1. The House of God - I finally made it around to reading this. It was difficult, at first, to properly appreciate what appeared to be the book's unyielding cynicism on the subject of medicine (aka, the final law of the House of God: THE DELIVERY OF GOOD MEDICAL CARE IS TO DO AS MUCH NOTHING AS POSSIBLE), but, read in a different way, quickly becomes not an admission of futility but rather a valiant argument for factoring goals of care into the discussion when considering how to treat the patient. This must have been particularly heretical in the age in which it was published, where the physician was lionized for his or her ability to harness all the tools at hand to preserve life at all costs. Of course, towards its conclusion the book, written by a medicine intern who becomes a psychiatrist, becomes unsurprisingly sycophantic about psychiatry (promoting it over medicine for its enhanced ability to cure people seems particularly silly), but I'll let that slide. And I do like law #3 (AT A CARDIAC ARREST, THE FIRST PROCEDURE IS TO TAKE YOUR OWN PULSE.)
2. The Emperor of All Maladies - Nevertheless, it was comforting to move on from House of God and onto Siddhartha Mukherjee's tremendous 'biography of cancer' - or rather, biographies of Sidney Farber and Mary Lasker with a history of chemotherapy intricately weaved in between. There were so many interesting aspects of this book, beyond its charting the course of how investigations into the fundamental mechanisms driving oncogenesis intersected (or more often, failed to intersect) with relevant and/or efficacious clinical interventions. In particular, I think the book's dissection of how the "vision statement" of cancer research morphed as both drug efficacy and public pressures shifted was amazing.
The book begins with the origins of cancer, from the Egyptian physician Imhotep to Hippocrates, who was responsible for the dual titles of kankros (latin for 'crab') and onkos (for 'mass', or, more poetically, 'burden'). Even as the staging of cancer began to be determined by both local and distant spread, the prognosis remained grim due to the lack of any efficacious therapy:
[Scottish surgeon John] Hunter [in the 1760s] had begun to classify tumors into “stages.” Movable tumors were typically early-stage, local cancers. Immovable tumors were advanced, invasive, and even metastatic. Hunter concluded that only movable cancers were worth removing surgically. For more advanced forms of cancer, he advised an honest, if chilling, remedy reminiscent of Imhotep’s: “remote sympathy.”
All of this changed when the first drugs, aminopterin and methotrexate, were shown to induce temporary remissions in acute lymphoblastic leukemia. This effort was first described by the remarkable Saul Farber (whom Mukherjee champions for his tenacity while not sparing him from the rebuke of overzealousness). In a report published in 1948 in the New England Journal of Medicine, entitled "Temporary Remissions in Acute Leukemia in Children Produced by Folic Acid Antagonist, 4-Aminopteroyl-Glutamic Acid (Aminopterin)" Farber demonstrated the first temporary cancer remission achieved with pharmacotherapeutic intervention alone.
Farber quickly organized studies of other pediatric tumors, including the very common Wilms' Tumor (response seen above) and quickly escalated to the hypothesis that chemotherapy would provide a unifying cancer cure. What was missing, according to Farber, was sufficient funding. For this, he turned to the highly influential fund-raiser and activist Mary Lasker, who quickly concluded that the gateway to real progress was achieving a mainstream, socio-political effort to wage a 'new war on cancer':
“Doctors,” [Mary Lasker] wrote, “are not administrators of large amounts of money. They’re usually really small businessmen…small professional men” – men who clearly lacked a systematic vision for cancer."
As research funds poured in, temporary remissions were seen with high dose chemotherapy in many forms of cancer, both liquid (hematopoieitic in origin) and solid. The public pressure that emerged from these temporary remissions caused a paradigm shift in the goal of cancer research, from mechanistic understanding to result-driven pharmacologic studies, a conversion in which Farber himself took part. He wrote, in a statement to Congress,
The 325,000 patients with cancer who are going to die this year cannot wait; nor is it necessary, in order to make great progress in the cure of cancer, for us to have the full solution of all the problems of basic research … the history of Medicine is replete with examples of cures obtained years, and even centuries before the mechanism of action was understood for these cures.
