿瘤病例的原因。
2）只要靶点不变，疗效不变是成立的。临床应该已经证实
3）间歇维持是临床上已经做的，如果出现复发，应该是靶点逃逸。
4）只要转移灶继续表达靶点一定有意义
5）CART类似靶向药，一定会造成抗原剥夺效果，所以一定会跟共存免疫抢饭吃
6）CART的最大贡献是演示了免疫细胞杀伤里的强大。真要指望临床应用会受靶点不特异的限制，这个两年前我在帖子里有论述。至今看我没有说错，不可能广泛应用的。

读过我新版《探论》的朋友大概还记得我在第二篇结尾的时候提到了Dunphy医生1950年的社论，其中讲了4个病例来说明癌症的不可测和背后的“自然抵抗力”。我说到将近70年快要过去了，主流医学还是没有人能够回答Dunphy医生当年的这四个病例背后的原因。探论讲了那么多，很多都是可以用来回答这些病例背后原因的，只是还没有一个专门针对这4个具体病例分析的文字。我想不管怎么说，做为医学界，我们必需对这些病例有一个“交待”，所以写了一个“读者来信”，投给新英格兰医学杂志（因为1950年Dunphy的社论就是他们发表的），希望他们能对这个历史遗留的问题给予答案和讨论。我不指望他们会接受并发表，但是我只能做我能做的：就是做为医学研究的一个晚辈，对前辈留下的“猜想”进行探索和回答。剩下的是编辑部的责任和良心了。好在他们发不发表你们都可以看见，因为做为见证，我把全文放在我的博客和这里。

Letter to the editor about two classic papers by J Englebert Dunphy on cancer
We read Dr J Englebert Dunphy's original article in the NEJM with great interest (1). He described four cases of cancer in man that had periods of spontaneous arrest or regression alternating with periods of growth. His hypothesis for this observation is that it is a function of local tissue resistance. We call this phenomenon concomitant anti-tumor immunity. We note that it is present in most cancer patients at some time of their disease process and clinicians need to be aware of it and use it to the advantage of the patient. In the first case, Dunphy described a dramatic spontaneous cancer regression occurring in a terminally ill patient. Spontaneous tumor regression is no longer a mysterious phenomenon as more and more cases have been reported (2-9); however, a dramatic reversal from near death to complete tumor regression is still rare and commends high attention. What caused this dramatic reversal and spontaneous tumor regression? And why did it occur before death? A systemic enormous anti-tumor effect like this can be explained by immunity, or what Dr. Dunphy called a "natural resistance". Subsequently there is a gradual decay of this immunity following the regression of the original tumor (7 years in this case) that may account for the recurrence. Furthermore, upon tumor recurring, the decayed immunity was stimulated and returned forming again a concomitant anti-tumor immunity. The description of well encapsulation of the recurring tumor is consistent with this explanation because tumor encapsulation is often the result of immune cell encirclement. Experienced surgeons realize that well encapsulated tumors have a better post-surgery prognosis as this is a sign of immune cell recognition and infiltration (10-12). In this case, the patient remained disease-free after removal of the recurrent tumor supporting the plausibility of the return of the anti-tumor immunity and its continued surveillance after surgery. This case represents several important aspects of cancer and immunity that are still poorly recognized in clinic today. For example, the presence of an anti-tumor immunity has long been acknowledged yet its exact role in each cancer patient remains unidentified and often totally ignored. In cases of dramatic spontaneous tumor regression like this, the role of anti-tumor immunity is well accepted, but not in any other patient where there is no clear sign of its presence. Does concomitant antitumor immunity exist broadly in cancer patients? Recent clinical success of the immune checkpoint therapy, such as PD-1 blockade, supports the presence of concomitant immunity in seemingly hopeless patients because its mechanism is the removal of inhibited anti-tumor immunity (13), implying that there was one to begin with. Then, what did the inhibited immunity do before it was inhibited? Or, what happens to such immunity when it is left after tumor removal? Like in this case, if the concomitant anti-tumor immunity protected this patient from further recurrence for a long period of time, then it may be the same for stage I-III cancer patients who have had their primary tumor removed by surgery and remain clinically disease free. If so, the strength of the concomitant anti-tumor immunity does not have to cause total regression of tumor, it just needs to be sufficient to protect the host from recurrence of tumor after surgery. After all, from an immunological point of view, a complete clearance of antigen signals the ongoing immunity to form an immunological memory (14, 15). It may not be critical how the antigen is cleared, by surgery, chemotherapy, radiation or immune response, as long as it is cleared in the presence of an effective immunity, there will likely be a subsequent immunological memory (15, 16). On the other hand, if the antigen is not cleared, the concomitant immunity not only fails to convert to memory, but may down regulate because of a reduced level of tumor antigens (14, 17). This may explain the accelerated progression of tumor following incomplete cancer resection (the 4th case cited by Dunphy, see below). The disease reversal just before death in this case is consistent with a late initiation of concomitant immunity. Further, we note that the cancer was not discovered by symptoms, but rather accidentally during surgery for a ventral hernia. It appears that there was no anti-tumor immunity at the time of diagnosis from two observations: the lack of cancer-related symptoms (inflammatory symptoms are a clinical sign of immune response) and the presence of wide spread of metastases (a finding that suggests lack of immune surveillance). Excision of tumor at this stage would not result in a long period of disease-free survival due to lack of immune protection. Even in some of the "early detection" cases where there was no metastases detected at the time of tumor removal, quick recurrences can occur after surgery (again, see the 4th case cited by Dunphy). A lack of concomitant immunity is likely the real reason behind these failed cases. On the other hand, both the development of a terminal stage and then the dramatic reversal may also be explained by heightened immunity. Immune response causes most of the suffering and even the fatality associated with various viral infections raging from flu, hepatitis to more lethal viral diseases such as SARS and Ebola. Why wouldn't immunity to cancer be similar? In this patient, the anti-tumor immunity eventually started and was amplified to attack the large tumor burden, This severe immune attack destroyed the tumor and also brought severe side effects from an inflammatory response. The difference between this patient and many other fatal cases is likely a balance between complete tumor eradication and host toxicity. In this regard, it is also puzzling that not all tumor destruction by anti-tumor immunity is associated with severe symptoms. We, and others, have observed that asymptomatic lung cancer diagnosed during routine annual checkups often presents with intense immune response at the site of tumor, indicating that these tumors regress quietly without ever being noticed. It is not clear why such a strong immune response does not cause symptoms. One observation suggests that these immune responses are always Th1-typy that inhibit tumor replication. So the scale and the type of the anti-tumor immune response (Th1,Th2,Th17, etc.) may determine the presence and severity of symptoms in cancer patients.

