Karen Rowan

Rising Costs of Medical Imaging Spur Debate

M edicare spending on medical imaging services reached

High-Throughput Screening Finds Potential Killer of Cancer Stem Cells

14 billion in 2006, more than double the 2000 spending, according to a report from the Government Accountability Office (GAO) released in June. The GAO also found that the proportion of spending on imaging services performed in physician offices rose from 58% to 64%, whereas the proportion of spending on imaging performed in hospitals dropped from 35% to 25% over that same period. This shift from hospitals to outpatient settings, along with a substantial variation in spending per benefi ciary in different regions of the country, has raised concerns that not all of the imaging being done is medically necessary, according to the report. The GAO recommended that the Centers for Medicare and Medicaid Services (CMS) manage the rising costs by implementing practices used by private health plans, such as requiring prior authorization. Although many agree that spending on medical imaging has indeed risen dramatically and may need to be constrained, there are still different ideas about the best way to proceed. At the heart of the debate is the diffi culty of pinning down the true benefi ts of imaging — its effect on diagnosis, treatment, and length of hospital stay, for example. Moreover, the rapidly advancing technology and ever-widening scope of diseases and conditions for which imaging is used are making it diffi cult to rigorously and thoroughly analyze the medical benefi ts, harms, and cost-effectiveness of imaging.

Fertility Preservation During Treatment Is a Growing Issue for Women

T he search for agents that target and kill cancer stem cells is on. In August, researchers reported in Cell that highthroughput screening could be used to identify drugs that target these cells, notorious for their resistance to existing treatments and their putative ability to generate new tumors. Killing cancer stem cells may be the key to preventing cancer’s recurrence, say researchers who have confi dence in the cancer stem cell model of carcinogenesis. The model holds that only a specifi c subset of cancer cells can give rise to new cells or metastases, and some say this explains why cancers can seem to disappear after treatment and then recur with a vengeance. However, there is a debate about how relevant such cells are to cancer treatment and even whether they exist ( see related article, News, J. Natl. Cancer Inst. 2009;101: 546 – 7). Those who believe that the model oversimplifi es the complexity of human cancers are wary of this study’s results. The successful use of high-throughput screening in fi nding the agents depended on developing a stable, in vitro stem cell culture, said Tamer Onder, Ph.D., who coled the work with fellow researcher Piyush Gupta, Ph.D. of the Massachusetts Institute of Technology, Cambridge, Mass. “It’s hard to maintain the cancer stem cell state in culture — that’s why it’s been hard to fi nd therapies that target them,” said Onder, now at Children’s Hospital Boston. “Stem cells isolated from patients either do not grow in culture, or when they do, they lose their characteristics.” Onder said the key to the culture was to induce the cells to undergo an epithelial – mesenchymal transition (EMT), which the team accomplished by inhibiting the cells ’ expression of E-cadherin. (Although the link is not completely understood, induction of the EMT activates the same transcription factors that give cancer cells the motility, ability for self-renewal, and resistance to apoptosis that marks cancer stem cells.) The resulting cells displayed three characteristics of cancer stem cells: They could form mammospheres in culture, had two known genetic markers of stem cells (high expression of CD44 and low expression of CD24), and could generate new tumors when injected into mice at a much lower dilution than could the control cells. About 16,000 compounds were then screened for their ability to kill the stem cells at a greater rate than the control cancer cells. The screen turned up 32 such compounds. The researchers winnowed the results down to the most promising and focused on one called salinomycin. Cancer stem cells treated with salinomycin were much less able to form new tumors when injected into mice. Further, mice previously injected with other human breast cancer cells and treated with salinomycin had tumors that were smaller and contained fewer cancer stem cells than mice treated with a control drug (paclitaxel). “We were happy to see that the tumors shrank and had fewer cancer stem cells,” said Onder. “This was the proof of principle for us.”

