One of my patients is famous!

Extra! Extra! Read all about it! One of my patients is famous!

Mackenzie is a girl I've been helping to take care of for almost 2 years now. Her story, published in the Baltimore Sun today, is the perfect inspiration for the holiday season.

When people ask me how I can take care of children with cancer, it's kids like Mackenzie that I think of as I tell them that it's actually a great job... probably the most rewarding I can imagine.

Happy Holidays!

Microchip Update

Last month, I wrote about a story that was broken by Associated Press reporting that implantable microchips are linked to the development of sarcomas in laboratory animals. On November 20, a group called CASPIAN (Consumers Against Supermarket Privacy Invasion and Numbering) released a comprehensive 48-page report reviewing the academic literature on this topic. They identified 11 articles related to implantable microchips. In 6 of these articles, tumors were reported in laboratory mice or rats adjacent to implanted microchips. Between 0.8% and 10.2% of the animals developed tumors, depending on the study. There were also two reports of microchip-related cancer in dogs.

In my blog entry, I suggested that one manufacturer of these chips (VeriChip) might have engaged in some less-than-honorable behavior by hiring as a board member the man who was the Secretary of the Department of Health and Human Services (HHS) at the time that these chips were being evaluated for safety. HHS directly oversees the Food and Drug Administration, the group charged with determining the safety of medical devices like these. This questionable behavior continued, as the CEO of VeriChip was quoted recently as saying that none of the tumors found in mice in a 2006 French study were malignant. This is not true – the study identified these tumors as sarcomas, and sarcomas are malignant.

In the words of the author of Cool Dog Hall of Fame, the decision to microchip pets has become much more difficult in light of these reports. Pet owners now need to weigh the risk of cancer against the benefit of potentially being reunited with a lost pet and make a tough decision. Much more research is necessary before the use of these devices in humans can be condoned. Based on the evidence available so far, Dr. Robert Benezra, head of the Cancer Biology Genetics Program at the Memorial Sloan-Kettering Cancer Center in New York, was quoted as saying, "There's no way in the world, having read this information, that I would have one of those chips implanted in my skin, or in one of my family members."

Cancer Vaccines, or Getting the Immune System to do what Chemo Can’t

Tumor vaccines are one of the hottest topics in cancer research these days. Most people think of vaccines as something we give to children to keep them from getting infections – and in the spirit of flu shot season - I am going to discuss the different types of tumor vaccines and whether they show any promise yet.

The simplest definition of a vaccine is that it is something injected into the body that stimulates an immune response. The flu shot, for example, is an injection of proteins that come from the influenza virus. These proteins will stimulate your immune system to respond to the virus that causes influenza and hopefully kill the virus before it makes you sick.

The idea behind a tumor vaccine is slightly different. Since the patient already has cancer, the purpose isn’t to prevent cancer (the way a flu shot prevents flu), but rather to strengthen the immune system to do what chemotherapy often cannot: kill the last few cancer cells and keep the disease from ever coming back.

There are several types of tumor vaccines. The two most common types are peptide vaccines and dendritic cell vaccines.

A peptide vaccine is most like the flu shot – a patient is injected with a piece of a protein that comes from a cancer cell in the hopes that this will trigger the immune system to respond to the protein and kill whatever cells (cancer cells in this case) have the protein. The major benefit of this approach is that patients rarely have a bad reaction to being injected with a small piece of a protein, so the side effects are minimal.

Unfortunately, the two main problems with the peptide vaccine are:
1. Not everyone is capable of reacting to every peptide
2. The patient’s immune system has to be relatively intact in order to process the peptide and respond appropriately.

Patients being treated for cancer often have very weak immune systems because of chemotherapy, making this a major limitation for peptide vaccines.

Peptide vaccines are being developed for many types of cancers, and early reports of success are already being published. In fact, one of my patients was treated on a peptide vaccine trial before coming to me for my clinical trial. Unfortunately, the vaccine was ineffective in his case.

