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The Right Treatment at the Right Time: Double-Hit Lymphoma 出奇制胜：双重打击淋巴瘤
On February 5th, 2018 I was asked to consult on a 53-year-old patient who was admitted to the hospital with a one month’s history of low back pain. An MRI of the lumbar spine a few days earlier revealed a mass impinging on the spinal canal extending down to the pelvis. 2018年2月5日，我被叫去给一位53岁、有一个月后背下部疼痛病史的患者做会诊。几天前的脊椎MRI提示有一个肿块压迫了脊髓，一直延伸到骨盆。
I arrived to find a strapping, healthy, vigorous gentleman complaining of pain. 见到患者的时候，这位抱怨背疼的先生看上去高大魁梧，健康并充满活力。
Diagnosis: B-Cell Non-Hodgkin's Lymphoma (NHL) 诊断：B细胞非霍奇金淋巴瘤
He had no evidence of neurological deficit and was able to stand and walk without difficulty. The differential diagnosis of a mass in the lower spine includes metastatic disease from a distant site i.e. lung, etc. versus a primary tumor such as chordoma versus lymphoma. 他没有神经方面的问题，能够自主站立并行走。下部脊椎肿块的鉴别诊断包括远端肿瘤转移，例如肺癌等，以及原发肿瘤例如脊髓瘤和淋巴瘤。
A needle biopsy confirmed B-cell non-Hodgkin’s lymphoma (NHL). As NHL is generally responsive to therapy we opted against surgery in favor of radiation. Although I would gladly have used the EVA-PCD platform to treat him, I suggested he move forward with radiation as I awaited completion of staging, flow cytometry and special studies. 穿刺活检证实了B细胞非霍奇金淋巴瘤。因为非霍奇金总的来说对放化疗应答良好，所以我们决定不做手术而做放疗。尽管我非常愿意用EVA-PCD平台（见注释）来治疗，但是我建议他先去做放疗，我等着分期，流式细胞术和特殊检查的结果出来。
Late Friday evening, 2 days after admission, the patient lost the ability to move his lower extremities and emergency surgery was undertaken that night. My colleagues in neurosurgery kindly provided a sterile portion of tissue to my laboratory for analysis. While I awaited final pathology, we set up a broad array of cytotoxic drug combinations, targeted agents and synergy studies. The patient slowly recovered but with impingement on the lower spinal cord it was uncertain whether he would regain the full use of his legs. 入院后2天，周五的深夜，患者突然失去了移动下肢的能力，当夜就接受了紧急手术。神经科的同事把一块消毒过的组织送到了我的实验室做分析。我们一边等着最后的病理报告，一边准备了一系列细胞毒性药物的组合，靶向药以及协同效应研究的材料。患者慢慢的恢复了，但是下部脊髓压迫的使得我们无法确定他是否能够完全恢复腿部的功能。
Functional Profiling Results 功能性分析的结果
A few days later the results of the EVA-PCD analysis returned. Though B-Cell NHL is considered highly drug sensitive, this patient’s cells could not have been more drug resistant. I was surprised by the degree of resistance to almost every drug and combination tested in the lab. Adriamycin, Vincristine, Corticosteroids, and Fludarabine were all inactive. 几天后EVA-PCD的分析结果回来的。尽管B细胞非霍奇金被认为是对化疗高度敏感，这位患者的肿瘤细胞简直是逆天一样的耐药。这种对几乎所有药物以及药物组合的耐药性让我感到非常惊讶。阿霉素，长春新碱，激素，氟达拉滨全都没有效果。
I was puzzled. Isn't B-cell lymphoma one of the success stories of modern oncology? Isn't this tumor supposed to melt away with treatment? Was there a mistake? 我有些迷茫了。B细胞淋巴瘤不是现代肿瘤学上成功的故事之一吗？这种肿瘤不是应该一治疗就像冰一样的融化吗？是不是哪里搞错了？
I reviewed his findings with our hematopathologist. What gives, I wondered? 我和我们的血液肿瘤病理医师一起又研究了一遍各种检查报告。我在想：问题到底出在哪？
Not Your Typical Non-Hodgkin's Lymphoma 不是典型的非霍奇金淋巴瘤
A week later, the answer to my question became clear. This was not a run-of-the-mill B-cell NHL. This was not one of those cancers you treat with conventional combinations. Quite to the contrary – this was a double-hit lymphoma, with over-expression of both the c-MYC oncogene and the Bcl-2 oncogene and a proliferation rate of more than 80%. 一周后，我的问题有答案了。这不是一个普普通通的B细胞非霍奇金淋巴瘤。这不是一个你可以用标准方案治疗的肿瘤类型。完全相反，这是双重打击淋巴瘤，同时高表达c-Myc和Bcl-2原癌基因，增殖指数超过80%。