In the second case cited by Dr. Dunphy, a 69-year old woman underwent cholecystectomy and appendectomy. Small breast cancer metastases were found in the appendix 14 years after apparently curative breast cancer surgery. Two weeks after the current abdominal surgery a pleural effusion developed and breast tumor cells were found in the fluid. A third tapping a year later showed no more tumor cells. Again, we see strong evidence for anti-tumor immunity. Breast cancer has a more favorable prognosis among several other major solid tumors such as lung, colon, ovarian, stomach and liver (www.sser.cancer.gov). It is not coincidental that concomitant anti-tumor immunity is also most prominent in breast cancer (18-21). Biopsy and surgery to excise tumor tissues from breast cancer patients consistently indicated heightened immune responses characterized by presence of large numbers of T cells that coincide with destruction of tumor structure and inhibition of tumor replication (22). As we have pointed in the previous case analysis, a strong concomitant anti-tumor immunity is likely to translate into better post-surgery protection through conversion into high levels of immune memory. In this second case, it had been 14 years. What is intriguing, or disturbing, is the rapid appearance of cancerous pleural effusion soon after the unrelated surgery to remove the appendix and gall bladder. Cancer recurrences are expected based on statistics, yet sometimes an unrelated disease or change of a body condition triggers a recurrence. For example, surgery may cause a temporary immune suppression and stimulation of tumor growth through factors that are secreted for wound healing (23-25). Local inflammation results in many factors that trigger cellular growth and angiogenesis, and may cause cancer recurrences that can occur even 5-10 years later. After a long latency period, only those disseminated individual tumor cells that cannot establish vascular supply by themselves are left, because those that can have done so already. The observation that latent cancer metastases from donor tissues develop in recipient patients following organ transplantation support this view (26). These observations suggest that cancer may be a life-time disease even when it is previously eradicated macroscopically (27). Recurrence and metastases seem to follow two modes of establishment: a self-driven way that establishes a vascularized growth based on the inherent ability of the disseminated tumor cell itself, and an environmental-driven way that accomplishes initial vascularization by the help of a changed local environment then followed by a self-sustaining fashion. In a predictable and consistent environment after eradication of primary tumor by surgery or other means, one would expect to see the action of the self-driven way, and it should follow an L-shaped curve with less and less possibility of metastases as time passes. This is the behavior we see by statistic in most cancer patients. But in each individual case, whether the vascularized cancer can progress further depends also on, among other host factors, the presence and strength of anti-tumor immunity. Only when such immunity is absent or decays in strength to minimal levels does establishment of metastases occur. In this respect, the residual strength of anti-tumor immunity following surgery should also be L-shaped, protecting the host more when there are more self-driven metastases, and less when the self-driven metastases dissipate. There should be a time when all self-driven vascularization is exhausted and anti-tumor immunity is also out of effective surveillance. Only after reaching this phase, an environmental-driven vascularization and progression of recurrent cancer will become relevant. In this second case cited by Dr. Dunphy, the quick appearance of cancerous pleural effusion following gall bladder surgery 14 years after the initial breast cancer surgery should be an example of such an environmental-driven recurrence. What is also intriguing and revealing, is what the decayed immunity did after the recurrence. In this case the disease did not progress further and even regressed macroscopically. Such docile behavior of recurrent cancer is rather exceptional by overall clinical observations. In general, most patients die of effects of recurrent and metastatic cancer rather than the primary tumor. It is the general observation that once a cancer recurs after surgery, the disease enters a much more difficult phase of management. But in this case, there was no treatments following cancer recurrence and the patient experienced control and subsequently the tumor eventually regressed. The observation is explained again as an action of anti-tumor immunity. It is known in immunology that a repeat stimulation with a recurrent antigen usually causes a heightened immune response compared to an initial stimulation. This behavior of immunological memory should not have exceptions when it comes to anti-tumor immunity. In this case, the return of the breast cancer due to surgery stimulation caused the return of the antitumor immunity that had been dormant due to a long time absence of tumor antigen. The fact that the cancer recurrence was accompanied by a large chest effusion indicated that the tumor recurrence initiated an inflammatory response by the host anti-tumor immune system that was either innate or antitumor-specific. The subsequent control and regression of the pleural effusion supported the fact that the specific anti-tumor immunity that protected the patient from post-surgery recurrence and metastases had returned and amplified. What this case has demonstrated is that like other adaptive immune responses, antitumor immunity behaves similarly in that it decays without persistent antigen stimulation and it will return upon further detection of antigens. This is important because it suggests that recurrent cancer patients should be managed differently from patients who present with the original cancer. If cancer returns after a long period (over a year) from surgery, it is likely that the primary tumor has maintained a concomitant anti-tumor immunity that has decayed. Similarly, we should expect to see that this decayed anti-tumor immunity will return and accompanied by symptoms due to an anti-tumor immune attack. This may explain some of the heightened symptoms associated with tumor recurrence such as pleural effusion, ascites and hepatitis. When the immune return is delayed, the recurrent tumor burden is large, often lethal consequences from immunopathology take place.