A dendritic cell vaccine, in contrast, involves taking immune system cells from the patient, putting the piece of protein that is being targeted by the vaccine into these cells in the lab, and then injecting the manipulated cells into the patient. In theory, this method is more efficient and requires less of a functional immune system to work. The difficulty lies in successfully manipulating the cells in the lab, a process that has not been perfected yet. There are a number of reasons why dendritic cell vaccines are more likely than peptide vaccines to work in the long run, however. I am proud to be an associate investigator on a clinical trial that is about to open at the NIH involving the development of a dendritic cell vaccine for patients with leukemia who have undergone a bone marrow transplant. (As soon as the trial is open, I’ll talk more about it and include a link to the website that contains a full description.)

A problem common to both vaccine strategies is figuring out what cancer cell proteins to use as a target. Interestingly, a gene known as WT1 that my laboratory has been studying for a number of years, appears to make a protein that is a prime candidate to be the target of a cancer vaccine. WT1 is found on many types of cancer and it may play an important role in the life of the cancer cell. Because it is found on very few non-cancer cells, normal cells are unlikely to be mistakenly attacked by the immune system, causing harmful side effects. Several cancer vaccine trials are ongoing using WT1 as a target, including this one and this one.

In summary, cancer vaccines are very promising because they should allow oncologists to utilize the patient’s own immune system to treat his or her cancer. As the immune system is usually very specific about what it attacks, cancer vaccines will make unwanted side effects far less likely than with traditional chemotherapy. Unfortunately, the field of cancer vaccines is still in its infancy, and much work remains before they become a routine part of cancer treatment. Hopefully, we and others will be able to make this a reality in the near future.

Stem Cells, or “A Rose, By Any Other Name…”

Over the past several years the media has been full of stories about stem cells.

The topic of stem cells is one that everyone, from President Bush on down, has a strong opinion about.

But what are stem cells? Are there different types of stem cells? And what kinds of things are researchers hoping to learn about by doing “stem cell research”?

I’ll try to answer some of those questions here.

First of all, what is a stem cell?

To answer that, I’ll start with one of the main principles of modern biology: in every organ in your body, there are cells that are fully developed (differentiated is the term scientists use), and cells that sit in reserve to replace the differentiated cells as they age. Those cells that sit in reserve are unique in their ability to both create copies of themselves (called self-renewal) and to create “daughter cells” that are more differentiated. These “daughter cells” are stem cells.

Stem cells come in two varieties: the ones that are found in mature organs (like bone marrow) and the ones that are found in a developing embryo and give rise to the entire body.

So what are the controversies that surround stem cells? Well, the major controversy is over the source of stem cells that scientists use for their experiments. For example, most people are not concerned about stem cells that are harvested from bone marrow, but they do object to embryonic stem cells that require the destruction of an embryo. I guess it’s obvious why some people find that objectionable but others do not.

What good are stem cells, anyway? What kinds of things do scientists think they can do with stem cells? I study stem cells. I know many other people who study stem cells. No one I know wants to do what the loudest anti-stem-cell-research voices are shouting about – clone a human. What we do want to do is exploit the potential of these cells to replace broken cells and cure human disease.

How might this happen? Well, let’s use spinal cord injury as an example. At the moment, there’s no way to reverse a serious spinal cord injury because the nerve cells that make up the spinal cord don’t regrow once they are damaged. But imagine if we could take stem cells and grow new nerve cells and we could put those cells into an injured spinal cord and fix it. We could reverse paralysis. That would be amazing.

Or… what if we could replace the cells in the pancreas that are destroyed in patients who have diabetes? If we could reliably turn stem cells into insulin-producing cells, diabetes would change from a disease that can be “managed” with multiple daily injections of insulin to a curable disorder. What a difference that would make!

