Kaposi’s Sarcoma and the Virus/Cancer Connection (Part 3): The Immune System Fights Cancer

In previous entries, I have discussed the connection between viruses and cancer, focusing on the roles viruses might play in the development of tumors, especially in patients with compromised immune systems. Today, I will discuss ways in which oncologists might exploit the virus/cancer connection to treat and prevent cancer.

First: Breaking News

Just to demonstrate that nothing in medicine is static for long, just this month another cancer was found to be associated with a virus. Interestingly, the discovery was made in the laboratory of the husband and wife team that identified HHV-8 as the cause of Kaposi’s sarcoma. Using a sophisticated DNA analysis technique, these scientists found that cells from a rare type of skin cancer called Merkel cell carcinoma (coincidentally, also a cancer found predominantly in the elderly) contain an embedded virus called polyoma virus. This adds Merkel cell carcinoma to the ever-expanding list of virus-associated human cancers, and increases the importance of understanding the complicated interactions between us and viruses.

polyoma virus through an electron microscope

Immune competence as cancer therapy

My discussion of viruses as a cause of cancer began with the identification of HHV-8 or KSHV as the cause of Kaposi’s sarcoma. I talked about how Kaposi’s sarcoma was an “AIDS-defining Illness” in the early days of the AIDS epidemic, and that it had virtually disappeared since the advent of highly active antiretroviral therapy (HAART), but was recently making a resurgence, at least in San Francisco. The observation that Kaposi’s sarcoma is an AIDS-defining illness that almost vanished when HIV infections became controlled with better combination treatments suggests a way to treat KS that I’ll talk about shortly.

But first… are there other virus-associated cancers that seem to depend on the patient’s immune status?

In fact, there are.

One of the most dreaded complications of organ transplantation (other than rejection) is the development of post-transplant lymphoproliferative disorder (PTLD). PTLD arises from an imbalance between lymphocytes infected with Epstein-Barr Virus (EBV) and those that keep them in check. As I discussed before, EBV is a very common virus. In the United States, estimates are that 90-95% of the adult population has had an EBV infection. Your body never rids itself of EBV. When the illness caused by the infection ends, the virus becomes dormant in white blood cells called B lymphocytes. EBV-infected B lymphocytes become immortal, and would grow without limit were it not for another type of white blood cell, called T lymphocytes, that keep the EBV-immortalized B lymphocytes under control.

Patients who have received an organ transplant must take immune suppressive drugs forever to keep from rejecting their transplant (although this may not be true… a topic for the next blog entry). When these drugs inhibit the T lymphocytes that control the EBV-infected B lymphocytes the B lymphocytes divide and grow, resulting in PTLD. PTLD can range from mild (just a swollen lymph node) to very aggressive, indistinguishable from Burkitt’s Lymphoma.

Lymph node biopsy

from a patient with

Burkitt's Lymphoma

Fortunately, the treatment for even the worst cases of PTLD begins with a very simple step – stopping the immune suppression. In many cases this is sufficient to restore the balance between the T and B lymphocytes and reverse the disease process. Ultimately, what doctors must do is find the right dose of immune suppression to prevent rejection while maintaining control over the EBV-infected lymphocytes.

Might this work for KS, too? Studies show that it might.

Patients who develop KS before they begin HAART, who are started on this treatment, have an 82.6% reduction in death from KS compared with patients who do not start HAART. In fact, HAART alone can lead to resolution of KS. Interestingly, it may be that a reduction in HIV viral load, rather than improvement in the function of the immune system, is what makes the KS go away. Regardless of why, restoring the immune system can make at least two types of virus-driven cancer (KS and PTLD) go away, with far fewer side effects than chemotherapy. Hopefully, we will continue to find ways to harness the immune system, based on this model, to fight off cancer.

When the ‘routine’ is anything but

The other day I had an experience in the operating room that I want to talk about. It helped remind me, in a very dramatic way, how nothing that we do is “routine” in the way most people understand the term.

One of my roles in our department is to be a member of the bone marrow transplant team. In that capacity, I am called upon to harvest bone marrow from healthy people who have agreed to donate, usually to a relative. Since I am a pediatrician, both donors and recipients are often children, and they are usually siblings. This puts parents in an awkward position because they have to subject one child (the donor) to some degree of risk in order to maximize the chance of another child (the recipient) surviving their cancer. The ethics of a child putting him/herself at risk to donate marrow is a very interesting topic, and I hope to discuss that in more depth in a future blog post.