The third case discussed by Dr. Dunphy is about different behavior of different sites of metastases in the same patient. The original liver metastases from colon cancer progressed slowly for over two years after colon surgery, while an ovarian metastasis of the same tumor progressed rapidly over 6 months to reach 12cm, demonstrating a variable growth rate of the same tumor at different sites in the same patient. The differential growth rate of the same tumor at different locations is common and is explained by a different environment that provides different nutritional and growth factors. But there may be an additional explanation based on differential control by antitumor immunity. Since metastases arise from a single tumor cell disseminated from a primary tumor that is often composed of a complex mixture of various mutated tumor cells with specific antigens, the antigenicity of each disseminated tumor cell may not be the same as the primary tumor. In this regard, it may be that a metastasis is a totally different tumor from an immune point of view. As such, a concomitant antitumor immunity raised and maintained by the primary tumor may not be able to recognize certain metastases from that tumor and thus may not curtail their progression. This heterogeneity in antigenicity may present a serious challenge to immunological management of cancer recurrence. For example, we have seen cases where a heightened anti-tumor immunity returned after a recurrence and caused severe local inflammation that resulted in ascites. During this process, some of the early recurrences disappeared whereas other new ones developed, making it difficult to explain why a heightened anti-tumor immunity strong enough to eradicate previously established early recurrences could not prevent establishment of others. In instances where these immune resistant tumors were surgically removed and analyzed for T cells by immunohistochemistry, the observations always showed a lack of immune infiltrates in such tumors that contrasted significantly to the heightened immune T cell response profiles in recurrent tumors that were sensitive to growth inhibition by concomitant immunity. These observations may explain the two extreme directions of change in tumor burden before death in patients with strong concomitant immunity: either significant tumor reduction accompanying life-threatening symptoms or systemic inflammation and wide-spread and explosive progressing metastases.