What about cancer research? Why do I study stem cells? Well, many oncologists believe that tumors, like normal organs, are composed of differentiated cells and stem cells. It is the stem cells that are resistant to chemotherapy and radiation therapy. It is the stem cells that are responsible for relapse. It is the chemotherapy-resistant stem cells that spread throughout the body and ultimately kill patients. So, unlike my colleagues who want to harness stem cells for good, I want to learn what makes them tick, learn their vulnerabilities, and exploit those vulnerabilities to develop treatments that will cure patients without making them as sick as our current chemotherapies do.

Several states, including California and my own home state of Maryland, have recognized the enormous importance of stem cell research and have designated significant sums to support stem cell research. In contrast, the federal government placed significant restrictions on stem cell research back in 2001. Hopefully soon they will realize the mistake they made, listen to Nancy Reagan, and give this vital area of research the support it deserves.

Children’s Oncology Group: A meeting of the minds in Denver, CO

Last week I had the pleasure of attending the meeting of the Children’s Oncology Group in Denver, Colorado. This is the umbrella organization of pediatric oncologists in the US and Canada. Together, we conduct clinical trials to figure out what is the best treatment for each type of cancer that kids get. Once a year, we all get together to discuss the result of our trials to date and to discuss the plans we have for future trials.

There were more than 10,000 people at the conference in Denver, CO, including physicians, nurses, data managers, and administrators. It was a great pleasure to see my friends and colleagues once again and to hear the updates about the progress we have made since last year. I took some pictures while I was there… pretty silly ones, but really, if you had to choose between posed pictures and silly pictures, what would you choose?

The first picture is from the lobby of the Adam’s Mark Hotel in downtown Denver. They had these lovely horses that were guarding us (and I, for one, was glad to be guarded).
These horses, I assume, guarded more than just us….



Every morning we were served a wonderful breakfast of coffee, pastries, and fruit. This allowed us the opportunity to socialize in a relative unformatted atmosphere. This is a very important function of the meeting – being able to network and form connections from one institution to another.



Of course, it wasn’t all work... what business trip is? They left us time to relax, because all work and no play makes Jack… OK… maybe none of use are like that, but we certainly need a break now and again. I spent one afternoon walking through the city, and happily discovered that Denver is not at all what I expected. I tried to take pictures, but that day I only had my cell phone camera with me, and that lens doesn’t do the scenery justice at all. So instead, I have a picture of the Colorado state capitol building, which I also thought was lovely. I caught it on a great day, with bright sunshine to reflect off the gold dome.



Like all trips, though, this one quickly drew to a close, and just in time - the day after I left, it snowed 4 inches! Now, for the residents of Denver, that is probably no big deal, but here in Baltimore, 4 inches of show shuts down the city for the day.

On an unrelated note, it seems mine is not the only medical blog to originate at Johns Hopkins. My colleague Lillie Shockney writes a blog for Yahoo! called Breast Cancer Chronicles. It’s really quite good, which makes sense given her role here as administrative director of the Johns Hopkins Avon Foundation Breast Center and a breast cancer survivor.

I Can Buy it Over the Counter: FDA Followup

In my last entry, I told you that cough and cold remedies marketed for infants had been removed from the shelves of drug stores across the country. This move was made in response to concerns raised by a group of pediatricians who charged that these medications are dangerous and ineffective. An FDA advisory panel met this past week to review these charges and to make recommendations about ongoing sales of these medications and what, if any, warning labels should be attached.

As reported yesterday in The Washington Post, “The Food and Drug Administration panel voted 13 to 9 to recommend against the use of the products for children in that age group [children under the age of 6] after concluding overwhelmingly that there was insufficient evidence the long-used remedies worked in youngsters.”

The group’s chair, Dr. Mary Tinetti, stated, “The sentiment here is that they should not be used.”

The problem is that these drugs have never been adequately tested in children, so there is no evidence that they work. There is evidence, though, that they are dangerous, and the same Washington Post article quotes a report from the Centers for Disease Control that at least 1500 children under the age of 2 suffered complications from the use of these products between 2004 and 2005. These were not minor complications, either, as these drugs have been linked to convulsions, heart problems, neurologic complications, and at least 123 deaths.

