Assessing the Benefit-Risk Ratio of Nitrates

Many readers may have come across a recent report linking the consumption of processed meats (sausage, bacon cold cuts, etc.) to the incidence of pancreatic cancer. Intriguingly, the higher risk seemed to only apply to men and not women. The explanation for this remains obscure, but may reflect other dietary habits more common to men or other factors, such as increased alcohol consumption or smoking. But this is only a speculation.

The presumptive mechanism of cancer causation seems to revolve around the presence of nitrates in these cured meats. Nitrates are added to meats as preservatives. Preservatives function to inhibit bacterial growth responsible for food spoilage. Nitrates under the acid conditions in the stomach, are converted to nitrites. And it is these nitrites, primarily in the form of nitrosamines, which may be the culprits.

When we exam these findings several issues must be considered. First, however nefarious the consuming public may think the meat packing industry, I for one am fully convinced that these companies do not add nitrates to cause cancer. Quite the contrary. The most dangerous organisms found in foodstuffs, through spoilage and lethal food toxins, are the anaerobic organisms. The most frightening of all is clostridium botulinum, which produces the fatal condition known as botulism. Nitrates converted to nitrites are potent inhibitors of clostridia.

In the grand scheme of things, it is highly likely, in fact certain, that many, many more people have been saved from nitrites in food than would ever die from pancreatic cancer. These risk-benefit ratios are the subjects that keep epidemiologists up at night.

Nitrates in food are not the only possible man-made exposures that we encounter on a daily basis. Take for example chlorinated water. The “chlorine” in water is, for all intents and purposes, bleach. That’s right every time you drink tap water you are being exposed to tiny quantities of bleach. It is probably unnecessary for me to explain to the average reader, the risks and hazards of common household bleach, which is a solution of hypochlorite. And, however toxic that bottle under your sink may seem, remember that is only a 5 percent solution.

Another example is fluoride. While the benefits of fluoridation of water are numerous, including bone density and improved hardness of the enamel of teeth, demonstrably reducing tooth decay, fluorine itself is not, at least theoretically, free of risk. We know that sodium fluoride is an inhibitor of phosphodiesterase, an enzyme responsible for regulating cyclic AMP and cyclic GMP levels in the cell. These protein kinase A signals events may be tonically affected by changing levels of fluoride in the cell, to what end it is hard to say.

Like chlorination or fluoridation of water, nitrates in food represent risks that we as a society have accepted, based upon what we deem as acceptable benefit-risk ratios.

It is possible, that the increased incidence of food-borne illness and enteric infections, increased dental caries associated with the elimination of all these risks, may far exceed the hazards associated with these exposures.

The human species evolved over millennia in an environment exploding with free radical activity, fortunately we have developed defenses, superoxide dismutase, glutathione, peroxidase, catalase, etc., that counteract the toxic effects of these chemical compounds. Whether the man-made exposure substantively changed the balance will be a topic of discussion for years to come.

The Molecular Origins of Lung Cancer

I had the luxury of attending the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; Biology, Therapy and Personalized Medicine held in San Diego earlier this month. I say luxury, for as my schedule closes in on me and I sometimes find myself working 13-hour days, it can be difficult to take even a couple of days away to attend meetings. But this conference was too good to pass up (hats off to Marge Foti and all the AACR staff for all their great work).

This symposium organized by David Carbone and Roy Herbst, brought together a broad spectrum of sophisticated scientists and international investigators, as well as community members and fundraising organizations who had the opportunity to present a special session on patient advocacy.

The meeting began with a keynote address examining microRNAs and lung cancer presented by Frank Slack from Yale University. He examined the growing recognition that lung cancer arises not only from gene mutations but also from small fragments of RNA that can up- or down-regulate normal genes in abnormal ways. This was the topic of discussion for many subsequent presentations.

As an aside, many of the readers will know that I am generally underwhelmed by genomic analyses for the prediction of cancer response. The fact that normal genes can function abnormally under the control of these small RNA sequences is just one more example of the genotype–phenotype dichotomy that cannot be adequately examined on static contemporary genomic platforms.