Down Syndrome Offers Fresh Clues to Angiogenesis

A merican Society of Clinical Oncology (ASCO) guidelines recommend that oncologists refer patients of childbearing age to a reproductive endocrinologist to discuss options for preserving fertility during treatment. But two recent surveys of oncologists suggest that fewer than half of respondents routinely make this referral. Fertility preservation experts say that the referrals are now more crucial than ever because of advances in cancer research, improvements in reproductive technologies, and major social trends. “There is a perfect storm going on right now,” said Teresa Woodruff, Ph.D. , director of the Oncofertility Consortium at Northwestern University in Evanston, Ill. Patient advocacy groups have pushed to raise awareness of the importance of fertility preservation, and advances in technologies, such as ovarian transplants and the maturation of follicle cells in vitro, have met with increasing success, she said. Combined with increases in cancer survival and delayed childbearing, fertility preservation is a growing quality-of-life issue. In one survey, 47% of respondents said that they routinely refer patients to reproductive endocrinologists. Led by Gwendolyn Quinn, Ph.D., at the H. Lee Moffi tt Cancer Center in Tampa, Fla., the analysis was based on responses from 516 physicians (a 32% response rate) who work in both academic settings and private practice. Male physicians were less likely to say they routinely referred (41% vs 58%). And among oncologists whose patients often ask about the effects of cancer treatment on their fertility, 64% routinely refer patients. Among those who said their patients seldom ask about the effects of treatment on fertility, 42% said they routinely refer. “Our results surprised me; I thought that number was too high,” said Quinn, whose work was published in the Journal of Clinical Oncology in December. Making the referral can be diffi cult and requires a working relationship between the oncologist and the reproductive endocrinologist, which doesn’t always exist, even in National Cancer Institute – designated cancer centers, she said. The other survey, led by Eric Forman, M.D., a resident at Duke University Medical Center, Durham, N.C., focused on female patients. It found that 39% of oncologists surveyed routinely refer women to fertility specialists. Forman’s work included responses from 249 physicians (a 15% response rate) from the top 25 cancer hospitals as ranked by U.S. News and World Report and was published in Fertility and Sterility in November. Quinn said that her survey was modeled after earlier work on sperm banking by Leslie Schover, Ph.D., at the University of Texas M. D. Anderson Cancer Center in Houston. Schover found that 91% of physicians who responded to a survey said that sperm banking should be offered to all men who may become infertile as the result of cancer treatment. But 48% of respondents either never brought up the topic or mentioned it to less than one-quarter of eligible men.

Micrometastases in Sentinel Lymph Nodes: Few Data Make for Hard Decisions

People with Down syndrome, who have an extra copy of chromosome 21, rarely develop solid tumors, and researchers are starting to put together the pieces of this genetic puzzle to learn why. In a recent study led by Sandra Ryeom, Ph.D., a researcher at Children’s Hospital Boston, scientists identifi ed two genes on chromosome 21, known as DSCR1 and Dyrk1a, that may play crucial roles in inhibiting the growth of new blood vessels. Ryeom’s team found evidence that the single extra copy of DSCR1 present in the cells of people with Down syndrome suppresses angiogenesis — a crucial ingredient in tumor growth. “This was an absolutely fascinating study,” said Nancy Demore, M.D. , a surgical oncologist at the University of North Carolina, who worked in the late Judah Folkman’s lab in the 1990s. Folkman, who founded angiogenesis research, long suspected that one could fi nd clues to angiogenesis by studying Down syndrome, or trisomy 21, said Demore, who was not involved with this study. “He would talk about the fact that kids with Down syndrome had lower rates of solid tumors and hypothesized that this difference could be due to genes on chromosome 21. It’s fascinating to see a paper published in 2009 completely validating his hypothesis from then.” Antiangiogenesis research is currently booming, but according to Demore, Ryeom’s work differs from the scores of trials under way that are focused mainly on inhibiting vascular endothelial growth factor (VEGF) with monoclonal antibodies. “This is another way to go: to look at the factors that stimulate angiogenesis and try to block multiple angiogenic factors,” she said. The study revealed that the two genes both encode proteins that disrupt the calcineurin pathway, which is involved in angiogenesis. It also showed that, compared with control subjects, DSCR1 protein levels are increased in the tissues of people with Down syndrome and in Ts65Dn mice — the mouse model of Down syndrome that has three copies of 104 of the 231 genes on human chromosome 21. Further, the researchers compared the growth of two common tumors, Lewis lung carcinoma and B16F10 melanoma, in the Down syndrome mice and in control subjects. Growth of tumors was suppressed, and the density of microvessels was statistically signifi cantly lower in the Ts65Dn mice than in the diploid control mice. Also, when induced pluripotent stem cells derived from an individual with Down syndrome were injected into immunodefi cient mice, the tumors that grew had reduced mi crovessel densities — less angiogenesis — compared with those grown from induced pluripotent stem cells de rived from a person without Down syndrome. The next step was to fi nd a link between the suppressed angiogenesis and the extra copy of DSCR1. The DSCR1 gene was fi rst identifi ed in 1997 and was implicated in the signaling pathway of VEGF, a key pathway involved in angiogenesis, in 2004. But the gene’s role in angiogenesis was not well understood. “We took a different approach because not a lot was known about the intracellular pathways that inhibit blood vessel growth,” said Ryeom. VEGF is well studied, but the VEGF signal acts at the cell membrane, and the pathway she was interested in is downstream of the VEGF signal. To show that extra DSCR1 could inhibit angiogenesis, the researchers created a transgenic mouse with an extra copy of that gene only. In a normal cell, VEGF signaling activates calcineurin, which dephosphorylates a transcription factor known as nuclear factor of activated T cells (NFAT). NFAT then moves into the nucleus and the transcription of genes needed for angiogenesis begins. Ryeom’s team found that NFAT remained in the cytoplasm of cells with the extra DSCR1 gene, indicating that the calcineurin pathway was disrupted. When melanoma and carcinoma tumors were planted in the mice with the extra gene, the number of endothelial cells that line the blood vessels within the tumors was statistically