I’m very proud that this action resulted from my colleagues in the Baltimore City Health Department speaking up, raising awareness, and pushing the issue, ultimately resulting in safer medication use for our children.

One final note: This issue has larger implications than just cough and cold medicine. These actions by the FDA are a result of inadequate testing of drugs on children, and on the false assumption that dosing of drugs in kids can be estimated by simply giving proportionally less medicine. But, as I was taught in residency – children are not just small adults. New drugs need to be tested not just on adults, but also on children, with particular attention to proper dosing and a real estimate of how well they work. If the financial hit to the pharmaceutical company from this action by the FDA is sufficient, maybe the net result will be more appropriate testing of new drugs in kids, something we sorely need.

I can buy it over the counter, doesn’t that mean it’s safe?

That’s what most of us believe. After all, the FDA watches over the pharmaceutical industry to ensure the safety of whatever we find on the drug store shelves, doesn’t it? No pharmaceutical company is allowed to market a drug they don’t know to be effective, right?

Well, a group of pediatricians in my home town (Baltimore, MD), didn’t believe that. Led by Baltimore's health commissioner, Dr. Joshua M. Sharfstein, these pediatricians petitioned the FDA to stop the sale of cough and cold medications for children younger than 6, saying that there are no data showing that the drugs actually work and there is growing evidence that they pose a risk of serious harm.

As reported in The Washington Post, The Baltimore Sun, and countless other news outlets, cough and cold medications marketed for infants were pulled from store shelves this past week. Is that because these drugs aren’t safe? Or might there be some other reason for this action?

Well… let’s talk about safety before we address the motive behind this “voluntary” withdrawal of product from the market.

In the past 6 years, 4 infants in Baltimore have died because of these medications. Two weeks ago, the FDA released a report that there were 54 deaths in the United States from 1969-2006 involving decongestants and 69 involving antihistamines. Most were in children younger than 2. In 2005, the U.S. Toxic Exposure Surveillance System, a national database of poisoning cases, recorded up to 88,000 calls about juvenile overdoses or adverse reactions to cough and cold medicines and antihistamines. That’s a lot of overdoses and adverse reactions to medications that treat the symptoms of otherwise minor infections. And 123 deaths over 7 years is unacceptable for cold medicine. If these drugs were treating life-threatening conditions like cancer, this would be OK, but who wants their child to die over a runny nose?

So… the big question is this: has the pharmaceutical industry spontaneously decided to stop selling a potentially dangerous product that doesn’t work? I’m not sure this is the case.

Cough and cold medicines are a huge market. Everyone gets colds. No one likes the feeling of a stuffy nose, a runny nose, or a nagging cough. When these symptoms strike children, parents want to do something about it. That’s only natural. According to AC Nielson, about 15% of American households bought cold medicine marketed toward children last year. Total sales reached $311.3 million last year. That’s beyond pocket change, and more importantly represents a 20% increase over the previous year. So it’s a large market, and it’s growing.

Statistics like this have caused leading consumer advocates to question the motives of the pharmaceutical industry. Peter Lurie, of the health research group at Public Citizen, said he believes the voluntary withdrawal was designed to head off a wider ban on marketing the drugs to children under 6 (see video here), which is one of the possible outcomes of FDA hearings scheduled for this week.

"One can only assume that it is fear of additional action that's causing them to take these steps," he said. "It's only the most obvious infant products they are recalling. They probably see the writing on the wall for the younger children and are trying to save the rest of the pediatric market. They are trying to rescue the market for a series of products that do no good, and sometimes cause harm."

This sentiment is echoed by Arthur Levin, director of the nonprofit Center for Medical Consumers and a past member of FDA advisory panels on prescription drug safety.

"At this point, they're worried about their exposure to liability," he said. "There's a level of concern that can't be ignored anymore." The industry, he said, might have calculated that this action would blunt some of the criticism and deflect the FDA from a ban that would extend to children as old as 6.

