You may love Apple computers and their devices including the iPod, iPad, and iPhone. Or you may like Windows computers or perhaps Linux boxes. Whatever you like about your computer, whatever it may be, it was Steve Jobs and

Apple - The Rainbow

Steve Wozniak’s abilities, vision, and salesmanship that has put one in your home.

Without Wozniak the engineer, and Jobs the guy with the vision, your computer would weigh half a ton and probably only be at your office. Back in the Homebrew Computer years the vision of a home computer was something that could display lights which if you could decode the binary message you would know the answer to 2 + 2. Bill Gates during those Homebrew years came up with the bright idea of selling and owning software starting with Basic. Not long after – it was licensing rather than owning software.

But Jobs had an idea that a computer could be more, and could be in many houses, not only in the homes of those who read Popular Electronics. IBM jumped on the bandwagon, but did not consider their PC market particularly important for several years. The hype in those early days made it difficult to determine what was going to be the best machine for business purposes. In those early years it was clear that IBM and DOS was more suitable for business rather than the Apple II. But still, it was Jobs that forced IBM’s hand to even making those smaller machines. Gates was clever enough to license both a DOS (disk operating system) and a Basic interpreter to

Altair with Cool Lights

more than one computer manufacturer. He escaped an exclusive arrangement with IBM and every other hardware manufacturer that he dealt with.

In 1979 Jobs visited Xerox PARC and liked what he saw. He came away with the idea of creating a graphic user interface, a mouse for data input, fonts, an improved menu system, and an overall friendlier computer system.
Out of this came the overpriced and failed Lisa and the game changing Macintosh. With the advent of the graphic user interface, Gates saw that DOS had a finite life and worked on Windows. The first widely distributed Windows Beta showed it’s gaming strengths which led from Reversi to Solitaire. And later to Doom, Quake and Warcraft. OS X is still not a gaming platform, although a speedy iMac can run a number of game programs quite well.

Not long after the development of the Mac, the dapper soda pop expert, hired by Jobs as CEO, boasted he did not have a computer on his desk. He proceeded to force Steve Jobs out of his company. Steve Jobs then founded NEXT and purchased PIXAR which no one had a clue would ever amount to anything.

Macintosh

As Apple appeared headed to certain failure, Jobs returned as CEO and the operating system of NEXT grew into OS X. With innovations in portable devices in addition to a solid, crash “lite” operating system, Apple met with considerable success. Jobs always asked the near impossible of his engineers and designers. Smaller and smaller, thinner and thinner all things became. The Titanium Macbook Pro was the first Apple computer I used. Being less than 1 inch thick, with the first DVD drive, and OS X, which is an attractive shell over what is mostly BSD UNIX attracted me (after finding that I liked Linux as an alternative to dealing with the faults, flaws, and security weaknesses of Windows.) Using Intel processors brought Apple a long way and the ability to run Windows on the same machine was welcomed by many. Personally, I’ve decided I like my windows on it’s own machine.

The iPod changed the way we listen to music. In many ways the convenience is for the better. But in deference to the music geeks, I’ll admit that we find ourselves in a “low-fi” world. With the loss of the ability to hear all of the high tones, it matters less to me right now. After giving in to reason, allowing video on the small device was a big plus. The iPhone was a bold step and did work quite well the first day right out of the box. A fine interface, an attractive device, an interesting combination of apps that worked well was a different model than other companies had used. Yes, it was certainly and still is a relatively restrictive environment, closed, not user friendly to jailbreak and less friendly after being jail broken. But the trade off has been a reliable and fun to use device. The iPad is a good size for many older people and has caught on well as a tablet. It has caught on so well, that others, such as H-P have even given up trying to compete.

Starting with putting a friendlier face on computing and the concept of computers for everyone, Jobs thought different. Interface and design intersected in ways not before conceived of in the computing world. Computers, email, face-to-face communication via your cell phone or computer, ease of access to information, research, music, and software have changed the landscape of the world. Jobs played a role in this, as did many others. But I give Steve Jobs much credit for the role he played.

Since Jobs developed  pancreatic cancer, which is often deadly within a year or so, and later had a liver transplant, his health has been shaky. Somehow he has still managed to bring enthusiasm and new products regularly to Apple. A biography of Jobs written by Walter Isaacson was originally scheduled to be published in March, 2012 and was to be called iSteve: The Book of Jobs. Publication has been moved up to November, 2011 and the title is now the more serious “Steve Jobs: A Biography”. I didn’t take that as a good sign.

I’m not sure what Apple will be like after Jobs. I’m sure it will be a solid company and will continue to be competitive. But, it will miss the driving vision and uncompromising principles of Jobs. The engineers will be able to relax a bit, but I’m sure the next 15 years will be much different than they would be in the absence of a healthy, strong, and visionary Steve Jobs at the helm. I send thanks and wish Steve Jobs well and as pleasant a transition as possible.