How much risk is involved? Not that much. In the years I have been participating in bone marrow harvests, first as a resident, then as a fellow, and now as the “surgeon of record,” I have seen fewer than half a dozen donors have complications significant enough to require overnight hospitalization. The vast majority of donors go home an hour after the procedure is completed, suffering nothing worse than sore hips and mild anemia.

This week, things threatened to turn out very differently.

The donor was an 8 year old girl who was giving bone marrow for transplantation into her 13 year old brother, who has acute myeloid leukemia (AML). Bone marrow transplantation (BMT) for AML is routine in the United States when there is an appropriate family member donor, and BMT clearly improves survival of children with AML. I met the donor, her father, and her aunt in clinic the day before the harvest to answer their questions. As expected, one question involved how risky the procedure is for the donor. I answered that the procedure is actually quite routine at our hospital, and in more than a decade, I have seen only 3 or 4 kids who were bone marrow donors require hospitalization to treat a complication of the donation, and never for more than a night. This reassured the father tremendously.

The next day, things started out in the operating room quite uneventfully. The patient came in with her mother, went to sleep, and her mother kissed her goodbye and left. We started the procedure, but part way through the patient required a bit more anesthesia. About 30 seconds after the anesthesia level was increased, the anesthesiologist noticed a sharp decrease in the patient’s blood pressure, and moments later could not feel a pulse in her neck. We abruptly stopped the harvest and called for help. As 5 additional anesthesiologists and nurses descended on our room, we turned down the anesthesia, flipped the patient over onto her back, and began chest compressions. Thankfully, within just a few seconds we could feel a pulse again, her blood pressure started to rise, and the crisis ended as abruptly as it had begun.

Next came an obvious question: do we continue? After all, the donor just had a life threatening event… what if it happened again? Was it worth risking her life for this procedure? Surprisingly, the answer to that question was easy. We had to continue, because her brother (the recipient) had already received what would otherwise be lethal doses of chemotherapy, and would surely die without getting bone marrow from her. So, with a choice of risk to one patient versus certain death of the other, the choice was easy. After a break to ensure that the donor was doing well and able to continue safely, we resumed our harvest.

This story, unlike some I have shared, has a happy ending. The rest of the harvest went smoothly, we got the marrow her brother needed, and everyone is currently doing great. The donor did stay overnight in the hospital, but she went home the next morning after observation and a blood transfusion, and she continues to do well. Her brother tolerated the marrow infusion without difficulty, and continues on his own road to recovery.

Despite the happy ending, this incident really shook us up. Was I rash to downplay the risks to the donor in discussing the procedure with the family? Are there any circumstances that would have justified stopping in the middle? What would the consequences have been if the donor had NOT done well after we resumed the harvest? How would her brother feel if his sister had passed away during this potentially life saving procedure for him? We (the BMT team) talked about these issues at length in the evening after the harvest. I think it’s fair to say that the experience has changed no one’s mind about the importance of bone marrow donation, and no one feels that anyone did anything wrong.

But it has changed one thing: I sure will be a lot less blithe in my reassurances in the future. Sure, the procedure is routine. Of course, I still haven’t seen anyone suffer a complication of donation that required more than an overnight stay in the hospital. But things certainly could have turned out very differently. I will absolutely remember that routine does NOT mean risk-free.

Another patient makes news!

Another one of my patients is having her 15 minutes of fame!

Natalie is a bright, beautiful little girl. You should have seen her face light up when she told me about the Hannah Montana concert! She has a wonderful, loving, supportive family, and her parents were thrilled that her treatment schedule still let her attend the concert.

Just like with Mackenzie, it's patients like this, who remain cheerful and full of life, despite their diagnosis, that make my job such a joy.

Nominated for the Medical Blog Awards - Thanks Everyone

DermDoc just let me know that I have made it to the finals of the Medical Blog Awards for Best New Medical Weblog. To whoever nominated me... thanks so much! I'm really honored. They have seven other categories that feature other excellent medical blogs, so please take a look.

To everyone who reads my blog... thank you!

You can click here to vote for Best New Medical Weblog.

Kaposi’s Sarcoma and the Virus/Cancer Connection (Part 2): In the beginning, there were chickens

On December 15th, I began a discussion about the virus/cancer connection and the role of HHV-8 in causing Kaposi Sarcoma, especially in AIDS patients. Is Kaposi Sarcoma the only cancer caused by a virus? No. In fact, the observation that viruses can cause cancer dates back to the beginning of the 20th century.