Another interesting observation from this case is the rather unusual slow progression of residual liver metastases following incomplete surgery. This forms a clear contrast to the next case cited by Dr. Dunphy that was about a 59-year old patient who also had colon cancer. The primary tumor was large, but resectable. At surgery, extensive lymph node metastases were present and the liver was free of visible disease. Nevertheless, the patient died of explosive progression of liver metastases in just 10 weeks following surgery. It seems clear that the cancer surgery had accelerated the death. The side-by-side comparison of the two cases is confusing. As Dr. Dunphy discussed in this case: "The question … is not what makes the cells suddenly grow but what has held them in abeyance for so long". Although there was insufficient information about this case, the two-year long symptom history and the lack of visible liver metastases at the time of surgery suggested that there was sufficient concomitant anti-tumor immunity that inhibited the establishment of liver metastases before surgery. This immunity was affected by subsequent incomplete antigen clearance at the time of surgery. It is likely that the residual abdominal lymph node metastases (the presence of which was confirmed at the time of surgery) presented a greatly reduced antigen load. Unlike the previous case where the residual tumor burden is large, the residual tumor burden in this case was small. This new antigen balance could no longer prevent the establishment of liver metastases. In addition to a weakened anti-tumor immunity, the growth promoting effects of surgery itself further made things worse. If so, this case demonstrates the ever more pressing need to preserve established concomitant anti-tumor immunity following cancer surgery. In order to do this, we can propose three approaches. First, complete surgical resection is critical because it assures the clearance of antigen and formation of memory. Second, to make sure that an immune response is not affected by reduction of antigen. This is common in the responses against acute infections where the immunity is intense till complete antigen eradication is achieved. The most critical difference between immune responses against invading microbes and cancer may not be antigen, but the source of antigen: self vs non-self as immunologists have long argued (28-30). In one mechanism, the difference is presented to responding T cells in the form of certain immune factors produced after seeing non-self by antigen-presenting cells (31). Such danger-associated factors will then modify antigen-activated T cells to make them committed to a strong response resisting down-regulation (32-35). Our previous studies have indicated that when antitumor immunity can be manipulated towards that of anti-infection by providing such a danger factor, dramatic antitumor effects including complete eradication of large tumor burdens can ensue (36). Further, when antitumor immunity can be activated through combination of chemotherapy and danger signal at the time of surgery, a strong post-surgery protection is obtained (37). The third is preservation of immunity made by continued supply of highly visible forms of antigen, this may be achieved through post-surgery cancer vaccine made with tumor materials removed at the time of surgery. In fact, supply of cancer antigen at the time of immunity decay should always be the primary consideration for any vaccine trial. If in a case like this one, the immediate decay of antitumor immunity due to incomplete surgery is the concern, tumor vaccine should be given immediately following surgery to keep the immunity from decreasing. In another case, if the post-surgery immunity keeps working for 1-2 years before decaying (like many solid tumor cases), tumor vaccine should be delayed till then. In this aspect, treatment is case-based, not protocol-based. All of these measurements can be utilized in cancer management, but currently have not. The reason is not technical, but conceptual. Up to now, the way to avoid the disastrous consequence of incomplete surgery has been to avoid it all together through rigid TNM staging guidelines that emphasize surgery for localized disease and avoidance of surgery for distant metastases. However, many stage IV cases have concomitant anti-tumor immunity that can be used as part of an effective treatment plan. In these cases, the balance between concomitant immunity and primary tumor and metastases effectively make them more manageable like Stage II and not Stage IV cases. If the primary tumor and the metastases can be completely excised (which is often able to be achieved), the host will be left with a protective immunity that is as same as surgery on Stage I and II cases. Similar good results have been previously reported without knowing the explanation. For example, in lung cancers with a single brain metastasis, multiple clinical trials have been done to determine the role of surgery. The results are variable with seemingly identical cases some achieving clinical cure and other suffering explosive recurrence and death (38-40). If concomitant anti-tumor immunity can be assessed in each of these cases, a surgery decision may be based on the status anti-tumor immunity and not the extent of disease. Thus the argument described here is that in many cases, the proper use of anti-tumor immunity will enhance the outcome for cancer patients.

In 1953 Dr. Dunphy, upon reflecting on these unpredictable behavior of cancer, published another discussion on cancer management (41) in which he described the ever frustrating nature of cancer surgery: "The most radical operation on a seemingly early lesion may be followed by widespread, rapidly progressive metastases and, contrariwise, a palliative resection undertaken with no hope for permanent cure may result in a extraordinary long period of time of well-being for the patient. Until an accurate appraisal of the growth potentialities of any given tumor can be made, the surgeon must continue to grope in comparative total darkness." 70 years have nearly passed and we have made no progress to answer the conundrum that Dunphy illuminated. The reason is because there is still no accurate way to assess the anti-tumor immunity of a given patient for his or her cancer. This is partly due to great variables in tumor growth and immune anti-tumor immunity in each different cancer patient; partly also due to our total ignorance of its variability and significance. Cancer is not one similar disease, but an individual disease that will ultimately need an individualized treatment that solves the problem in an individual patient. One key to the problem solution is the host anti-tumor immune response. Individual assessment of the underlying host anti-tumor immunity at any given time in any given patient will be critical to understand and aid such an effort. Currently we do not have a technical method to accurately measure anti-tumor immunity. But this may not be because of our technical capability, but rather our conceptual acceptance. At least in our hands, applying the concepts and approaches discussed here, we have started to obtain favorable clinical results in a number of difficult cancer cases. Dunphy’s observations raised important clues to the value of the host immune response to cancer. We hope that this letter will stimulate others to look into its prevalence and value as it appears to be the key to his conundrum.

