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What’s wrong with Steve Jobs, revisited

It’s no secret that, when it comes to computers, my preferred axe has been the Apple Macintosh. Indeed, back in the 1983-1984 school year I was in college living in a house with five other guys, and one of my roommates was a a total Apple geek. He had, as one might expect, an Apple IIe, and I immediately decided that, when it came to computers, I definitely liked the Apple product better than the IBM PC that my other roommate had. Of course, at the time I was nowhere well off enough to be able to afford either, but these two roommates were both computer science majors. They had to have a computer; and both somehow came up with the cash. (Back in those days PCs cost several thousand dollars.) In any case, my first experience with the Macintosh dated back to the original Macintosh, delivered to my Apple-loving roommate through a student discount plan in the early part of 1984. I immediately fell in love with the machine.

I realize that my younger readers will have a hard time believing this, but it’s true and it wasn’t at all uncommon in the 1980s. I didn’t own a computer for about eight years after that, including through medical school and the first two years of graduate school. Instead, I had to rely on computer lab machines and, later, the machine’s in my Ph.D. thesis advisor’s laboratory, which, fortunately, was a Macintosh. The first computer I ever bought for myself was a Mac LC; I could barely scrape together the cash. Now that I’m incredibly fortunate enough (especially in this economy) to have a good income, I have a MacBook Pro and a Mac Pro at home; my wife has a MacBook; and I have multiple Macs in my lab, all relatively new, even though our IT department is about as Mac hostile as it can be without simply banning Macs and requiring Windows XP boxes. Fortunately, that is changing, thanks to my insistence and that of two other faculty who prefer Macs. Finally, Mac geek that I am, I even bought an iPhone 3 GS on the day it was released. (Yes, I like it. A lot.)

All of which is a revisitation (or, depending on your point of view, a regurgitation) of why I care about Apple and why what happens to Steve Jobs interests me. Last year, when Steve Jobs was looking gaunt and various reports were coming out about his health, full of dire speculation about what was wrong with him, I wrote a post about what I suspected to be going on. Basically, Jobs had had a neuroendocrine tumor of the pancreas, for which he had undergone a pancreaticoduodenectomy (colloquially known as the Whipple procedure) in 2004. As I pointed out at the time, Jobs had been incredibly lucky in that the mass discovered growing in the head of his pancreas turned out not to be a run-of-the-mill pancreatic cancer (adenocarcinoma of the pancreas), which has an absolutely dismal five year survival. (Patrick Swayze has metastatic adenocarcinoma of the pancreas and has thus far beaten the odds by surviving more than a year since his diagnosis.) Rather, it turned out to be a rare type of tumor known as a neuroendocrine tumor, which, in contrast to pancreatic cancer, is eminently curable with surgery. A year ago, I speculated that the reason for Steve Jobs’ gaunt appearance was a complication from his Whipple operation, specifically the dumping syndrome. When earlier this year Steve Jobs took a leave of absence from Apple for a few monthsi due to an “endocrine disorder,” I was, quite frankly, flummoxed. I couldn’t reconcile the reports with my previous speculation.

If a story in the Wall Street Journal is correct, it would appear that I was pretty darned wrong. Indeed, if this story is correct, it would appear that Steve Jobs underwent a liver transplant:

Steve Jobs, who has been on medical leave from Apple Inc. since January to treat an undisclosed medical condition, received a liver transplant in Tennessee about two months ago. The chief executive has been recovering well and is expected to return to work on schedule later this month, though he may work part-time initially.

Mr. Jobs didn’t respond to an email requesting comment. “Steve continues to look forward to returning at the end of June, and there’s nothing further to say,” said Apple spokeswoman Katie Cotton.

When he does return, Mr. Jobs may be encouraged by his physicians to initially “work part-time for a month or two,” a person familiar with the thinking at Apple said. That may lead Tim Cook, Apple’s chief operating officer, to take “a more encompassing role,” this person said. The person added that Mr. Cook may be appointed to Apple’s board in the not-too-distant future.

Apple has previously drawn criticism from some shareholders over what they have called limited disclosure of Mr. Jobs’s health problems, which began in 2004. In this case, it is unclear whether the surgery is material because Mr. Jobs was already on leave. Material information like that must be disclosed only “if you are asking shareholders to make a decision based on [that] information,” said John Olson, a senior partner at Gibson, Dunn & Crutcher in Washington. “You can’t expect the company to give a blow-by-blow account of Steve Jobs’s health.”

Oh, well. I guess I’ll have to take my lumps with the rest of them. I totally missed the boat last year, although at the time it certainly seemed like a reasonable guess that Jobs had malabsorption or dumping syndrome, both of which are not-so-infrequent complications of the Whipple procedure. Now, given that I have never actually seen or taken care of Jobs, some trepidation remains about just how much I should speculate based on this WSJ story, but I’ll see what I can do. Interestingly, this information about Steve Jobs supposedly needing a liver transplant is not new. Back in January, in an article I totally missed, Bloomberg actually reported that Steve Jobs was looking for a liver transplant. Even back then, it was speculated that Jobs’ neuroendocrine tumor, specifically an insulinoma (a tumor that secretes insulin) had metastasized to the liver, and, during an interview with Dr. Steven Brower, professor and chairman of surgery at Mercer University School of Medicine in Savannah, Georgia, it was speculated that Jobs was undergoing a liver transplant in order to treat these liver metastases. Then, in April, Barron’s Online and peHUB discussed rumors that a swank house in Memphis had been purchased for Jobs, that he was planning to move to Memphis to treat his cancer, and that he would live in that house while being treated.