In 1909 Peyton Rous discovered that a virus could cause sarcomas in chickens. For discovering the Rous Sarcoma Virus, Dr. Rous was awarded the Nobel Prize in 1966. This discovery led directly to the discovery of cellular oncogenes (genes that cause cancer) by Bishop and Varmus, which also was rewarded with a Nobel Prize.

Subsequently, numerous other human cancers have been associated with viral infections. The most important of these is Burkitt’s lymphoma. Burkitt’s lymphoma comes in three varieties: one form is endemic to sub-Saharan Africa and is most likely caused in large part by infection with a virus called Epstein-Barr Virus (EBV, which also causes mono), one form is sporadic (as opposed to endemic), and one form is associated with immunodeficiencies such as AIDS. The endemic form of Burkitt’s lymphoma typically causes a large, painful jaw mass, while the sporadic form more commonly involved the intestines. Interestingly, another name for EBV is Human Herpesvirus-4 (HHV-4). EBV, or HHV-4, also causes nasopharyngeal carcinoma in southeast Asia (and elsewhere). It is clear that there is a real connection between viruses and cancer.

EBV is a very common virus. According to the Centers for Disease Control, 90-95% of the US adult population has had an EBV infection. When contracted in early childhood, EBV causes the common cold. When contracted during adolescence, the same virus causes mononucleosis 35-50% of the time. While most people who get EBV will not develop cancer, some unfortunately do. Why? No one fully understands yet, but there is a lot of active research trying to better understand the relationship between viruses and cancer.

So maybe we’ll have to change the answer to the question I posed before: Is cancer a contagious disease? No, but contagious diseases might contribute to the development of some forms of cancer. This is why it is important to continue research on understanding and controlling infections.

How do viruses cause cancer? Well, EBV and HHV-8 are both thought to cause cancer by controlling the activity of genes already present in cells called proto-oncogenes. A few years ago, a group of scientists in Spain proposed another way viruses might cause cancer. These scientists were investigating Ewing’s sarcoma (one of my main research interests), the second most common bone cancer in adolescents and young adults.

This is an x-ray of the leg of a patient

with Ewing's sarcoma.

Almost all cases of Ewing’s sarcoma have a particular chromosomal abnormality in them, where a piece of either chromosome 11 or chromosome 21 is attached to chromosome 22. This so-called “translocation” results in the production of a new protein, not found anywhere else in the human body, which is thought to be the direct cause of the cancer.

This is a diagram of a translocation

between two chromosomes.

The Spanish scientists announced, in an article published in 1999, that a gene called E1A (from a kind of cold virus called adenovirus), when put into cervical cancer cells in the laboratory, caused the characteristic translocation between chromosomes 11 and 22 found in Ewing’s sarcoma. Other groups have not been able to repeat this finding, so it remains very controversial, and yet if true, this would suggest that there are numerous ways that viruses could cause cancer in people and would potentially dramatically increase the number of types of cancers that could be related to viruses.

Fentanyl Revisited

One of my most faithful readers, Elizabeth Munroz, suggested that I expand on my discussion from my last blog entry about pain management and the role of fentanyl. I think that’s an excellent idea, because this is a topic I feel very strongly about.

A computerized search of the medical literature (http://www.ncbi.nlm.nih.gov/sites/entrez/) for articles about chronic pain turned up 45,290 articles. Clearly this is a topic of intense research, and my goal here is not to write a textbook, but rather to touch on the highlights of pain management in the cancer patient, so that articles in the popular press about pain medications can be read in this context.

Acute vs. Chronic Pain

One of the points I made, and one of the concerns raised by the FDA in their recent warnings regarding fentanyl patches, is the difference between acute and chronic pain. At its simplest, the difference is obvious: acute pain happens suddenly (think of your last headache) and eventually goes away, while chronic pain lasts a long time (like someone with a bad back, whose back hurts every single day). But upon a closer look, these differences become less distinct. Someone with a bad back might have pain every day, but if they try to lift something heavy, that can send a sharp spasm of significantly increased pain shooting through them. Is that acute pain? Actually, for people who have pain every day, we usually think in terms of chronic pain with acute exacerbations. This acute jolt of pain takes place on the background of the daily pain… an important distinction for treatment.