署名（略去）

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昨天国内著名民主人士，政治犯刘先生因晚期肝癌医治无效过世。因为我在海外，所以从刘先生确诊起就知道这个消息，也看到很多病程和治疗的报道，多少算是了解情况吧。我这里不是评述刘先生的生平，而是用这个病例来讲讲主流治疗的误区。因为从6月中确诊到7月中去世一共大约一个月时间，而确诊时的身体状况基本上正常，没有黄疸和严重的肝炎，有中度疼痛。直到治疗开始前患者都是处于生活自理，行动自主的状态。然而，两周的治疗后患者迅速衰竭，一周后死于全身器官衰竭（号称感染性休克）。因为是敏感人物，并且有境外势力的巨大压力，给刘先生治疗的是国内最高水平的医疗团队，还有中医专家配合，后期还邀请了美德专家会诊并认可中国医生的治疗方案。然而事实是就是：这样的世界顶级医疗团队（肝癌在中国是拥有最高治疗水平的），在出手治疗两周后，患者的病情急剧恶化后死亡。现在要说的是：1）患者的迅速死亡是不是医治无效造成的？还是这个疾病的自然进程，无法改变？2）如果是按照探论治疗，会不会不一样？我就从探论的角度说说这两个问题的分析吧。
刘先生已有20年以上的乙肝和轻度肝硬化病史。确诊前两周出现肝区阵发疼痛，就诊检查后发现肝脏有巨大占位（10公分以上），穿刺确诊是肝脏的原发肿瘤。进一步检查证实有多发骨转移。之前一次的肝转检查应该不超过半年，没有发现占位。就是说这个肿瘤和转移灶都是在半年内发生的。从刘先生身体状态，发病前一年内体重变化，肝脏功能指标看支持这是一个迅速新发，而非陈旧病灶的判断。从探论的角度看，这个肿瘤从建立到确诊应该没有共存没有建立（多发骨转），但是确诊是由于疼痛，而疼痛往往是因为炎症，炎症是因为肿瘤坏死。如果有炎症就有可能有抗原释放和免疫识别。就是说确诊前的疼痛预示免疫识别的前兆或者说免疫已经识别并开始攻击肿瘤。探论认为几乎没有免疫不识别的肝脏肿瘤（或者很多其他实体瘤，脑瘤除外），只是识别的早晚差别。但是早识别和晚识别有很大差别：早识别不会造成严重的症状，因为免疫很快与较低肿瘤负担达成平衡，之后缓慢随肿瘤负担增加而增加；而晚识别最大的问题就是免疫在短期内从无到有，激升去达到与肿瘤的平衡，在这个过程中，免疫带来的各种症状会威胁生命。然而晚识别的好处是免疫因为肿瘤负担大而需要攀升的水平也高，有可能完全战胜肿瘤。这其实就是Dunphy病例中的那个临终逆转的原因。只是大多数不干预情况下都是以患者死于免疫过激结束的，包括刘先生的这一次。其实那个顶级团队所做的主要治疗是针对肝癌的主流靶向药索拉非尼，并没有进行像介入和射频消融这类“侵入性”治疗。按说靶向药有效是可能下调炎症，抑制免疫攻击的，也可能缓解免疫过激。但是从后来的发展看，这个治疗并没有起到这个作用，甚至有可能通过释放肿瘤抗原进一步加剧了免疫过激。这就是第一个问题的答案：这个病例的最大问题是迟来的免疫识别，不是主流治疗造成的（但有可能加剧）。第二个问题就来了：既然知道如此，探论怎么治？这个病例再一次告诉我们晚期的免疫攻击肿瘤有多么危险。一方面，没有免疫的肿瘤治疗很难控制局面，我们都盼着免疫能启动；另一方面，免疫启动了如果失控宿主往往在肿瘤消失之前死亡。在这种情况下，最好的结果就是抑制过激的免疫，但是不完全抑制。说来容易，做起来难，因为抑制过激的是一个概念上的突破，而不是手段上的缺失。比如目前已知的免疫抑制手段其实是有效的，就拿器官移植的排斥来说，早动手全面封杀基本上不会发生，即便是发生了赶紧抑制也可以灭火。对待一个晚启动，急速攀升的抗肿瘤免疫应答，如果是拿出应对GVHD的勇气和手段，很可能是可以压下去的。当然这又与应对器官排斥不同：不是要把免疫都压下去，是部分压下去，或者说是压倒不至于害死宿主的程度。这样就可能软着路，既能达到免疫完成与肿瘤的平衡，又能不杀死宿主。但是除了打压，还要其他手段比如疏导和转移。很多中医的治疗就是在这个方向上有建树。比如腹泻就是一个很关键的疏导手段。在免疫攻击下，肝脏大量的死亡癌细胞如果不运走就会导致附近的正常肝细胞因为局部高炎症而死亡，进而导致肝脏的失代偿，肝衰竭，肝性脑病和死亡。在有经常腹泻的情况下，这个问题就可以得到缓解，而在治疗肝病上，目前只有中医有这个手段和思路。还有有些中医采用制造皮肤炎症（膏药）的手段来转移内脏炎症也是短期可行的。但是到目前为止，所有的手段都是割裂的，不仅是西医和中医的割裂，甚至中医之间也是各有各的秘方，互不相关。这本质上还是思路的问题，不是手段的问题。试想：本着赶尽杀绝思路的西医主流碰上刘先生肝癌晚期免疫启动杀伤这么一个病例，难道是缺少赶尽杀绝手段，还需要再研发更好地杀伤手段的问题吗？中医虽然有腹泻和炎症转移，但是在针对抗原特异的过继免疫过激的情况下也显得力度不足。广西的中医肝癌名医陈振风一生的经历很好地说明了这个局限性。回到刘先生的治疗上，我现在可以说说我的想法了：这个病例因为是免疫启动，在确诊时是可以看到迹象的（穿刺组织的病理染色），第一时间就应该采用预先刹车手段。低剂量的激素加上免疫抑制剂，联合环磷酰胺就可以减缓这个免疫启动时的速率（探论的若干病例证明有效）。当然这个不会停止这个免疫启动，只是会缓和一下。免疫启动后的治疗是加大抑制，联合诱导腹泻，以及其他中医炎症转移手段，其核心还是刹车。在看到免疫明确建立，腹泻维持的情况下进行放疗减负和刹车（我们现在的病例就可以证明）。放疗不仅杀死肿瘤，也杀死免疫（特别是慢放）。最终要达到的效果是病灶缩小稳定，免疫共存。在不计代价的情况下，这也就成就了肝移植的条件。移植后靠疫苗维持免疫。这个病例就可以此收官。