With that as a background, this is what the WSJ article reports:

In early January, Mr. Jobs said he had a hormone imbalance that was “relatively simple and straightforward” to treat. But about a week later, he announced that the issue was more complex than he had thought, and in a letter to employees he said he would be taking a leave and Mr. Cook would take over temporarily.

William Hawkins, a doctor specializing in pancreatic and gastrointestinal surgery at Washington University in St. Louis, Mo., said that the type of slow-growing pancreatic tumor Mr. Jobs had will commonly metastasize in another organ during a patient’s lifetime, and that the organ is usually the liver. “All total, 75% of patients are going to have the disease spread over the course of their life,” said Dr. Hawkins, who has not treated Mr. Jobs.

Getting a liver transplant to treat a metastasized neuroendocrine tumor is controversial because livers are scarce and the surgery’s efficacy as a cure hasn’t been proved, Dr. Hawkins added. He said that patients whose tumors have metastasized can live for as many as 10 years without any treatment so it is hard to determine how successful a transplant has been in curing the disease.

Before I start discussing the medicine and science behind whether neuroendocrine tumors of the pancreas that have metastasized to the liver can be successfully treated with liver transplant, let me first point out an aspect of this that disturbs me if this story is indeed true. Livers (and indeed, all other organs for transplant) are precious and scarce commodities. Steve Jobs lives in California, specifically the San Francisco bay area. So what was he doing getting a transplant at a Tennessee hospital? According to the WSJ, here’s why:

The specifics of Mr. Jobs’s surgery couldn’t be established, but according to the United Network for Organ Sharing, which manages the transplant network in the U.S., there are no residency requirements for transplants. Having the procedure done in Tennessee makes sense because its list of patients waiting for transplants is shorter than in many other states. According to data provided by UNOS, in 2006, the median number of days from joining the liver waiting list to transplant was 306 nationally. In Tennessee, it was 48 days.

How many people are capable of getting themselves listed for transplant in a state nearly 2,000 miles away from their home? When a liver becomes available, there isn’t much time to get to the hospital. That means a person seeking a transplant in another state either has to stay in that state for as long as it takes to get an organ or be within a distance to be able to fly there within a very short period of time. Moreover, organs eligibility and availability are determined by the United Network for Organ Sharing, which maintains the donor lists. When an donor is identified, regional and state organizations (in my home state, for example, Gift of Life, where one of my relatives works), obtain consent, arrange for organ harvest, and decide, based on fairly strict criteria published by UNOS regarding medical need and practical matters like how long it will take to get the organs out and to the hospitals where they are needed, which people on the waiting list for the state will receive each of the organs harvested. If this story is true, what Jobs did is not illegal, but it sure does leave an unpleasant stench of the rich and powerful taking advantage of regional differences in organ availability, perhaps at the expense of a lifelong Tennessee resident who needs a liver.

Worse, the indication is somewhat shaky. For one thing, as was pointed out in the article, neuroendocrine tumors are generally very slow growing and take a long time to metastasize. One of the more “common” subtypes of the rare neuroendocrine tumor in particular, a carcinoid of the appendix or the rectum, is particularly prone to metastasize to the liver and is notorious for causing carcinoid syndrome, which is due to serotonin secretion by these tumors and causes flushing, diarrhea and other unpleasant symptoms.

In any case, the indications for liver transplant for neuroendocrine tumors are a bit controversial, but a good summary can be found at the Mayo Clinic website, the NCI website, and the American Cancer Society website.

In general, for neuroendocrine tumors metastastic to the liver, the first options to be considered are ablative options. These can include surgery, if the tumors are resectable, or ablation by various methods, such as radiofrequency ablation (RFA, or, as we like to say, “cooking the tumors”) or cryoablation (cryo, a.k.a. freezing the tumors). Surgery can be curative if the lesions are confined to a volume of liver that can be completely resected, and RFA is generally reserved when there are lesions in multiple lobes not amenable to surgical resection. For the consideration of a liver transplant, a patient must have multiple lesions in multiple lobes of the liver that are too numerous even to be cooked by RFA or frozen by cryo. Moreover, there can be no evidence of tumor anywhere other than in the liver. If there is evidence of tumor spread anywhere other than in the liver, then even liver transplant would not help. Given these indications, if Steve Jobs did undergo a liver transplant, it’s safe to assume that he had multiple liver metastases that were not amenable either to resection or ablation.

