Brain Surgeon, A Doctor's Inspiring Encounters with Mortality and Miracles

之前读过英国神经外科医生 Henry Marsh 写的《Do Not Harm》。再来读下这本美国非裔神经外科医生 Keith Black (俗称“黑医生”(Dr. Black)。美国著名神经外科专家、西达-赛奈医学中心(Cedars-Sinai Medical Center, a 501c3 non-profit hospital)神经外科研究所及脑肿瘤中心主任医师) 的回忆录。

FOREWORD By Forest Whitaker

Forest Whitaker. 福里斯特·史蒂芬·惠特克 美国黑人演员。

Chapter 1. Tiger Country

Chinese naturopath: 美国人对所谓“中医”的称呼。
naturopath /╵neitʃrəpæθ; ╵netʃərə╷pæθ/ 
n person who treats illness by suggesting changes of diet╷ exercise╷ etc and without using medicines 自然疗法家（通过改变饮食、锻炼等而不用药物治病者）.

glioblastoma 胶质母细胞瘤, aka glioblastoma multiforme (GBM, glioma)—the most malignant of all brain tumors. 在神经外科类型作品里出场率非常高。也是最常见的原发性脑肿瘤（占比>=50%), 恶性程度非常高。
在当时，这种肿瘤确诊后的中位生存期(Median survival)是 9-15个月。

Anything less than an image-complete resection, where no visible tumor can be seen on the post-operative MRI scan, usually does little to extend the life of the patient. As a surgeon, I know that I must get 99.9 percent of the tumor out in order to have a significant impact on my patient’s survival.必须做到影像学意义上的完全切除肿瘤(术后的CT、MRI等影像学检查图像上肿瘤完全消失)才有手术指征。并且这种手术意义是延长生存期而非彻底治愈。

Over the years I’ve learned that my patients are people who
can live an entire lifetime in six months or a year. What they do with this time represents a much higher quality of life than that enjoyed by “normal” people who are caught up in the trivia of day-to-day, and not really focused on what is important. When you are given a year with the people you love, you don’t squander the gift. You don’t sit around playing video games or watching reruns—not if you have a young son or daughter with whom you need to build a relationship they will remember for the rest of their lives, or a spouse you might fall in love with all over again.

People often ask me, “How can you work with these patients, knowing that so many of them are going to die?” I cannot imagine better people to work with. I learn from them, as I watch them cherish every moment of their days. These people teach us all about the meaning of life well-lived.

Chapter 2. A Love Affair with the brain

作者7岁时就能用手术工具麻醉并解剖青蛙、为被玩具枪击伤的小鸟做手术取出BB弹并清创伤口。

14岁(8年级)时能独立给狗做人工心脏瓣膜(heart valve)置换手术(当时的人工心脏瓣膜相当原始)，甚至还可以参与狗的心脏移植手术。在学校学高等数学(微积分)和德语。作者用当时刚刚出现的扫描隧道显微镜做实验时意外发现了开胸手术中使用的体外心肺机(heart bypass machines)导致红血球畸形的现象。畸形的红血球无法自由变形以通过直径较小的毛细血管，会导致毛细血管堵塞。如果这发生在大脑，将可能导致小型中风。这可以解释(当时)开胸手术后患者出现的记忆和认知障碍并发症。

17岁时作者把对上述研究写成论文发表并获奖。

本书中出现的美国俚语单词好多。

Phineas Gage. 费尼斯·盖吉（1823年－1860年5月21日），美国铁路工头。他在一场意外事故中，被一支长铁棍由左下脸颊刺入，穿越左眼后方，再由额头上方头顶处穿出脑壳。导致前额叶(frontal lobes)严重受损。他虽然奇迹似的生存下来，但自此性格大变。在他后来的12年中，经由治疗医师的长期研究，对人类大脑的机能探讨大有贡献。

读过的几乎所有医生的回忆录都写到了他们主刀的第一个手术对其职业生涯选择的决定性影响。那是一种神奇的满足感和成就感。


What an absolute joy! This was a level of gratification I could only imagine before. Working with my hands and my brain, I was able to restore this man’s language and his ability to move. It was an exhilaration I wanted to feel again and again。