@自然奥秘 2017-07-27 16:54:26
老师你好：
现在全世界癌症数量大的惊人，世界每年都有一两千万的新增癌症病例。如果您的理论实践是正确的确实可以挽救无数生命，但却因为种种原因没有被重视发现接受或是若干年几百年后人们才意识到这种思考的正确性，那也只能说是人类的愚蠢，现实制度的可笑可悲。我是一个对医学科学有兴趣空闲时间喜欢钻研东西的人，也因为周围癌症越来越多，有一些疑问想不明白希望老师给出解答：
（1）曾经帖子中问到过世......
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这个问题的答案类似与乙肝病毒的母婴传播。为什么母亲传给婴儿的病毒就会存在下去，而机会感染的98%的可能会被灭活？就是免疫系统把母亲传过来的病毒当成自身了，因为这个抗原是在免疫系统形成之前存在的，都会当成自身抗原处理。而只有在免疫系统建立后才出现的抗原才有可能是外源的。同样的道理，目前体内转给婴儿的癌细胞如果是在免疫系统形成之前形成抗原的，那么就会当作自身对待，而没有形成抗原的，将来形成的时候是可能被排斥的。我想大多数是后者的情况，只是这个情况我么无从考察证实，只能推测。

@发家致富 2017-07-31 11:11:27
陈昭妃博士，著名美国华裔科学家“营养免疫学”的创始人。1997年，她荣获“美国十大杰出青年奖”。难道是楼主？.....
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你瞧，前天还有人想通过揭我的身份证明我不可能在癌症的治疗上有真知灼见：因为我没有名气！所以不可能。这个背后的逻辑是：智慧和创造力应该是与知名度成正比。这是普通人的偏见。人群的许多特性都是正态分布的，包括智慧创造力与知名度的关系（如下图显示）。在正态分布的左边看，这个逻辑是成立的。但是他们永远不明白正态分布的另一半是怎么回事：难道最大的天才鬼才不是最有名的人？不是人人推崇的目标？而你是反过来推论：既然这么有才，只能是名人！还是“外貌协会”啊。而真相和人类历史的规律就在我下面的这张图中。