Micro NMR (Sci Trans Med)

Miniaturization of technology continues to bring new innovations in science and technology. The very latest innovation which you probably have not seen yet is a miniature NMR. On a larger scale this is the old familiar MRI machine. The micro-NMR is coupled to a Smart Phone and used to analyze cell surface proteins. A study published this week in Science Translational Medicine showed that this micro-NMR (μNMR) device run by a smart phone could be used to analyze a series of proteins/markers (pCAM (epithelial cell adhesion molecule), MUC-1 (mucin 1, cell surface associated), HER2, EGFR (epidermal growth factor receptor), B7-H3, CK18, Ki-67, p53, and vimentin]) showed a 10% to 20% improved diagnostic accuracy over traditional cell staining and other traditional techniques.

The current study analyzed needle aspiration biopsies. The study was limited to intra-abdominal cancers. The researchers found that 4 markers: MUC-1, HER2, EGFR, and EpCAM provided high diagnostic accuracy. These 4 markers used in conjunction gave the  correct diagnoses in 48 of the 50 initial patients examined and in 20 of 20 in the next round. For biology, science and technology geeks this was a fascinating article. I’ll link below to the Editor’s summary.

As we wonder what our Smart Phones can do besides play music surf the web, and track our running mileage, we see that forward thinkers are finding new ways to use the smart phone along with creative and new ways to use current technology. And yes, genomics and proteomics have a future.

Reference:
Sci Transl Med 23 February 2011: Vol. 3, Issue 71, p. 71ra16 DOI: 10.1126/scitranslmed.3002048. Micro-NMR for Rapid Molecular Analysis of Human Tumor Samples. Haun J. et. al.

Science, Numbers, Journalism and Critical Thinking

I believe it was on a Merlin Mann podcast, where someone jokingly mentioned the concept of an iColon website which in typical Web 2.0 fashion people could share the images and films of their colonoscopy procedures. This week the New York Times managed to demonstrate where their heads were at regarding simple mathematics and statistics. An article by one of their most popular reporters reviewed a new study that showed that colonoscopies were not all they were cracked up to be as far as picking up colon cancer and in their ability to prevent future cancers from developing from detection and removal of polyps.

The American Cancer Society still strongly recommends the colonoscopy as a useful  screening procedure. and the physicians I know who both perform this procedure and recommend it all strongly feel that it is one procedure that can actually save lives. We will however take a quick and simple look at the use of math and see a lack of simple math skills and the failure of editorial checking at the New York Times.

The NY Times reported on a study that demonstrated that colonoscopy missed virtually all polyps on the right side of the colon. The  article stated that 40% of all cancers and polyps originated on this side. Of those on the left side of the colon up to 30% of those were missed. The article then went on to quote and conclude that rather than preventing up to 90% of colon cancer from devleloping it might only be useful in preventing 60% to 70%. Now, this seems to be a fairly simple math problem. And a quick glance by anyone even one with only minimal math skills just looks and sounds wrong on the surface of it all.

If 40% of the lesions occur on the left side but are undetectable, than you have remaining 60% of the lesions to deal with that you can find. If 1/3 of these ones are not found, by splitting them into 3 equal parts of 20% 20% and 20%, and you remove 1/3 you are then left with 40% of the lesions that you would be able to find.
Hence, it is clear that it is not 60%-70% number of lesions that you’ll expect to find, but a number significantly less than 50% and which clearly looks to be 40%. The physician interviewed in the New York Times encourages people to have the colonoscopy as a screening procedure, but to not necessarily expect to be safe for the next 10 years. It is strongly recommnended that you follow the colon cleaning procedures prescribed prior to undergoing the procedure.

There will be more studies in the future and likely ones that will be quite positive on colonoscopy. Techniques will likely be modified that also result in improved detection of right sided lesions. Until then, we now and always will need clear heads to do the math and keep evidence based medicine, based on evidence and not on an easily obtained quote.

Up soon we may dissect an article published within the last few months that looked at the longevity of runners and non-runners. If you know the study, here’s a hint: check out the disparate population groups studied and see if it looked like a well designed and controlled study.

New Math From the New York Times:

“In the new study, the test missed just about every cancer in the right side of the colon, where cancers are harder to detect but about 40 percent arise. And it also missed roughly a third of cancers in the left side of the colon.

Instead of preventing 90 percent of cancers, as some doctors have told patients, colonoscopies might actually prevent more like 60 percent to 70 percent.”

Evidence Based Medicine vs. Sensationalism
The New York Times, today, in a fairly sensational manner, discusses Non-Hodgkins Lymphoma and medications in vogue in reference to two medicines, including Zevalin, which at this time is used in cases of failure of other therapies. The accusastion being made is that physicians are not using Zevalin, a radioactive drug, that can only be administered in a hospital using a complex protocol, because of incentives to use more established and well studied protocols including Rituxan in conjunction with “CHOP”.