This was a B-cell lymphoma that was not going to play by the rules. As I examined my laboratory findings one result stood out, the clear and unequivocal activity and synergy for Gemcitabine and Cisplatin, used clinically as R-GemOx. 这不是一个守规矩的B细胞淋巴瘤。在我检查实验室的报告时，有一项结果映入眼帘，吉西他滨与顺铂的组合，即临床上常用的R-GemOx方案，显示出了明确的活性和协同效应。
在我的实验室里，我们对这些组合研究了二十多年，先前也发表过有关的研究成果。在卵巢癌，三阴乳腺癌，膀胱癌和其它肿瘤中我们率先使用过这样的方案。
Today these doublets are used around the world. 今天，这些组合全世界都在用。
However, R-GemOx the one we found for this gentleman is never, ever used in the first line (newly diagnosed) setting. Never! I returned to meet with the patient, now bedridden, as a physical therapist worked to recapture the use of his lower extremities. We sat and had a long heart-to-heart discussion. 但是，R-GemOx从来，或者说自古以来从未被用于这位先生的情况下的一线治疗（初治）。从来没有！我又去见了患者，他现在已经起不来床了，我就像一位理疗师一样去了解他的下肢恢复的情况。我们坐在一起唠嗑谈心。
Contrary to the guidelines, the literature and the NCCN (National Comprehensive Cancer Network), I was recommending that this patient take a “so called” salvage regimen as his first-line therapy. It was more than uncomfortable, as I could easily be criticized for failing to provide the patient potentially "curative therapy" with R-CHOP, R-EPOCH, CODOX, hyper-CVAD or others. What would possess me to use my EVA/PCD laboratory studies to make changes in a patient's management when everyone knew that R-CHOP or modified R-EPOCH were the standards of care? 与指南、文献和NCCN相左，我推荐这位患者将所谓的“挽救性”方案作为一线方案。我感到极度的不安，因为我可以很容易的被人指责未向患者提供有治愈可能的方案例如R-CHOP ,R-EPOCH ,CODOX ,hyperCVAD等。我到底是被什么鬼附体了，竟然放弃其他人都用的R-CHOP或改良的R-EPOCH，仅仅根据我的EVA-PCD实验室研究结果改变患者的治疗选择？
Thinking Out of the Box 跳出思维定势
The answer was not all that hard to find. One need only read the literature more closely to see that double-hit lymphoma requires out of the box thinking. 答案并不难找。只需仔细的阅读一下关于双重打击淋巴瘤的问题就能看出双重打击淋巴瘤需要特殊的思维。
It is now well-recognized that conventional treatments like R-CHOP are inadequate. 现在大家都认为传统的方案例如R-CHOP是不适当的。
One investigator from the Wilmot Cancer Institute at Rochester University said “…it is clear that R-CHOP is not sufficient induction therapy for this group of patients, since the majority of patients will have disease progression after standard therapy “ (Jonathan Friedberg, MD BLOOD 2016). 罗切斯特大学Wilmot癌症研究院的一位研究者说：“……对于这组病人R-CHOP显然是不够的，因为大部分患者在标准治疗后会出现疾病进展。”
None-the-less, in 2018 and in the absence of controlled clinical trials, physicians continue to give these patients R-CHOP, R-EPOCH and related regimens. If I were to diverge from these standards of care, say to provide first-line R-GemOx, would I be viewed as compromising his well-being? 但是，在2018年，在没有对照性的临床试验的前提下，医生继续给这些患者R-CHOP，R-EPOCH和相关方案。如果我脱离这些标准方案，比如说给患者一线上R-GemOx，我会不会被看成损害了患者的利益？
My Dilemma 进退两难
This was a crisis, a dilemma. 这是一个危机，一个困境。
I knew that the patient needed R-GemOx. My instincts told me that he should receive it, but I was clearly veering off the standard guidelines and about to commit the most heinous of all crimes, diverging from "community standard.” 我知道患者需要R-GemOx。我的直觉告诉我他应该接受这样治疗，但我显然偏离了标准和指南，犯了不可饶恕的大错。
The patient's wife had brought her husband to me in the first place because she was the close friend of one of my longest surviving lung cancer patients, a delightful young woman who lived nearly a decade with highly aggressive non-small-cell. 这位患者的妻子把她的丈夫交给我，是因为她是我的一位生存期最长的肺癌患者的好朋友，这位乐观的妇女被诊断为高侵袭性的非小细胞肺癌后生存了几乎十年。