@梦想飞翔Q 2017-08-02 16:21:22
免疫治疗、个性化治疗，这些都是医学的一部分，还有基础免疫学，肿瘤免疫学，这都是主流学科。这些不属于探论，而是主流科学成就，大家共有的。
除了这些基础部分外，探论里存在的猜想和推论，严重缺乏实验数据，更无临床试验依据。任何一条小的实践指导，都是需要临床数据支持的。探论需要严谨的举证这些猜想和假设，以及临床方法的正确性。探论从未超越主流免疫学和主流医学，甚至是落后的。如果探论认为超越了，就需......
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到底如何开战癌症的临床研究？探论里面有明确地论述，就是要放弃以统计数据为主要判别的分组盲试，而是聚焦于每一个病例本身的特殊条件。最大的差别可能就在这里。探论首先强调个性化治疗，因为每个病例后面的个性化原因都不一样。共存免疫这个影响最大的差别最大的因子都不明确的情况下如何分组对比？II起与II起真的一样？IV期与IV期真的一样？在目前的认识水平下只能通过个性化来治疗。将来可以进一步甄别时自然可能分组（比如假四期与假四期去比较）。拿探论挑出来的假四期去跟主流医院的真假四期混合的病例比当然要好于他们，但是这个没有什么意义。我自己都懒得去比，比完了发表了才是误导。这类的误导文章我这一生已经见到太多，难道还要参与制造一个不成？可是如果你们有人非要认定大数据分组的双盲试验，否则其他的个性化描述不可信，我也没办法。各种方法的研究都不是最完善的，都有局限性。关键是采用某个方法的人自己应该清楚。在什么情况下怎么能够以理服人才是关键。探论在目前的初期阶段只能是采用个性化单一的分析和治疗才能取得最大生存这个“疗效”。这是我的看法，也是探论的实践。如果认为这个看法不适合探论有讨论的余地，如果逼着探论用主流的方法就不用操心了。你们的意见我看到了，怎么做是我的事。

@梦想飞翔Q 2017-08-02 18:03:04
探锁的心 08-02 17:47
评论 梦想飞翔Q：探论还是讨论一下获得探粉授权的大数据吧，难道科学不应该如此吗？我的回答是：我不这么认为，谁认可谁遵循，我不认可。我认可个性化的单一病例分析。
梦想飞翔Q 08-02 18:01
那大家追随的规范不同，就没有必要讨论了。我不认可探论没有证据的自定义标准。不过探论可以清晰发表自己的评价标准，并举证标准有效性。这也可以的，权威杂志非常欢迎，比如免疫治疗不就出了新......
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探论当然阐述了这些标准和判断手法，并且尝试回答70年前Dunphy医生振聋发聩的疑问。但是近70年过去了，Dunphy医生给出的4个病例还没有一个答案，而探论尝试用个性化的解释给予说明（见8174楼的原文）。只是权威杂志并不欢迎，而且我也并不为此感到奇怪（见8228楼的图解）。如果你看了有不同意见可以讨论，但是如果非要说必须是主流杂志接受的文章我也没办法了。

@zhmg77 2017-08-03 08:31:51
？
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你要是不想讨论你家的病例就不要在这里提及你家病例，并给探论扣上失败的帽子。你作为一个过去探论的急先锋，自己称之为我的学生的人今天的举动就像其他病友说的那样是新版的“农夫与蛇”。你难道想让我把你的那些私下里怎么讨好我的话说给大家听听？你难道想让我公布你家射频治疗前后你自己的角色？我给你留着面子，更多是隐私，但是你还是胡搅蛮缠。以至于底下很多人都在问：梦想是抽的什么疯？我认为是你不能敢作敢当，更不愿承担应有的责任和风险，靠转嫁治疗失败（未必是失败）来保护自己的那点小地位和面子。探论不可能替你背这个黑锅的。
你违规转发那个已经禁言的ID的话，就是说你把自己与那个人等同了，既如此就是请我把你与他同等对待是吧？那就怪不得我了。

@梦想飞翔Q 2017-08-03 12:26:07
我前边的回复已经足够说明问题所在，但探论避而不答，却非要我按探论的套路出牌，连评判标准都完全集中在探论手里如何证明探论优于主流疗效？
和上帝，万能的主，有啥好争辩的，跪下山呼万岁没什么不妥。探论极力反对权威？到了自己这边却玩双重标准，探论官方管理员千方百计维护权威。
探论要求和我讨论我家的病例，并说我躲闪，实际上我家病例在我喜欢的科学和医学场所一直都是公开的，没有什么秘密。我只是不想浪......
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你要是不想讨论你家的病例就不要在这里提及你家病例，并给探论扣上失败的帽子。你作为一个过去探论的急先锋，自己称之为我的学生的人今天的举动就像其他病友说的那样是新版的“农夫与蛇”。你难道想让我把你的那些私下里怎么讨好我的话说给大家听听？你难道想让我公布你家射频治疗前后你自己的角色？我给你留着面子，更多是隐私，但是你还是胡搅蛮缠。以至于底下很多人都在问：梦想是抽的什么疯？我认为是你不能敢作敢当，更不愿承担应有的责任和风险，靠转嫁治疗失败（未必是失败）来保护自己的那点小地位和面子。探论不可能替你背这个黑锅的。
你违规转发那个已经禁言的ID的话，就是说你把自己与那个人等同了，既如此就是请我把你与他同等对待是吧？那就怪不得我了。