Inflammatory Breast Cancer: New Hopes and Many Hurdles

with 1% for those who had ALND or axilla radiotherapy. The sentinel lymph node, which is the fi rst node that lymph fl uid enters after draining from the breast, is the most common site of breast cancer metastasis, and patients who are node negative — meaning that the biopsy turns up no cancer in the sentinel node — have a better prognosis than those who are node positive. Under present U.S. guidelines, patients with micrometastases, which range from 0.2 mm to 2.0 mm, are considered to be node positive, and some experts say they should be treated as all other node-positive patients: Their biopsy should be followed by

Proton Therapy Use Incites Debate Over Clinical Trials

T he field of inflammatory breast cancer (IBC) research is rife with enigmas and grim statistics. It is more aggressive and deadly than other breast cancers ( see Stat Bite), and the mechanisms driving its rapid progression and metastasis remain unclear. Also perplexing is why the disease disproportionately strikes African American women and women of North African or Middle Eastern descent. Even its name needs deciphering; the typical redness and swelling of the breast seen in IBC that superficially resemble inflammation are actually due to lymph ducts that have been clogged with tumor cells. But recent fi ndings have begun to unlock IBC’s mysteries. The search for molecular markers is revealing the genes at work in this disease, and research is turning up clues to how metastasis may unfold. With new cell lines and animal models in the works, and promising fi ndings in several recent studies, those in the fi eld are hopeful for future insights and therapies. “We are entering a very exciting time in infl ammatory breast cancer and in aggressive cancers in general where we are uncovering brand new targets,” said Sofi a Merajver, M.D., Ph.D. , codirector of the breast cancer research program at the University of Michigan, Ann Arbor. “They seem to be hugely informative about the behavior of these cells.”

Oncolytic Viruses Move Forward in Clinical Trials

P roton therapy is going through a period of enormous growth, with five centers now operational in the U.S. and seven more planned to open over the next 4 years. Compared with conventional radiation, which uses photons, proton treatments can, at least in theory, offer patients fewer side effects and a decreased chance of developing secondary cancers from radiation. But as this nascent field grows, a debate has arisen over whether randomized clinical trials comparing proton therapy with photon radiation are needed to clearly demonstrate proton therapy’s benefits — and whether now is the appropriate time for such trials to begin. Proton therapy differs from conventional radiation in several ways. In conventional radiation treatments, a linear accelerator fi res photons at a tumor. These photons, which are delivered as highenergy x-rays, can damage the DNA of tumor cells and kill them. However, they also damage other cells in their path through the body. In proton therapy, hydrogen atoms are accelerated to a high speed, and protons are separated from the rest of the atom. Protons, which are positively charged particles, act differently in the body from photons — protons deliver most of their radiation in a sudden burst at a given point, rather than delivering it gradually over the course of the their path. Because protons may be able to deliver a lower radiation dose to nontarget tissue, doctors can administer higher doses of radiation and, ideally, kill tumor cells more effectively. Massachusetts doctors ran the fi rst proton therapy treatments in 1961 on one of Harvard University’s particle accelerators when the machine (as large as three city blocks) was not in use for physics experiments. Though few patients were treated, the data suggested that the treatments were as effective as x-irradiation at killing cancer cells but had far fewer side effects. Consequently, the fi rst hospitalbased proton treatment center was built at Loma Linda University Medical Center in 1990. Today, there are proton therapy centers at Massachusetts General Hospital, the University of Texas M. D. Anderson Cancer Center, Indiana University, and the University of Florida at Jacksonville. Over the last two decades, proton therapy has been used primarily to treat pediatric patients or patients with tumors that are relatively close to the surface of the body and are near critical body structures — such as cancers near the base of the skull or spinal column, or eye cancers. The key potential benefi t of protons is that they release almost all of their energy at the point of their Bragg peak, the point at which the particles come to a rest. This method is different from that of photons, which deliver radiation both before and after they reach the tumor site. This approach makes protons potentially better suited to target tumors that lie dangerously close to other body structures. Earlier worries that proton beams may also produce damaging neutrons have been allayed by data that show that few neutrons are produced, and researchers are now focusing their efforts on advancing the precision of the technology.