In addition, another indication is that symptoms must be such that they can’t be controlled by medical therapy. For an insulinoma, controlling the symptoms due to hypoglycemia can actually be quite difficult; so the type of tumor Jobs produced symptoms that are more difficult to palliate than the average neuroendocrine tumor. The NCI website lists these recommended methods:

  • Combination chemotherapy: doxorubicin plus streptozocin or fluorouracil plus streptozocin in patients when doxorubicin is contraindicated.[1,2]
  • Pharmacologic palliation: diazoxide 300 to 500 mg/day
  • Somatostatin analogue therapy (SMS 201-995).
  • atients with hepatic-dominant disease and substantial symptoms caused by tumor bulk or hormone-release syndromes may benefit from procedures that reduce hepatic arterial blood flow to metastases (hepatic arterial occlusion with embolization or with chemoembolization). Such treatment may also be combined with systemic chemotherapy in selected patients.

So what are the results of liver transplant for neuroendocrine tumors? Because these tumors are so uncommon, there’s never going to be a randomized clinical trial. All that can be found in the literature is around less than 200 patients who have ever undergone liver transplant for neuroendocrine tumors. A recent series published out of Mount Sinai reviewed the literature and found five year survival rates for liver transplants for neuroendocrine tumors are all over the map, ranging from 33% to 80%. The series itself reported reported 36% five year survival. However, all of these were very small series, some only a handful of patients; so it’s hard to generalize any conclusions from them. However, it’s the best data available right now. The kindest and most generous characterization that can be made is that that the evidence for treating neuroendocrine tumors metastatic to the liver with liver transplantation is mixed at best. On the other hand, the symptoms from an insulinoma can be quite troubling, including the symptoms of hypoglycemia, plus weakness, confusion, personality changes, headache, and ataxia, and palliation is difficult, even if it does tend to grow very slowly. Moreover, in a patient with lots of liver metastases, liver transplantation is the only modality that holds out even a hope for cure. Still, it’s arguable whether it should be done in these cases, given the scarcity of organs and the questionable results.

Some guidance came from a recent review of the management of neuroendocrine tumors concluded:

After considering published studies and data, some recommendations may be given, although these are based on a low level of evidence. After excluding extrahepatic tumour manifestations by imaging procedures and diagnostic laparoscopy, the indication should be chosen restrictively. Few prognostic markers, for example age below 50 years and absence of concurrent extensive surgery, were identified by multivariate analysis in a large retrospective analysis. The prognostic impact of primary tumour localisation is still controversial. However, further indicators of favourable long-term prognosis are needed. Tumour biology characterised by Ki67 and E-cadherin expression may help to identify patients with a favourable outcome so that patient selection can be improved, but this needs further evaluation in larger patient cohorts. Orthotopic liver transplantation for patients with remission of disease or stable disease under medical treatment, and orthotopic liver transplantation for palliative reasons, should be restricted to selected individual cases.

It’s very, very hard to tell whether Jobs would fall into one of the groups likely to have a good outcome from just the news reports, given Jobs’ secrecy with regard to his health. Certainly, Jobs is over 50 and had prior extensive surgery (a Whipple is about as extensive as it gets!), both of which, according to this review, are poor prognostic markers. If there’s one thing that can be said, though, it’s that, based on publicly available information, Jobs’ medical condition was far worse than he had let on, and his prognosis is far more tenuous than is being advertised. Again, this is all assuming that the WSJ article is accurate. I don’t know if Jobs will fall into the group with an 80% chance of five year survival or a 35% chance, but, as a longtime Apple aficionado, I’m worried. I wish nothing but the best for Jobs. After all, he has, more than anyone else, been responsible for the resurgence of Apple’s fortunes over the last decade or so. However, I also hope that he has a succession plan in place. I really hope he doesn’t need it, but the numbers suggest in the best case a modest chance and in the worst case a major chance that he will in the next five years.

That is, if the WSJ story is accurate. The story is, after all, remarkably free of named sources or anonymous sources, as John Gruber at Daring Fireball points out, although it might also be, as Gruber speculates, a timed leak on a Friday afternoon of the biggest Apple product launch of the year, one that sent its stock soaring.

Maybe Jobs did have a liver transplant, after all.

By Orac

Orac is the nom de blog of a humble surgeon/scientist who has an ego just big enough to delude himself that someone, somewhere might actually give a rodent's posterior about his copious verbal meanderings, but just barely small enough to admit to himself that few probably will. That surgeon is otherwise known as David Gorski.

That this particular surgeon has chosen his nom de blog based on a rather cranky and arrogant computer shaped like a clear box of blinking lights that he originally encountered when he became a fan of a 35 year old British SF television show whose special effects were renowned for their BBC/Doctor Who-style low budget look, but whose stories nonetheless resulted in some of the best, most innovative science fiction ever televised, should tell you nearly all that you need to know about Orac. (That, and the length of the preceding sentence.)

DISCLAIMER:: The various written meanderings here are the opinions of Orac and Orac alone, written on his own time. They should never be construed as representing the opinions of any other person or entity, especially Orac's cancer center, department of surgery, medical school, or university. Also note that Orac is nonpartisan; he is more than willing to criticize the statements of anyone, regardless of of political leanings, if that anyone advocates pseudoscience or quackery. Finally, medical commentary is not to be construed in any way as medical advice.

To contact Orac: [email protected]

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