The combination of a sudden shift in approach from mechanistic to therapeutic studies, combined with increasing public pressure for early approval of chemotherapeutic drugs with even potential efficacy led to the widespread initiation of high dose, toxic chemotherapies under the idea that simply pushing maximal doses would push temporary remissions to complete cures (despite the lack of evidence to support this theory.)
This was pretty ironic, given that, just years earlier, Dr. Min Chiu Li had been fired from the National Cancer Institute for even attempted a prolonged (let alone toxically high) course of chemotherapy for patients with metastatic choriocarcinoma, a treatment which produced the both the first ever quantifiable serum cancer marker and the first ever sustained cancer remission, described in an awesome New England Journal of Medicine paper in 1958. It's heartwarming, in a sad sort of way, to see that many scientists retained a sense of caution and even averseness to this rapid increase in drug development, Nobel prize winner James Watson among them:
“Doing ‘relevant’ research is not necessarily doing ‘good’ research. In particular we must reject the notion that we will be lucky…instead we will be witnessing a massive expansion of well-intentioned mediocrity.”
Over the following twenty years, more and more toxic doses of chemotherapy were administered to patients, despite the lack of evidence that they were of any morbidity or mortality benefit. Mukherjee is unrelenting in his depiction of the hubris of oncologists in pushing toxic therapies with the hopes of achieving a 'cure,' without paying attention to the impact on the patient's quality of life.
The allure of deploying a full armamentarium of cytotoxic drugs – of driving the body to the edge of death to rid it of its malignant innards – was still irresistible. So cancer medicine charged on, even if it meant relinquishing sanctitiy, sanity, or safety. Pumped up with self-confidence, bristling with conceit, and hypnotized by the potency of medicine, oncologists pushed their patients – and their discipline – to the brink of disaster. “We shall so poison the atmosphere of the first act,” the bioligist James Watson warned about the future of cancer in 1977, “that no one of decency shall want to see the play through to the end.”
As the famous breast cancer survivor and patient advocate Rose Kushner noted chillingly, "the smiling oncologist does not know whether his patients vomit or not."
This all culminated, finally, in the sorely misguided initiation of autologous bone marrow transplant for rescue of irreversible bone marrow failure caused by high-dose chemotherapy for metastatic breast cancer. Not only did patients fail to respond to higher doses of chemotherapy, but the toxicity from such high doses caused not only bone marrow suppression but malignant transformation and untreatable myeloid leukemias. 
It was only this highly publicized failure that led oncologists to realize that more was clearly not better. Mukerjee chronicles the subsequent return to the drawing board in which cancer biologists and oncologists focused once again on the fundamentals of disease pathogenesis. He describes the painstaking process by which the viral theory of oncogenesis is largely disrupted and the oncogene model is established, and brings us to the forefront of modern oncology by relating the thrilling origins of both monoclonal antibody therapy (the story of herceptin) and small molecule inhibitors (the discovery of Gleevec). Rarely has one book made me rejoice and despair so many times.