Different Types of Pain

Pain can not only be acute or chronic, but there are different types, one of the most important being neuropathic. Imagine the pain that comes from bumping into a bruise on your thigh. Now imagine the pain that you feel when your leg has “fallen asleep.” The first of these is what pain management doctors call “nociceptive pain” and arises from tissue damage or inflammation, and the second is “neuropathic pain” and arises from damage to a nerve. Biologists have learned that these different types of pain are transmitted through different types of nerves and using different molecular mechanisms. Doctors have learned that these biological differences mean that the management of these different types of pains requires different strategies.

How do we feel pain?

There actually is no easy answer to this seemingly simple question. However, scientists do understand to some extent. When there is damage to tissue (such as from trauma or inflammation), nerves sense this damage, fire a signal to the brain, and the brain interprets this signal as pain. There are proteins in the brain called opiate receptors. These proteins help determine how active certain nerves are – the nerves that mediate the sensation of pain. Your body makes substances that attach to opiate receptors and turn down the activity of the pain-sensing nerves, decreasing the sensation of pain.

How do pain medicines work?

Opiate receptors are the targets of narcotic pain medicines, like morphine and fentanyl. The medicine attaches to the opiate receptor and turns down the activity of the nerve. Inflammation is the target of most over the counter pain medications, like ibuprofen. Less inflammation means less tissue damage, which means less activity of the nerve, and less pain. Neuropathic pain arises from damage to nerves, and medicines like neurontin help treat neuropathic pain by directly turning down the activity of the damaged nerve. These differences are very important, because the different types of pain have different causes and need different medicines to treat them.


Courtesy of NIAAA
The figure shows how some nerves make opioids (endorphins) that send a signal to other nerves. Narcotics (exogenous opiates) mimic this signal, turning down the activity of a nerve involved in sensing pain. Naltrexone is a drug that blocks the action of opiates by blocking their ability to attach to the opiate receptor.

How are narcotics different from each other?

All narcotics work basically the same way – they attach to the opiate receptor. So what’s the difference between morphine and fentanyl? The major differences relate to how the drug is handled by the body. Fentanyl attaches much more tightly to the opiate receptors than morphine, so you need much less drug to ease the same amount of pain (in fact, fentanyl is about 100 times more potent than morphine). But fentanyl doesn’t last as long in the body. A dose of morphine can kill pain for 4-6 hours, compared to only an hour or so for a single dose of IV fentanyl. This short duration is the reason for the development of fentanyl patches… by slowly releasing the drug into the body, it can be made to last much longer. A fentanyl patch can provide pain relief for days at a time.

What about tolerance?

In an earlier article, I talked about the difference between tolerance and addiction. How does tolerance happen? Well, if the opiate receptors all have narcotic attached to them, the nerve senses this and makes more receptor. Now there are new opiate receptors that are not bound up with narcotic, and the pain comes back. With more opiate receptors on the nerve, a higher narcotic dose is needed to turn off the nerve’s activity. We call this tolerance. This happens to every chronic pain patient. They need to take more medicine to experience the same degree of pain relief. This isn’t a character flaw, and it isn’t addiction. It’s the body’s response to being treated with the drug every day.

Tolerance is exactly why fentanyl patches are meant for chronic pain and not acute pain, and why putting on a fentanyl patch for a headache can lead to an overdose. Fentanyl, being so potent, rapidly saturates the opioid receptors on the nerves of patients who don’t take these medications every day.

Pain management strategies for the chronic pain patient

So how do I treat pain in my patients? The first step is to try to determine the type of pain, so that I’m using the right drugs. If the patient has neuropathic pain, morphine won’t work as well as neurontin. If the patient has chronic pain, they need something long lasting, like a fentanyl patch or methadone. But even chronic pain patients have acute pain episodes on top of their chronic pain. For these acute pain episodes, the patient needs something that will work quickly to relieve the pain fast, but won’t last too long, so that when the pain is gone, so is the medication. Oxycodone is perfect for that type of pain: it starts to work in minutes and only lasts a few hours (unlike the sustained release version, oxycontin, which takes an hour to kick in and lasts for 8-12 hours).