Bible (Luke 12:48)： Of those to whom much is given, much is expected.
约翰肯尼迪曾引用过这段。

想起刚刚看完的《War doctor》后记里作者妻子的话：people of great strength doing remarkable things. 最能概括这种观念的句子是"With great power comes great responsibility" (大いなる力には、大いなる責任が伴う)(这个Wiki词条没有中文条目)。这句话因为《蜘蛛侠》作品而变得家喻户晓。这也是 Linux 里 (第一次)输入"sudo" 命令时出现的三条提示之一：

We trust you have received the usual lecture from the local System Administrator. 
It usually boils down to these three things:

    #1) Respect the privacy of others.
    #2) Think before you type.
    #3) With great power comes great responsibility.

Chapter 3. Risks and Rewards // The story of Gerard Kelly

clival chordoma 克利夫脊索瘤

Harvey Cushing 哈维·威廉斯·库兴（1869年4月8日－1939年10月7日）是美国的神经外科名医、美国陆军退役军医上校。他是脑外科学的先驱、最早提出库兴氏症候群的学者，后世称之“现代神经外科之父”。

There are two types of tumors: primary and metastatic. A primary originates in the
brain. A metastatic starts somewhere else. Of these two types, metastatic tumors are far more common.

clival chordoma 脊索瘤 // 外科手术经鼻或经口建立路径到达肿瘤部位。

Chapter 4. Thoughtful warriors in the brain

They (young brain surgeons) need to become thoughtful warriors in the brain, doctors who are both knowledgeable enough and cautious enough to take only absolutely necessary risks for their patients.

The way to do that is to make sure they treat every patient as if that person were a loved one of their own—a child, a parent, a wife or husband. I told the parents of that twenty-three-year-old young woman with the cyst in her brain stem that I was treating their daughter exactly the way I would treat my own daughter, and I was absolutely sincere. Bonding with your patient on a personal level is the difference between being just a good technical neurosurgeon and being a truly great one. I believe that some neurosurgeons are born with more ability to empathize than others, and when I see that ability to deeply connect with the patient, I nurture it as much as possible.

作者的观点和英国心脏外科医生 Stephen Westaby 完全相反。后者认为只有与患者在情感上保持距离才能成为一个优秀的医生。

作者的观点很明确：risk-benefit analysis 是衡量神经外科决策的最终依据。

Brain tumor vaccine: WTF ? 我记得唯一可以通过疫苗预防的癌症是子宫颈癌——已明确病因是HPV病毒。

Chapter 5. Outsmarting the Tumor // Innovation besides surgery

Unfortunately, the majority of benign tumors don’t stay that way. Over time, approximately 70 percent of low-grade, noncancerous tumors will eventually morph into higher-grade, more aggressive tumors. This malignant transformation is perhaps the most compelling reason of all to skip the biopsy and simply remove the tumor.

白三烯（Leukotriene, LTs）是一类含三个共轭双键的20碳直链羟基酸的总称，是与过敏性反应有关的生物活性物质，其他与过敏性反应有关的生物活性物质包括组胺、缓激肽、血小板活化因子等。白三烯由于最早是在白细胞中发现故而得名。它们在体内的主要作用是引起气管平滑肌的收缩，同时也增加微血管通透性。白三烯的过多释放是引起哮喘和过敏性鼻炎的主要原因之一。白三烯拮抗剂(Leukotriene antagonist)可通过抑制白三烯的产生和活动达到治疗哮喘和过敏性鼻炎的效果。

作者年轻时发现 Leukotriene 与脑水肿可能有相关性，并展开研究。进一步研究发现注射Leukotriene会导致大脑（因物理、热刺激、肿瘤等原因）损伤部位的毛细血管变得Leaky(BBB失效)，但对正常大脑部分的BBB无效。历史上第一次发现了一种选择性开启血脑屏障的机制。

blood-brain barrier (BBB): 血脑屏障（大脑毛细血管壁的选择性通透性）。水溶性物质(water soluble)(包括水本身)无法穿透。仅容许脂溶性物质进入。Only drugs that can be dissolved in oil, or lipids, can cross it.
// About 98 percent of the drugs that could be therapeutically useful in the brain are water soluble, and thus cannot get across this blood-brain barrier.