Many presentations examined the molecular biology of lung cancer with important distinctions being drawn between adenocarcinoma and squamous cell carcinomas. While adenocarcinomas reveal a growing number of targets – EGFR, ALK, ROS, RAS, and others – all the subject of small molecule inhibitors; squamous cell carcinomas provide fewer opportunities for the use of these classes of drugs.

One of the interesting discussions was the frequent mutation of LKB1 in lung cancers. Work going back several years by John Minna, a pioneer in this field, identified changes in this metabolic regulator as a common finding in lung malignancies.

Additional presentations examined chemoprevention, molecular pathology, new mechanisms to categorize lung cancer subtypes, and a very interesting discussion of field cancerization. In a particularly interesting analysis, Ignacio Wistuba from M.D. Anderson, showed that molecular changes in the surface epithelium of the lung bronchioles recapitulated the molecular biology of the final tumor in a step-wise manner, inversely related to the distance to the tumor. That is, starting at the main bronchi, one or two mutational changes were detected. Moving closer to the site of the tumor, additional mutations were accumulated. Finally arriving at the site of the established malignancy, all of the constituent mutations associated with this particular cancer became manifest; a saltatory slide into cancer presumably associated with exposure to carcinogens.

Among the other exciting presentations were updates on redox-based approaches to cancer presented by Kenneth Tew and Garth Powis.

Jeff Engelman presented an update on a new class of agents that target the RAS pathway. This is ongoing work that he and his group have reported on over the last several years. We have been engaged in related work using an MEK/ERK inhibitor similar to the compound that Dr. Englemen reported on at this meeting. It is exciting indeed to see early clinical results with this class of compounds, for we have identified many patients who might benefit from this pathways’ inhibition. We wait with great anticipation for FDA approval of these compounds so that our patients currently being identified as candidates in the laboratory may soon receive these treatments.

Vitamin D and Cancer

A report issued earlier this year (available on Medscape once you register) on Vitamin D levels in breast cancer, identified low levels of this nutritional factor as a risk for breast cancer. Dr. Kristin Skinner reported at the American Association of Breast Surgeons, that the most aggressive forms of breast cancer (i.e. ER negative, triple negative or basal-like) were associated with lower blood levels of vitamin D.

This is one of many reports associating vitamin D levels with disease. Indeed, so many reports on this topic have been published that vitamin D consumption in the U.S. has exploded. While some physicians have made careers promoting the concept, the science of vitamin D is indeed credible and very interesting.

What is vitamin D? Well, although we refer to it as a vitamin, it is, in fact, a hormone. It is obtained from the diet or from exposure to sun. The most potent form of vitamin D is that associated with sunlight exposure. Once in the body, vitamin D interacts with cells at very specific receptors. The term receptor reflects the role of these “landing sites” contained within the cell’s nucleus. As the vitamin D molecule traverses the cell membrane and enters the cell nucleus, it binds with the vitamin D receptor, which connects to the chromosome at a hormone response element and drives the cell machinery forward.

The vitamin D receptor is part of a large collection of genes called the steroid super gene family. These include receptors for estrogen, progesterone, testosterone, and, yes, vitamin D.

What makes the field so interesting is the interaction between these factors. Inside the nucleus are a large variety of receptors. Vitamin D and the other molecules are known as ligands. When the ligands enter the nucleus, they must compete for receptors. This leads to a complicated collection of down-stream events that are unique to the individual. If, for example, your nucleus has a number of orphan receptors (receptors with unclear ligand associations) and these orphan receptors have some binding affinity for the vitamin D, then the down-stream signaling will reflect this new biology.

Many studies have associated vitamin D levels with disease. Prostate cancer, colon cancer, even blood-born tumors may, in part, arise in vitamin D deficient states. But, the most compelling evidence in several analyses supports its protective effect against colon cancer. In one study there was a 15 percent risk reduction for every 10 ug/ml increase in circulating blood levels of calciferol (Gandini S, Int J Cancer. March 11, 2011). What is interesting about the report from the University of Rochester is that it was the most aggressive forms of breast cancer that were found to be associated with Vitamin D deficiency. To date, the correlations with the more common forms of breast cancer have been less positive.

Cardiovascular disease and musculoskeletal diseases are also associated with vitamin D levels. So critical is vitamin D to the well-being of the human that mankind could not easily migrate far north from the equator until he found a source of vitamin D unrelated to the skin synthesis. This source proved to be fish and animals that survived by eating fish. Older readers will remember cod liver oil as a remedy doled out by grandparents. It is ironic that cod liver oil is an excellent source of vitamin D.