Based on that experience, she was determined that her husband be treated under my care, no matter what. As a nurse and someone who knew my work, the treatment that I recommended was going to be the treatment her husband would receive, regardless of guidelines or protocols. 基于这段经历，她决定无论如何要把她的丈夫交给我来治疗。作为一位护士以及了解我的工作的人，我所建议的方案就将是她的丈夫所接受的方案，不管什么指南或者规范。
We agreed to move forward with the laboratory-identified R-GemOx. The patient required radiation and we arranged one course of chemotherapy before it began. As this chemotherapy combination is too toxic to combine with radiation, I had to bide my time until the 10 days of radiation were complete. The next day, I again instituted R-GemOx. 我们同意采用经实验室确定的R-GemOx方案。患者需要做放疗，我们在放疗之前安排了一个疗程的化疗。因为这个方案与放疗结合毒性太大（吉西他滨有放疗致敏性：译者注），放疗完成后我足足等了10天，10天一过，我马上开始了R-GemOx。
How the Patient Responded 患者反应如何
Slowly, the patient's lower extremity strength improved. He began to use a walker. 慢慢的，患者的下肢力量开始改善。他开始用助步器。
Every two weeks, I treated the patient, shepherding him from the rehabilitation hospital to the acute care hospital and back each time. 每两周，我治疗这位患者，把他像赶羊一样从康复中心接到治疗医院然后再送回去。
Two cycles later, he was able to be discharged. Once discharged, the patient continued physical therapy as I treated him every two weeks. At first, he came with a walker, then with a cane and then recently, walking without assistance. 两个疗程后，他可以出院了。患者继续进行理疗，而我每隔两周给他做一次治疗。一开始他用助步器，后来换成了拐杖，最近，已经可以自主行走了。
I had known from the start that a "double-hit lymphoma" would require bone marrow transplantation. I wrote a letter of referral to a colleague at a large transplant center but anticipated that the response might be one of dismay at my choice of therapy. 我一开始就知道，双重打击淋巴瘤将需要做骨髓移植。我写了一封转诊信给我在一家大型移植中心的同事，但是期待会收到对我的治疗选择表示不理解的反馈。
After all, we had diverged from protocol; we had used a non-standard salvage regimen, as his first-line therapy. We had not applied the standard of care and had instead veered off the path, using the laboratory to guide our drug selection. I was concerned that he might be disqualified. 不管怎么说，我们脱离了常规。我们采用了一个非标准的挽救性方案，作为一线治疗方案。我们没有采用标准治疗，偏离了原有的路径，采用实验室的结果来指导我们对药物的选择。我非常担心移植中心认为他不合格。
Despite my concerns, it was obvious that with each cycle, the patient's condition improved. 尽管有这些担心，随着每一个疗程的化疗，患者的情况显著改善。
I was buoyed by his physical well-being and improving parameters of his disease. The PET/CT revealed near complete resolution of all measurable disease after only 3 doses. 我被他的身体情况的好转和疾病指标的改善所鼓舞。PET/CT显示仅在三个疗程后他就几乎达到了完全缓解。
Time had come. He was ready for his consultation at the transplant center. 时机到了。他准备在移植中心接受评估。
Just before he departed, I repeated all of his laboratory measures of his disease and had them forwarded to my colleague. All were completely normal. I waited with some trepidation, anticipating a critical review of my unconventional therapy recommendation. This week, the patient and his wife returned. 在他出发之前，我把他的疾病的所有实验室检查再重复了一遍并发给了我的同事。一切都完全正常。我心怀不安的等待着，期待着收到对我非常规治疗方案的批评。本周，患者和他的妻子回来了。
They had met with the trans-planters. The conversation had proven quite jovial. 他们见到了移植医生，谈话气氛非常融洽。
This accomplished consultant smiled when she looked at the patient's PET/CT and lab results. 当看了患者的PET/CT和检查指标后，这位专家笑容满面。
She pointed out that this was not the standard of care. 她指出，这不是所谓的标准治疗。
But then went on to say that she knew my work, and that although I had veered off the path, she very impressed with the good result. She would indeed accept the patient into the transplant program. He will undergo, what I hope will prove to be, a curative bone marrow transplant in July. 但她接着说她了解我的工作，尽管我偏离了常规，她对结果却非常满意。她会接受这位患者在中心做移植。他将在7月份接受我希望是治愈性的骨髓移植。