bench-to-bedside translational research: 研究室で行われた研究の結果を直接用いて、患者を治療するための新たな方法を開発するプロセスを表現するのに用いられる用語。
// to bring what we were learning in the lab—the bench—to the treatment arena—the bedside.
// Conversely, to take what we were learning at the bedside and bring it back into the lab to readjust and improve the treatment.

dendritic cell vaccine // Made with the body’s own dendritic cells (树突状细胞。免疫细胞，作用是结合病原体表面蛋白并呈递抗原给杀手T细胞)
The preparation of the vaccine itself involves filtering out the dendritic cells from the patient’s blood, growing them in the lab, and then exposing them to the patient’s tumor cells that we obtained during surgery
// 用于肿瘤手术后预防复发。

if cancer is indeed a terrorist, then glioblastoma multiforme, or GBM, is Osama bin Laden.

Chapter 6. Fight the terrorist // The story of Mr. Tao

I often talk about risk-benefit analysis in weighing various treatment options for my patients, but when risk-benefit analysis turns into cost-benefit analysis, it makes me exceedingly uncomfortable. This, I think, is one of the real tragedies of managed care.

What the study showed was that with Gliadel wafers in the brain, survival was extended by eight weeks. The mean survival for these patients was four months, so that instead of surviving for four months, the patients survived for six. That is a statistically significant increase in survival, but initially a lot of insurance companies refused to pay for the wafers. Medicare itself denied payment until 2007. It doesn’t take much to do the math and figure out that at least at the outset, insurance carriers and Medicare had reached the conclusion that two months of life was not worth even $8,000. From their perspective, at those prices, an additional eight weeks did not pencil out.
花费8000美元延迟2个月寿命。至少相当于 48000$ / 每 QALY (实际更高，因为末期患者生命质量下降）

There was no way to tell how long the good news would last. Mr. Tao was in a battle for his life, and the odds were against him. Even with his excellent response to radiation and chemotherapy, and the prospect of his participation in the dendritic vaccine trial, his days were probably limited. A year? Maybe two? Perhaps three? It was hard to say.

所以这位 Mr. Tao 最后到底死没死？
我认为是死了。

Chapter 7. The doctor’s dilemma // The story of Elishadie

For reasons I do not fathom, private health insurance pays neurosurgeons a lot more for spine surgery than for brain surgery. The way that the codes have been set up, there is a huge disparity in the reimbursement system. Payment for a relatively simple spine operation is greater than for a long and complex brain tumor operation. A neurosurgeon can do a single thirty-minute spine operation and make more money than I would get for doing Elishadie’s eight-hour tumor operation—if it had been covered by insurance.

Save the Children

Chapter 8. Breaking Barriers // 作者作为南方出身的黑人神外医生成长经历

Stand in the Schoolhouse Door // 阿拉巴马州, 1963。林达《我也有一个梦想》里详细生动地介绍过这个案例。

作者成长期经历了美国民权运动对南方种族隔离制度的深刻变革。但作者认为当代美国的种族歧视并没有完全消失。

Chapter 9. Optimistic Alternatives // again, Mr. Tao

Pharmacology is really just herbal medicine, only more concentrated and more precise. If we believe that the bark of a particular type of evergreen shows promise in treating cancer, we can grind up that tree bark and give it to you, and you may get some benefit out of it. On the other hand, we could take that bark into the lab and figure out why it works. When we start, we may not know exactly what the helpful component may be, but the one thing we know going in is that not everything in that bark is therapeutic. If I can isolate that substance, concentrate it, and give it to you, the effect is going to be much more consistent, much more controlled, and probably much more effective. That’s the way a cancer drug called Taxol was developed, which comes from the bark of Taxus brevifolia, the Pacific yew tree.
// 所以中医唯一的出路——如果有的话——是废医存药。

if you are the CEO of the pharmaceutical company paying those huge Phase III bills, you want some reasonable assurance that you’ll be able to recoup that $300 to $400 million over time. Your responsibility is to your stockholders. With a brain tumor vaccine, you may never get it. There are approximately 22,000 new cases of primary malignant brain tumors each year. As a neurosurgeon, I think that’s too many. But if I’m that CEO of the drug company, I think maybe it’s not enough.