They highlight the essentially anecdotal evidence of 3 patients who have done well after failing other protocols. That is both the manner in which Bexxar and Zevalin are to be used and the manner in which they have been studied so far. While studies that will indicate if survival time is increased should be complete soon, there is no study that by the principles of Evidence Based Medicine (EBM) do this yet. EBM requires evidence of a high order in well conducted studies that effectively, objectively and statistically demonstrate the utility of a treatment.

This is a higher standard than media generated sensationalism or pharmaceutical company based marketing offer. The studies must stand on their own merit. So far the medications are being used as studied and demonstrated. They are used after failure of other treatment. They are complicated and difficult to administer. They should be used though where needed. Hopefully, the studies that will reportedly be completed soon will demonstrate their superiority, effectiveness, and utility for Non-Hodgkins Lymphoma. Knowledge is increasing fast in this area, but of course not fast enough.

A sensational article like this one, discussing treatment, witholding of treatment, and implying decicsion making is arbitrary and even selfish without even the mention of what EBM is, is not responsible.

You can do your own literature search at PUBMED for more information.

U.S. Clinical Trials – searchable database. You may find active studies using Zevalin or other products here.

Selected Literature Search ResultsExpert Rev Anticancer Ther. 2002 Oct;2(5):485-93
The current indications are: low-grade or follicular lymphoma refractory to rituximab, and relapsed or refractory, low-grade, follicular or transformed lymphoma. Additional studies have been initiated to further define the role of this new therapy in the treatment of patients with B-cell non-hodgkin’s lymphoma.

Semin Oncol. 2003 Dec;30(6 Suppl 17):17-22.
Gregory, SA. Selecting patients for treatment with 90Y ibritumomab tiuxetan (Zevalin).

Yttrium 90 ibritumomab tiuxetan (Zevalin; Biogen Idec Inc, Cambridge, MA) was the first radioimmunotherapeutic agent approved by the US Food and Drug Administration. It is indicated for treating patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma, including patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. Proper patient selection is essential for optimizing the efficacy and safety of treatment with (90)Y ibritumomab tiuxetan. It may be advisable to use (90)Y ibritumomab tiuxetan relatively early in a patient’s course of treatment because overall and complete response rates, and the estimated median duration of response, are higher among patients who have had fewer median prior antineoplastic regimens than among those who have had a greater median number of such regimens. Furthermore, the myeloablative effect of multiple courses of chemotherapy can preclude the later use of (90)Y ibritumomab tiuxetan. In contrast, other therapies, including chemotherapy and rituximab, can be used safely and successfully after (90)Y ibritumomab tiuxetan without concerns about increased hematologic toxicity from the previous radioimmunotherapy. The main adverse event associated with (90)Y ibritumomab tiuxetan therapy is hematologic toxicity and, as a result, only patients with adequate bone marrow reserves and less than 25% lymphoma marrow involvement should currently be considered for clinical therapy.

Cancer Biother Radiopharm. 2005 Apr;20(2):185-8.

Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) induces long-term durable responses in patients with relapsed or refractory B-Cell non-Hodgkin’s lymphoma.
Wiseman GA, Witzig TE.
Mayo Clinic, Rochester, MN, USA. gwiseman@mayo.edu

AIM: Yttrium-90 ((90)Y) ibritumomab tiuxetan (Zevalin) radioimmunotherapy is an effective treatment for relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL), with overall response rates ranging from 74% to 82%. This retrospective analysis was conducted to determine the number of patients achieving long-term durable responses with (90)Y ibritumomab tiuxetan treatment. MATERIALS AND METHODS: The medical records of patients (n = 211) with relapsed, refractory, or transformed indolent CD20+ B-cell NHL who were treated with 90Y ibritumomab tiuxetan were reviewed. Time to progression (TTP) of > or =12 months was noted in 78 patients (37%), who were identified as long-term responders and were further characterized. RESULTS: Median age of the long-term responders was 58 years (range, 24-80 years) with 44% over 60 years, and 55% were male. Notably, 59% of patients had received > or =2 prior regimens, 33% had received > or =3 prior regimens, and 37% had failed to respond to immediate prior therapy. Median response duration was 28.1 months (range, 10.5-80.3+ months). Median TTP was 29.3 months (range, 12.1-81.5+ months). In patients with ongoing response, median TTP was 53.9 months (range, 49-82+ months). CONCLUSIONS: (90)Y ibritumomab tiuxetan produces durable long-term responses in patients with relapsed/refractory B-cell NHL. Failure to respond to prior therapy does not preclude achieving a long-term response with 90Y ibritumomab tiuxetan.