谢谢楼上各位的正义感。探论的一个很少提及的作用就是透明，把病情看透。即便是无解，也不至于迷茫，不至于被创收，更不至于被过度治疗。在这一点上当年Dunphy医生在自己身患前列腺癌晚期的时候写下了另一篇社论（On the Caring of Patients with Cancer)，其中就讲到癌症患者其实不适怕死，是怕不知情。如果医生告诉他们真相，他们会感谢医生的。探论的很大部分就是判断一个病例的走势和预后,这就是真相。很多的患者和家属都是在跟我讨论之后告诉我，心态放平了，不再盲目焦虑了。就是说探论也在帮心。可能一个病例的先天共存免疫条件不好，后来的治疗也未能启动，但是尝试了就不后悔了。
另外今天听到美国国会终于通过了全国的“right-to-try”法案，其本质就是开始放开允许医生，药厂，和使用者在疾病晚期无解的情况下尝试未经FDA批准的实验性药物，仪器等治疗手段，甚至付费使用都可以。这个运动从最初的艾滋病自己给自己治疗（就相当于现在的靶向群)到现在30多年了，终于向正确的方向迈出了一步（或者从错误的方向退后了一步），可见之难。我早就质疑过：自杀在任何社会都不犯法，为什么自救犯法？这个法案开始告诉美国人，自救不犯法。虽然实施上会有很多问题，但是看看题目：right-to-try!谁的right?当然是患者的。探论是一整套见解，并且有实践的可行性。我认为癌症患者最有权决定要不要尝试实施，别人无权干预。

@专为探论而注册 2017-08-04 10:04:53
特意注册了一个天涯帐号来看看。就想看看到底有几个有效的站出来说话。目前看来，为数不多。成百上千个病例，就那么几个有效，行，，真行，，，果然行，，，，不行都行，，
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只有患者和家属才知道什么叫有效。“金标准”是什么呢？是患者满意！

@专为探论而注册 2017-08-05 22:04:39
尊敬的探锁老师，我看到过你陪同其他病友去医院就医，为了病人你独自一人坐着吃盒饭的场景，从心里我高度认可你的为人及出发点。但是在严谨的医学面前，人与事，我们不能混淆，我作为家属，提个小的不能再小的要求，当然，你可以不回答。请问:1/探论有没有致命缺陷？2/探论是否被探子探孙们过度演绎？3/探论是否被探子探孙们刻意隐瞒或者弱化失败病例？4/探子探孙们所制造的疫苗是否符合“疫苗”的要求？
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另外，由于你看到或没看到的原因，我要求每个找我求助的新老ID除了在病例帖6891楼的评论中留下认可，还应该在10377楼下面留下评论，证明你看到过这个忠告。认真读过这个忠告贴后如果还是认可探论，来这里通知我，我会继续指导。

1、这个问题我在帖子里屡次说过，今年的新年贺词也有提及。探论是一个不断进步，不断完善的过程。你想知道缺陷是什么对吗？可以去看新版探论，看看有没有之前没有提到的，有没有对之前的看法有修改的。随着时间，还会有更新版的探论出来。
2、3、你说探子探孙就开始自己否定自己之前说的“人与事不该混淆”，开始人身攻击了。就我个人，我认为病例是患者和家属的隐私，正反都不应该宣扬，必需刻意隐藏。这个是最起码的原则。你作为患者家属可以自己把你家病例贴到病例贴去，只要你不要隐藏，我没有意见，也不会封杀。己所不欲，就不要要求别人做了。但是原则还是就事论事，不要做人身攻击。
4、患者要尝试的办法是不是符合你的要求和其他人的要求我看不到关你什么事。如果伤害到你家患者，你可以去告我。如果你是在替别的患者质问，我的回答是谁希望使用可以来问我，前提是我需要知道为什么需要？没有病例判断我怎么知道你是否需要？

最后说说人品，既然你提到了。探论之所以能够让患者相信，不仅仅是一个理论，还有这个理论背后的人品。在患者和家属来看，一个骗吃骗喝骗钱的忽悠贴，和一个真诚，担当，为人类医疗进步探索的理论贴是很容易识别的。如果有人识别不出来，我说了：不要告诉我你没看懂才误入歧途，那是你智商和道德有问题，与我无关。但是拿这个说事来诬陷我，攻击探论就与我有关了。我已经告诉你道理摆在这里，我尽力而为帮助你，你还要让我替你负责，天下有这等道理吗？这才是看出人品的地方。在这上面探论没有污点。你们好自为之吧。