Brain Radiation Linked to Strokes in Childhood Cancer Survivors

Increased risk of stroke must now be added to the list of adverse late effects that are possible in survivors of childhood cancers who received high-dose cranial radiotherapy (CRT), according to new findings from the Childhood Cancer Survivors Study (CCSS) published online November 6 in the Journal of Clinical Oncology.

Lead author Dr. Daniel C. Bowers of the University of Texas Southwestern Medical Center at Dallas and colleagues used the longitudinal CCSS to assess risk of individuals treated as children for leukemia or brain tumors, compared with a control group of 3,846 siblings who did not have cancer as children.

Although strokes occurred in a small percentage of children surviving more than 5 years after treatment, the effect of CRT on this risk was significant. When radiation was directed at particular areas of the brain, the risk of stroke increased as the radiation dose increased. Chemotherapy had little effect on stroke risk in leukemia patients but more than doubled the risk in brain tumor patients who also had CRT.

The study found that childhood leukemia patients who received CRT were 6.4 times more likely to have a stroke than those in the control group, while brain tumor patients treated with CRT had a significantly larger risk of 29, compared with controls.

The authors conclude that this study "identifies a significantly increased incidence of stroke among long-term survivors of childhood leukemia and brain tumors. This study also identifies the use of CRT, in a dose-dependent fashion, as contributing to the increased risk of stroke, and justifies efforts to continue to reduce radiation doses among both leukemia and brain tumor treatment regimens whenever practical."

Public Awareness of HPV Link to Cervical Cancer Is Low

In 2005, before the approval of the human papillomavirus (HPV) vaccine, awareness among American women about HPV and its link to cervical cancer was low, according to an NCI study presented this week at the AACR Frontiers in Cancer Prevention meeting.

NCI scientists analyzed data collected from more than 3,000 women aged 18 to 75 who responded to the 2005 Health Information National Trends Survey (HINTS). The researchers found that only 40 percent had ever heard about HPV and less than half of those were aware of the virus' connection to cervical cancer. Awareness of HPV and cervical cancer was especially low among women who were older, less educated, or less exposed to health information.

Dr. Jasmin A. Tiro, an NCI Cancer Prevention Fellow who led the study, commented, "Our data also suggest that women learn about HPV after experiencing an abnormal Pap or positive HPV test. Clear, consistent information about HPV transmission, prevention, detection, and the link to cervical cancer needs to be provided before a woman becomes infected."

Media coverage and pharmaceutical marketing efforts for the HPV diagnostic test and the HPV vaccine "will likely increase awareness," Dr. Tiro predicted. "NCI is conducting studies to track the diffusion of knowledge to make sure that all women have accurate knowledge about HPV and how to prevent and detect cervical cancer early." Understanding HPV infection and its relationship to cervical cancer is needed to make appropriate, evidence-based health care choices among existing strategies, including the Pap test, HPV DNA test, and HPV vaccine, the researchers concluded.

New Therapeutic Targets Identified in Leukemia

A translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, causes expression of a chimeric and constantly expressed form of the protein BCR-ABL. Aberrant expression of BCR-ABL in bone marrow cells leads to chronic myeloid leukemia (CML) and B cell acute lymphoblastic leukemia (B-ALL). The drug imatinib (Gleevec) inhibits BCR-ABL, and has become the standard of care for chronic-phase, Philadelphia chromosome-positive leukemias. However, imatinib cannot eliminate all leukemia cells expressing BCR-ABL, and many patients eventually develop resistance to the drug.

A new study published online November 7 in the Proceedings of the National Academy of Sciences shows that while imatinib inhibits BCR-ABL, it does not affect downstream proteins in the BCR-ABL signaling pathway called SRC kinases. Using mouse models of CML and B-ALL, investigators from the Jackson Laboratory in Bar Harbor, Maine, determined that these SRC proteins may play an important part in the malignant transformation of cells in the bone marrow, contribute to disease progression, and allow leukemia cells to survive imatinib treatment until resistance develops. Treatment of mice with the drug dasatinib inhibited both BCR-ABL and SRC expression; this dual inhibition suppressed B-ALL and significantly prolonged survival of mice with CML. However, dasatinib was unable to completely kill residual leukemia cells.

The authors next identified sets of leukemia cells with stem-cell-like properties in mice with B-ALL and CML. These cells were not killed by either imatinib or dasatinib, and were capable of inducing leukemia when transplanted to healthy animals. While dasatinib may be effective in producing long-term remission, explained the authors, "identification of unknown pathways in CML stem cells will be critical for developing curative therapies for the disease."

Experimental Melanoma Drug Shows Early Promise

A drug containing parts of the diphtheria toxin may have benefited a small number of patients in the advanced stages of melanoma skin cancer. Five out of seven patients with stage IV disease experienced significant regression or stabilization of their tumors and the spread of cancer while taking the drug, according to preliminary findings from a phase II clinical trial.

The trial is testing the effectiveness of the experimental drug denileukin diftitox, also known as DAB(389)IL2 or ONTAK, for treating the deadly disease. The median life expectancy for patients with stage IV melanoma is normally about 8 months. All of the patients were still alive after 12 months. The two patients in whom the melanoma progressed were on a lower dose of the drug than the others.

The drug is thought to prompt the immune system to attack tumors by depleting a subset of regulatory T cells thought to directly suppress the activation of the antitumor T cells. Research in mice has suggested that if the regulatory T cells are depleted by targeting them with denileukin diftitox, then T cells in the immune system known as CD8+ T lymphocytes would be able to attack and kill melanoma cells.

Lead investigator Dr. Jason Chesney of the University of Louisville's Brown Cancer Center presented the preliminary findings November 9 at the Symposium on Molecular Targets and Cancer Therapeutics in Prague.

Oncolytic Virus Kills Malignant Glioma Cells

Canadian researchers have shown that an "oncolytic virus" they have developed is effective at infecting and killing malignant glioma cells, and targets the main tumor when administered intravenously. Oncolytic viruses are viruses that are engineered to infect and kill only cancer cells.

Dr. Peter Forsyth and colleagues of the University of Calgary tested the effects of recombinant vesicular stomatitis virus (VSV^ΔM51), a mutant strain of vesicular stomatitis virus, on 14 human glioma cell lines, a glioma mouse model, and human tumor specimens. They also compared the effects of VSV^ΔM51 with reovirus serotype 3, another oncolytic virus under investigation for the treatment of brain tumors, on human glioma cell lines.

The study, published in the November 1 Journal of the National Cancer Institute, found that all 14 glioma cell lines were susceptible to infection and killing by VSV^ΔM51, while only 12 of the lines were susceptible to infection and killing by reovirus serotype 3. Neither VSV^ΔM51 nor reovirus serotype 3 had an effect on the normal cell lines. Mice that received live VSV^ΔM51 intravenously had improved survival compared with mice that received dead VSV^ΔM51 intravenously. The virus also infected both multifocal glioma cells and invasive glioma cells.

The ideal oncolytic virus for cancer "should have effective delivery into multiple sites within the tumor, evade innate and acquired immune responses, produce rapid viral replication, spread within the tumor, and infect multifocal tumors," the authors wrote. "This is precisely what we found using the attenuated live virus we constructed (VSV^ΔM51)."