While deficiencies of vitamin D are likely to be deleterious, substantially exceeding the normal levels of 30 micrograms/ml have not been shown to further enhance health. It is prudent for patients to monitor their vitamin D levels and highly appropriate for physicians to recommend replacement. Interestingly, a scientific colleague recently commented that sun exposure, by providing active vitamin D, is greatly under appreciated as a healthful activity. He wondered whether the broad use of sunscreens would ultimately save or cost more lives when the aggregate impact of vitamin D levels upon cancer and health is finally understood.

“Big Box” American Medicine

Over the last several months we have been engaged in construction work on our home. The kitchen and adjoining rooms required new floors. To accomplish this goal, we went online and examined the types of floors, patterns and qualities that met our needs. We shopped at various venues including small privately-owned flooring shops and larger national chains. The one-stop-shopping aspect of the larger chains (cabinetry, flooring, carpets, appliances, etc. all under one roof) had a certain appeal. After considering our options we proceeded with one of the chain stores. Although we greatly appreciated and respected the expertise of the consultant who worked with the big box store, the results proved less satisfactory.

First, we needed our space measured. The big box store contracted with a group who did their flooring measurements. Second, we needed to purchase the material. This was done through the large concern acting as our purchasing agent. Finally, after the several weeks delay for the “special order materials,” our flooring material was delivered to yet a third party, the flooring installation experts.

Despite the delays, everything was moving along reasonably well. And then came the problem. Our contractor had needed to resurface a section of our entranceway. This left a gap from the bare wood up to the existing surface that was about to be recovered by the installation staff. We contacted the installation group the night before their scheduled   arrival to explain that they would need to match the new surface level with that of the old one. And then the wheels came off.

“We can’t do this job for a fear that there could be a need for asbestos remediation.”

“What asbestos?” I responded.

Their response, “We don’t know, but it’s a possibility.”

“Well then, come out and take a look.”

“Oh, no, we can’t do that, it will be at least a week.”

I felt stymied. Our carefully scheduled flooring, followed by appliance replacement, followed by painting, followed by cabinetry installation was now on indefinite hold. Luckily, I had a personal contact with a privately-owned flooring company who provided their own installers. They arrived the next day, examined the situation and explained that there was no asbestos risk whatsoever. They neatly matched the floor levels using a plywood sheet and proceeded to perfectly complete the flooring job.

After all was said and done, I suddenly realized that I had almost double the flooring material I actually needed. After much discussion, we convinced the big box store to accept the excess material in return and to compensate us for the difference.

So what’s this got to do with medicine? Quite a lot I would suggest.

Like the big box stores, American medicine is migrating towards generic care with each function contracted out to a different entity. The internist who diagnoses the problem is then forced to refer the patient to an outside contracted diagnostic service provider (i.e. radiology, CT, MRI). Results then slowly percolate back to the primary care physician who, one or two weeks later, recognizes the problem and recommends hospital admission. At this point a contracted hospitalist starts all over again, examining the patient and taking a detailed history in an attempt to uncover that, which the internist already knew. With the best data the hospitalist can accumulate, he then turns again to a contracted provider for a final intervention. The patient all the while has waited weeks, undergone numerous  interventions and investigations and more often than not gets more, or in some circumstance less, than what they really needed.

As we continue to undervalue the abilities and expertise of individual private physicians functioning as quarterbacks in patient management, we abdicate the management of a patient’s delicate problems to the intersecting tectonic plates of medical systems: HMO, PPO, VHA, Medicare, HHS, AARP, etc., etc., etc.

Like the big box stores that adequately meet the average needs of the average customer with an average problem, these medical behemoths lack the insight to meet individual patient needs. Duplication of services and inefficiency are the inevitable result. In retrospect I would gladly have paid a slightly higher fee for a privately owned concern to have measured, purchased and installed my kitchen floor. The savings associated with big box stores, are like those associated with HMO care . . . nonexistent.

So long as you are 42 ½ years old, have a viral respiratory infection and don’t have any allergies or prior medical history, HMOs provide great care. For everyone else,  Caveat Emptor!