孤儿药法案(Orphan Drug Act)定义罕见病(rare disease or condition)为美国患病人数<=200,000的疾病。考虑到恶性脑肿瘤确诊后的中位生存期（可能只有1-2年？）。在任意时间点已经确诊的仍然生存的恶性脑肿瘤病人数量<20万。所以脑癌应该属于罕见病。

Studies have shown a correlation between the side that a patient uses their cell phone and the side of the brain where their glioblastoma occurs, a correlation I’ve noticed in a great many of my patients.

Chapter 10. Cellular Signs // The story of Tionne Watkins

Tionne Watkins

We were taking every precaution to protect Tionne’s hearing and her facial functions. After she was under anesthesia, we placed speakers in both ears that would produce clicking sounds throughout the surgery. These clicking sounds would be transmitted to her inner ear, where they would be converted to electrical waves that would travel up the hearing pathways in her brain stem to her brain. Electrodes were then placed over her scalp to detect these electrical impulses. The impulses travel rapidly to the brain in a characteristic five-wave pattern and at a predictable speed. In the OR, these brain-stem auditory evoked responses, or BAERS (pronounced “bears”), as they are called, would be constantly monitored by a specially trained technician. During surgery, any slowing of these waves, or any decrease in their size would immediately tell us that the hearing nerve or the brain stem was in danger.

To protect Tionne’s facial nerve, small electrode needles were placed at numerous points in her face to aid in locating the facial nerve within her brain. As I operated, I would stimulate various areas within the tumor. If her facial muscles twitched, that would tell me that the facial nerve was in the vicinity.

Chapter 11. Continuing the Fight

Gerard Kelly died 6 months after his (final) surgery.

It was that last bit of his tumor that we had been unable to remove. Had it regrown away from the brain stem, it might have been several years before it became life-threatening once more. Instead, it grew back into the brain stem, compressing the delicate nerve pathways that governed all of his body functions. At that point, there was nothing more that could be done.

I was very forthright with both Gerard and his brother that the odds of significantly extending his life were maybe 5 to 10 percent. Unquestionably, it was a lot of surgery for him to go through to try for that 5- to 10- percent shot. Nevertheless, he wasn’t ready to give up, and I was confident I could buy him at least another six months with the surgery.

I have learned many lessons from my patients, but one lesson I will always treasure is how one can live an entire lifetime in a few years, or even a few months, and to zero in on what really matters.

One of the most exciting developments in cancer research is the discovery of the cancer stem cell. Within the body, stem cells are primitive, undifferentiated cells that evolve into heart cells, lung cells, brain cells, and other kinds of cells specific to our body’s various organs. From our earliest moments until the moment we die, stem cells are hard at work, replenishing our dying cells with new ones. The cancer stem cell, it seems, functions in much the same way, enabling the tumor to grow by populating it with new cells.
This means that a malignant brain tumor is dependent on cancer stem cells to survive and expand. We now believe that very few of the cells in a cancer can replicate themselves for long periods of time. Approximately 95 to 97 percent of the cells in a tumor are not cancer stem cells, and can divide only a few times before dying out.

In a way, cancer stem cells play the same role as the queen termite in a termite colony. Only the cancer stem cell—the queen termite—produces significant numbers of new tumor cells. These stem cells make up only 2 to 5 percent of all cells in the cancer, but they drive tumor growth, much like the queen termite reproduces to expand her colony. The key to finding a cure for cancer may be to focus on killing cancer stem cells. As in nature, if you want to get rid of the colony, you have to go after the queen.