Some final thoughts

Pain is manageable. The key to helping a cancer patient with their pain is to understand the different types of pain, why some medications work for some kinds of pain but not others, and to work hard to balance the benefits of pain medications with the side effects in order to maximize the quality of the patient’s life. Thankfully, here in the US, we have an abundance of pain medications available, and no one needs to live in pain for lack of taking pain medications (which is not the same thing as saying no one needs to live in pain, because unfortunately, we can’t relieve all pain). Fentanyl is a potent drug, but it’s the misuse of fentanyl that the FDA is warning about, not the correct use. Used properly, fentanyl is (in Elizabeth’s words) “a godsend” for patients with chronic pain. It shouldn’t be taken off the market, it should be used correctly.

Breaking News: the FDA (re)issues warning about fentanyl

In September, I wrote about the double-edged sword of narcotics and pain control for cancer patients. Around that same time, there were news reports of patients dying from improperly prescribed Fentora, which is a preparation of the powerful narcotic, fentanyl, that is absorbed through the lining of the mouth.

Fentanyl is in the news again this week. This time, the issue is with fentanyl patches. These are a favorite tool for oncologists, because the drug is absorbed through the skin. This means the patient need not swallow a pill, a big deal for patients receiving chemotherapy (notorious for causing nausea and vomiting). Fentanyl patches are also great for managing chronic pain in patients who have significant prior narcotic exposure, and it’s hard to imagine practicing oncology in the US without this tool.

However, like all tools, improper use can result in great harm.

At a news conference last week, the FDA reissued a 2-year-old warning about fentanyl patches, which have been linked to at least 120 deaths. They repeated their advice that these patches be reserved for patients with chronic pain and a tolerance to opioids. The patients who have died have all been prescribed for acute pain (in one case, a headache) and had never taken narcotics before.

Fortunately, the FDA does not seem likely to heed the call from some people to limit the ability to prescribe fentanyl patches to pain specialists. This would be a big mistake, because there are only 4,000 pain medicine specialists in the US, and many, many patients with chronic pain are treated safely and effectively by experienced physicians without specific pain training.

Bottom line? Pain medicines are powerful medicines. Used incorrectly, these medications can be deadly. But, used correctly, they can make life tolerable for people who would otherwise suffer terribly. That fact alone is sufficient to keep them on the market, and in the hands of doctors who know how to use them and patients who need them.

Kaposi’s Sarcoma and the Virus/Cancer Connection (Part 1)

Is cancer a contagious disease? The simple answer to that question is “No.” At least, that’s what we tell people. You can’t catch cancer from someone who has it. If a cancer patient is isolated, it’s to protect the patient from us, not the other way around. But, as is often the case, the truth is not quite so simple.

Let’s take a trip back in time. It’s 1984. Arguments rage about what to call the newly discovered virus that seems to cause this new disease called Acquired Immune Deficiency Syndrome (the American group proposed calling the virus HTLV-III while their French competitors wanted to call it LAV). When the dust settles, the virus is called HIV, and it quickly becomes clear that infection with HIV is not the same thing as having AIDS. So how do we define AIDS? Well, a person has AIDS if s/he is infected with HIV and has one of the so-called “AIDS Defining Illnesses.” Interestingly, one of these is a kind of cancer called Kaposi’s Sarcoma. Kaposi's Sarcoma causes nodules or blotches that may be red, purple, brown, or black. They are typically found on the skin, but spread elsewhere is common, especially the mouth, gastrointestinal tract and respiratory tract. Growth can range from very slow to explosively fast, and may be fatal.



All of the other AIDS defining illnesses, however, are infections that usually strike people with weakened immune systems (like cancer patients). So what is Kaposi’s Sarcoma doing on the list?

That question remained a mystery for quite a while. After all, although Kaposi’s Sarcoma was first described in 1872, it was originally known as a disease that affected older men from the Mediterranean region or who were of Ashkenazi Jewish descent. Yet, these men didn’t have AIDS, and no one knew why Kaposi’s sarcoma seemed to disproportionately affect this population. There is also a form of Kaposi’s Sarcoma endemic to sub-Saharan Africa, and although HIV infection is prevalent there now, that was not the case when endemic Kaposi’s Sarcoma was first described.

An answer to this mystery became apparent in 1994 when a group at Columbia University showed that Kaposi’s Sarcoma is actually caused by a virus. Originally they called it Kaposi’s Sarcoma Herpes Virus (because it is closely related to the viruses that cause herpes), but is has since been renamed HHV-8 (human herpesvirus 8). Subsequent work has shown that all forms of Kaposi’s Sarcoma are associated with an HHV-8 infection.