As a parent, what should you do? Keep in mind that these drugs have never been shown to be any more effective at treating symptoms than drug-free interventions, like drinking plenty of liquids, using a humidifier, and using salt water solutions to treat nasal congestion and sore throats. These methods are safe, and they cost a whole lot less, too!

Giving Bad News Without Destroying Hope

Today’s topic is another one that is near to my heart – how to deliver bad news. Not just any bad news, but the worst possible news: the news that there is no longer a realistic curative option for your child’s cancer. No parent wants to hear this. No parent wants to lose all hope that their child can be saved.

But this is truly the art of pediatric oncology: how to tell a parent the worst without destroying their hope.

As usual, I’ll start with a patient of mine - a former patient, unfortunately. She was 9 when she was diagnosed with metastatic Ewing’s sarcoma. She had the expected response to her initial therapy, but 3 months after her treatment was done, she had new tumors in her lungs. That’s when we had to have the talk. Because, realistically, the chance of curing her at that point fell to less than 5%.

So… how does the talk go? Well, I believe in being frank with my patients. So in this case, I sat the family down and told them how things looked. We talked about Phase II trials, about Phase I trials, about treatments outside of a clinical trial… But it was necessary to tell them that the bottom line was that their daughter would probably die of her disease.

Why did I tell them this? Did telling them this destroy their hope? Should I have allowed them to put all of their hopes in untested treatments? Should I have let them believe that their child would be among the 3 in 100 that get a clinical benefit from a Phase I trial?

I’m not sure that there is a perfect answer to those questions.

That honesty between a doctor and his/her patients is necessary should go without saying. But the truth can be so elusive. The patient I described above had 3 pulmonary nodules – 3 new cancerous tumors in her lungs. A surgeon removed the pulmonary nodules and we gave her chemotherapy. I’ve seen patients with relapsed cancer who were cured that way (and blogged about them). But those patients are the exception, not the rule. I tell patients and their family stories like the story of K… to help them maintain some hope, but I also try to help them to be realistic about their child’s chances.

Why? Don’t I want them to be hopeful?

Of course I do. But I also feel strongly that hope should be tempered with realism. People need time to prepare to die. There are things they want to do while they still can (travel the 48 continental United States, visit Japan, hunt bears, etc). There are relationships to be mended (although this usually applies more to adults than to children). And there are treatment choices to be made. I think the most important gift I can give is to help them make decisions that, when they look back in 10 years, they don’t regret. For some families, that means feeling like they did everything and tried everything and traveled everywhere in search of that slim chance of cure. For some families, looking back without regrets means helping the child accomplish a treasured goal or simply ensuring that the child died without pain and with dignity.

These decisions can only be made if the family is given a realistic assessment of the situation, including being told explicitly that there is little or no chance of long term survival.

Does that statement destroy hope? I don’t think so. I think it changes hope, it keeps their hopes realistic. When the patient is first diagnosed, the hope is for a cure. Toward the end, the hope could be for a trip to Hawaii, a high school graduation, or a death without pain. But those are still hopes. Important hopes. Hopes that no one can ever destroy.

Cancer Research Blog Carnival and My Sister

A couple of weeks ago, I was invited to submit some of my blog entries for the second Cancer Research Blog Carnival, organized by The Bayblab, and hosted by the blog of a University of Chicago medical student who is simultaneously pursuing an MD and a PhD .

So… here is Cancer Research Blog Carnival #2. My colleagues have posted some amazing pieces and have some amazing blogs – so check it out, you’ll be happy you did.

While I’m announcing blogs – I recently found out that my baby sister, an elementary school teacher, has her own blog: Mrs. Holman’s Third Grade. Take a peek, and tell her I said “Hi”

Narcotics for pain control: When is enough too much?

Ask 100 cancer patients what they fear most, and I’m sure almost all will say the same thing: pain. What do people think of when they think about cancer? Pain. So what is one of the most important things I can do for my patients? Control their pain.