Final Thoughts 最后的想法
This story is emblematic of my philosophy in medicine, that patients should receive the right treatment the first time, every time. But it represents a broader collection of issues. 这个故事，代表了我行医的理念，即患者应该在初治，以及后来的每一次治疗中接受正确的治疗。但是这里面存在很广泛的问题。
First, in medicine today, we do not reward physicians for success but we punish them severely for failure. 首先，当今的医学不会奖励成功的医生，但是会惩罚失败的医生。
Had this patient had less than a perfect response, I would have been pilloried for not administering standard treatment; despite their well-recognized lack of benefit. In this environment, physicians are increasingly afraid to do the right thing. I must admit my own concern when I followed what I knew to be the right course of therapy for this patient, fearing the consequences of failure. 假如这位患者对治疗的反应不是很完美，我会被当作是不采用标准治疗方案的坏典型。在现在的环境下，医生越来越不敢做正确的选择。我必须承认当我采用了自己认为是正确的方案的时候，心里不免害怕失败的后果。
Second, there are no right treatments, even for the most treatable malignancies. 其次，即使是最可治的恶性疾病，也没有所谓正确的方案。 Each patient is a unique story unfolding in real time. I am gratified by this patient's good outcome and feel a particular sense of accomplishment in that the patient's referral was predicated on the good outcome of one of my longest surviving lung cancer patients who received laboratory directed therapy as well. 每一位患者都是实时发生的独特的故事。我对这位患者的良好结局表示满意，而且这次转诊也是基于我治疗的最长生存期的肺癌患者的良好结局上的，也是由试验结果所指导的疗法的结果，对此我很有一些成就感。
Finally, the key to each patient’s diseases lies within their own tissue. Failing to use each patient’s tumor to select treatments relegates them to protocol therapies that may be very wrong for them. 最后，每一位患者的疾病的根源在于他们自己的肿瘤组织。不能够用每一位患者的肿瘤组织来选择治疗方案而只能用标准方案可能是非常错误的。
I will await the patient's final PET/CT scan with anticipation but look forward to the very real likelihood of curing this patient with, what many oncologists might consider, an incurable lymphoma. As always, I appreciate your thoughts and comments. 我将等待着这位患者的最后的PET/CT，非常希望能够治愈这位患者，尽管很多肿瘤医生认为这是一种不可治愈的淋巴瘤。一如既往，感谢你们的意见和建议。 UPDATE - June 29, 2018: 更新： 2018年7月29日
It is with a particular sense of pleasure that I report the findings of today’s PET/CT: “No evidence of residual lymphoma”. 怀着激动的心情，我向你们报告PET/CT的结果：“没有残余淋巴瘤的迹象”。 I am more than pleased by this result. His outcome is the very essence of what we do and why we do it. It is a vindication for the use of unconventional approaches when the conventional ones won’t do. 对这个结果我感到非常高兴。这就是我们要这样做，以及为什么要这样做的具体事例。这证实了当传统方法不灵的时候我们要采用非传统的方法。
It is a life saved; a family reunited and, in the end, has proven to be a relatively simple solution to a very complex problem. I am sure that the readership will join me in congratulating this patient on his splendid outcome. 一个生命被挽救了，一个家庭团圆了，最终，一个非常复杂的问题却有一个相对简单的解决方案。我相信读者们将和我一起恭喜这位患者的良好结局。 Dr. Robert Nagourney, has been internationally recognized as a pioneer in cancer research and personalized cancer treatment for over 20 years. He is a TEDX Speaker, author of the book Outliving Cancer, a practicing oncologist and triple board certified in Internal Medicine, Medical Oncology and Hematology helping cancer patients from around the world at his Nagourney Cancer Institute in Long Beach, California. For more info go to Nagourneycancerinstitute.com
注释：EVA-PCD，即Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD) ，程序性细胞死亡体外分析。简单的说就是把患者的肿瘤细胞放在试验皿里，然后用各种药物和药物的组合去试验，观察肿瘤细胞凋亡的情况，据此来判断哪个化疗方案最合适。
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