Over the years since the beginning of the AIDS epidemic, we have gotten pretty good at treating HIV infection, and with HAART (highly active anti-retroviral therapy), HIV infection has morphed from a rapidly fatal infection to a chronic disease. A by-product of the advent of HAART was the apparent disappearance of Kaposi’s Sarcoma. What was once an AIDS-defining illness, affecting as many as 80% of AIDS patients, there have been very few cases in the past 10 years.

Until now.

15 Kaposi’s Sarcoma cases were recently identified by doctors at San Francisco General Hospital. Surprisingly, these cases occurred in patients whose HIV infections were well controlled on HAART. This has prompted speculation about what happens as the immune system ages. These men all have undetectable HIV levels and normal numbers of white blood cells. Of course, so do the Ashkenazi Jewish men who used to be the primary group of KS patients. So what does this mean? Right now, no one is certain. But like all medical mysteries, we will all be a lot smarter once we figure it out.

Blog Carnival, Part Deux

Some months ago, I was invited to participate in the second Cancer Research Blog Carnival. I recall what an honor it was to be asked to participate, and how pleased I was to see the excellent entries that my colleagues had contributed. Well, I’m happy to say that there is another Cancer Research Blog Carnival. If you have a moment, please stop by and read some of the entries. They are all excellent… it is once again an honor to be in such company.

A Day in the Life of a Pediatric Oncologist

No, not a Beatles song… but rather a look at a typical day for an academic pediatric oncologist. Actually, one of the things I love about my job is that no two days are alike. So there really isn’t any such thing as a “typical day.” Some days, though, see a good combination of clinical work and lab research, so I’ll try to describe what this past Tuesday was like for me.

It’s Tuesday. I get to my office around 9am. The first order of business is checking email (I live on the internet, despite being in my 40’s). Most mornings there are quite a few waiting for me, and this morning is no exception. One email has to do with making some changes to a clinical trial protocol that were suggested by the FDA, so I open that file, make the changes, and send it off to Tammy, my research nurse, so that we can submit the protocol to our Institutional Review Board (IRB). All clinical trials have to be approved by an IRB to ensure that they are ethical, and under certain circumstances (like testing very high doses of a new chemotherapy drug) this can’t happen until the protocol is approved by the FDA.

I answer a few emails, and then I go downstairs to my lab to check on my staff. I spend an hour and a half talking with the folks in the lab about our various research projects. As usual, some are going well, and some are progressing more slowly. I visit each person in turn and we talk about their data from the last week, what it means, how to interpret it, and what we need to do next.

On Tuesdays we have Tumor Board, which is a meeting I run. Tumor Board is the largest regular meeting we have, and is attended by my colleagues in pediatric oncology (including faculty, fellows, nurses, social workers, and pharmacists), as well as by colleagues from surgery and radiation oncology. For the next two hours we will discuss each new patient, review scans that patients have had that require a change in therapy, and talk about the progress of every inpatient. Time permitting, we also have a 20 minute lecture by one of the fellows on a topic relevant to one of the current patients. On Tuesday there were so many scans to review, and the decisions to be made required so much discussion, that we did not have time for the fellow’s lecture. The conversations we had were important, though, because we were able to make treatment plans as a multi-disciplinary group, thus assuring the patients that all of the doctors were in agreement and were communicating well with each other.

After Tumor Board comes the weekly meeting of our bone marrow transplantation (BMT) group. This group typically meets twice a week. On Mondays we talk about upcoming patients, and on Tuesdays we discuss patients currently being treated. As one of my patients is in the ICU, we talk about him for a while. Fortunately, though, he is getting better, and we decide to just hold the course and keep doing what we’re doing.

After the BMT meeting, I stop in to see some of my hospitalized patients. The visit to the ICU is the hardest, because even though the patient is slowly getting better, he is still very sick, and I really want him to get well. I touch base with the ICU staff and discuss his status with them and with the patient’s mother, offering her words of encouragement along the way.

Finally, it’s time to go back to the office. In the last few hours before I head home, I can work on one of the many writing projects I am balancing, including a manuscript describing some new findings from the lab and a draft of a grant application soliciting money to support our lab work. It’s quiet in my office most afternoons, so I get a fair amount done before I go home.

It’s been a long day, so I’m looking forward to being home. Of course, there’s always more work to be done, so after the kids are in bed, I’m sure I’ll get back to work on the grant application. It will be close to midnight before I put that aside and relax for a bit before I go to sleep.