There are many ways to control pain. Sometimes, when the medicines we use to treat cancer shrink the size of the tumor, the pain is eased as well. Sometimes medicines that are approved by the FDA for treating pain can also treat the cancer. A great example of this is Quadramet, an injectible radioactive drug, approved to treat bone pain in patients whose breast or prostate cancer has spread to bones, that we are using in a clinical trial to treat bone cancer, osteosarcoma.

Much more common, though, is the use of narcotics to treat cancer pain. But like almost every medicine, these drugs come with side effects. Feared ones. The two biggest fears among patients? That they may become addicted or they may die.

Let’s talk about addiction.

I’ll tell you about my patient, Q (not her real initial, given the sensitive nature of her story). When Q was diagnosed with osteosarcoma, the cancer had already spread throughout her lungs. She completed the usual course of chemotherapy and had a major operation to remove the tumor in her leg, but when it was all done, she was in pain and still had cancer in her lungs. Throughout her course, we were giving her oxycodone and OxyContin to control her terrible pain. After experimental treatment and truly heroic lung surgeries, however, she achieved a remission.

But as the pain lingered on, so did the use of oxycodone and OxyContin.

Soon she experienced one of the problems most narcotic patients go through – tolerance. She needed more and more medicine to achieve the same degree of pain control, because her body “got used to” the drugs.

Next she experienced another of the common problems with narcotics – dependence. Her body got so used to the drugs that attempts to take them away caused symptoms: sneezing and yawning weren’t so bad, but chills and diarrhea and pain? Those were terrible. So to ward them off, she took more painkillers.

Tolerance and dependence are normal reactions of a normal healthy body to chronic narcotic use. Tolerance and dependence are not the same as the dreaded “A” word – addiction.

Most people who use narcotics correctly never get addicted. Unfortunately, Q became addicted. Addiction is a psychological dependence on the drug… a strong feeling of NEEDING the drug. Dependence and tolerance are biological, they relate to how the body processes the drug, and can be easily managed. Addiction is an altogether different matter. Managing and dealing with addiction is NOT easy for either the person addicted or for their family members. Recovery from addiction is possible, but it is all too often a long and difficult process.

But imagine a world without pain medicines – a world where people suffer through physical pain without any relief. Awful, isn’t it? Unfortunately, as reported in the New York Times on September 10, 2007, this situation is all too real for many of the world’s poorest people. Their governments, so concerned about protecting people from addiction, have all but banned the use of these drugs. This has left cancer patients, and many others, to die a slow, painful, and horrifying death. They die with a pain that is altogether preventable, but is not because of government fear of addiction.

But addiction is a real danger, even when these drugs are used properly. OxyContin made a big splash when it was introduced, because its manufacturer, Purdue Pharma, claimed that, because it was a slow release formulation, it was not addictive. This is not true, and Purdue Pharma paid a hefty price for misleading physicians and consumers.

Death is also a risk, especially if these drugs are used incorrectly. Within the last two weeks, the Food and Drug Administration issued warnings after several patient deaths were linked to improper use of Fentora, a formulation of a powerful narcotic called Fentanyl, that is absorbed through the lining of the mouth.

So should we fear narcotics? Should they be banned like they are in parts of Sierra Leone (as reported by the New York Times)? Certainly not. No one should have to suffer like this woman.


Photo courtesy of NYTimes.com

But we do need to respect them. These drugs need to be used properly. They need to be used carefully. And patients need to be warned that tolerance and dependence are expected, but that they are NOT signs of addiction.

And we need to remember that addiction is treatable. I just saw Q for a routine follow up appointment 2 weeks ago. After several inpatient detox stays, she has kicked her narcotic habit (she had graduated from OxyContin to heroin) and she was back in college. What an inspiration Q is! First she beat cancer, then she beat addiction. I’m sure she’ll beat whatever other challenges life throws at her on her way to the top!