3. The Amazing Adventures of Kavalier and Clay: I'm not going to write as much about this book, but not due to any fault of Michael Chabon's. This is easily one of my favorite novels of all time. Chabon brilliantly depicts how two young immigrants struggle, one with a sense of obligation followed by vengeance, one by fear and shame, and channel these feelings into their superhero, the Escapist. Their superhero serves as their escape from paralyzing loneliness, helplessness, and isolation. It's equally fascinating that their story is modeled after Jerry Siegel and Joseph Shuster, two Jewish immigrants who created Superman as teenagers. Their hero, Superman, seems all-powerful and invulnerable, but in many ways reflects their struggles: an immigrant in a new and foreign world, largely isolated, who escapes to his Fortress of Solitude. (Also, similarly, Siegel and Shuster were screwed out of their earnings). Chabon also acknowledges Jack Kirby, the creator of Captain America who, much like the Escapist, punches out Hitler in an iconic DC cover. Anyways, this book was awesome.4. The Checklist Manifesto: So, admittedly, a book about checklists is not going to be Atul Gawande's most fascinating book (particularly when his last book, Better, featured him iconically tying on a surgical mask. That is way cooler than a check mark.) But that's all the more reason to applaud him for writing a book that is basically antithetical to the surgeon's "my hands are my life" mentality. Gawande's premise: that reduction of simple, avoidable mistakes could actually improve mortality, was no doubt regarded as preposterous among his fellow attending surgeons, who no doubt thought of such checklists as a waste of their prodigiously valuable time. But time and again, Gawande shows that targeted, methodical incorporation of checklists improves outcomes. I was stunned to read of the study in Karachi, Pakistan, in which simply giving families instructions on proper use of soap in six vital situations reduced disease burden:
“The secret was that the soap was more than soap. It was a behavior-change delivery vehicle. The researchers hadn’t just handed out [soap] after all. They also gave out instructions – on leaflets and in person – explaining the six situations in which people should use it. This was essential to the difference they made. When one looks closely at the details of the Karachi study, one finds a striking statistic about the households in both the test and the control neighborhoods: at the start of the study, the average number of bars of soap households used was not zero. It was two bars per week. In other words, they already had soap.”
Gawande is not so naive to think that all problems can be solved with a set of instructions. He differentiates between 'simple' problems (such as reducing infection with introduction of proper cleaning procedures) from 'complex problems' (such as how to increase teamwork in the operating room.) In the case of complex problems, he fully admits that a checklist won't solve the problem, but suggests (and is supported by data) that pro-active communication between members of a team in combination with decentralization of decision-making capacity can similarly improve outcomes.
Gawande then describes the construction of a pre-operative surgical checklist to prevent common complications in the operating room. He is forthcoming about his struggles in generating a checklist that properly reduces commonly overlooked errors while not restricting autonomy. The ultimate results of the checklist study cannot be doubted or overlooked; a significant reduction in complications and mortality is seen across eight different institutions of varying size, patient population, and level of resources. But rather than stopping there, Gawande takes a step further and discusses the lack of widespread implementation of checklists despite the undeniable results of the study. In doing so, he does not flinch in his critique of himself and his colleagues. His assessment is that the hesitation of doctors to use a simple checklist to reduce mortality is two part: first, the idea that something so simple as a checklist could improve mortality (and its accompanying implication that doctors frequently err in such preventable ways) is insulting to a physician's ego, That’s what happened when surgical robots came out – drool-inducing twenty-second-century $1.7 million remote-controlled machines designed to help surgeons do laparoscopic surgery with more maneuverability in side patients’ bodies and fewer complications. The robots increased surgical costs massively and have so far improved results only modestly for a few operations. Nevertheless, hospitals in the United States and abroad have spend billions of dollars on them…By the end of 2009, about 10% of American hospitals had either adopted the checklist or taken steps to implement it.
and second, that physicians wrongly assume that systematic approaches such as checklist work against the ability of doctors to think creatively:
The prospect [of checklists] pushes against the traditional culture of medicine, with its central belief that in situations of high risk and complexity what you want is a kind of expert audacity – the right stuff. Checklists and standard operating procedures feel like exactly the opposite, and that’s what rankles so many people...they imagine mindless automatons, heads down in a checklist, incapable of looking out their windshield and coping with the real world in front of them. But what you find, when a checklist is well made, is exactly the opposite. The checklist gets the dumb stuff out of the way, the routines your brain shouldn’t have to occupy itself with, and lets it rise above to focus on the hard stuff.
Gawande is unmoved by such argments, and I'm with him. And while the implementation of checklists such as this seems to be more useful in the surgical world, I can think of plenty of scenarios in which they are useful in medicine (a simple checklist at the completion of a patient history and physical, a systemic approach to cardiac arrest) and I don't think that anyone feels that are the first step to doctors becoming automatons.
Whew! That was long.
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