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Melanoma vaccine promise increases
SCIENCE AND MEDICINE
News in brief Misoprostol misuse The mothers of 47 of 96 Brazilian children diagnosed with Möbius syndrome took misoprostol in the first trimester of pregnancy, report Anne Pastuszak (University of Toronto, Canada) and colleagues (N Engl J Med 1998; 338: 1881–85). Only three mothers of 96 infants with neural-tube defects had taken the drug (odds ratio 29·7, 95% CI 11·6–76·0). “Attempted abortion with misoprostol is associated with an increased risk of Möbius syndrome in infants”, conclude the authors (see Lancet May 30, p 1624–27). Breast-cancer surgery timing Does the timing of breast-cancer surgery affect survival? New York clinicians asked 614 premenopausal women having such surgery about menstrual cycle length and date of last menses. From 1978 to 1981, and from 1982 to 1983, surgery at the time of ovulation was associated with a lower risk of death than that done at the time of menses (relative risks for the two time intervals were 0·43 and 0·25, respectively). The same association was not seen from 1984 to 1988 (RR 1·48). These results “should not be used to support recommendations that surgeons perform breast carcinoma surgery on any particular days of the menstrual cycle”, write the authors (Cancer 1998; 83: 76–88). Not now, I have a headache Daily headaches are surprisingly common, reported researchers from Johns Hopkins School of Public Health (Baltimore, MD, USA) at the recent meeting of the American Association for the Study of Headache (San Francisco, CA, USA; June 26–28). Of 13 343 people aged 18–65 interviewed about their headaches, 4·1% reported more than 180 headaches a year, 53% of headaches were chronic tension-type headaches, and frequent headaches were nearly twice as common in women as in men. Bowel-disease genes Scientists are a step closer to understanding inflammatory bowel disease. A genome-wide study has pinpointed regions on chromosomes 1p, 3q, and 4q that may contain genes that trigger disease onset (Proc Natl Acad Sci USA 1998; 95: 7502–07).
40
Melanoma vaccine promise increases
E
xpectations that vaccines for post-resection treatment of malignant melanoma will be effective are realistic, said Jean-Claude Bystryn (New York Medical Center, New York, USA) at Dermatology 2000 (Singapore; June 18–20). Vaccines are also being assessed for treatment of lymphomas and autoimmune disease, he added. Bystryn told delegates that the rationale for testing vaccines against melanoma was their ability to stimulate a patient’s immune response to a tumour, thus preventing or delaying disease progression. Many vaccines are now being tested in clinical trials, and they differ according to the purity of the antigens they contain, he said, adding that vaccines containing a single antigen seemed to be less effective than those with multiple antigens. The main difficulty so far, said Bystryn, has been choosing the correct antigens. Bystryn and colleagues are testing a polyvalent vaccine derived
from melanoma surface antigens. So far, more than 500 patients have been treated. Toxicity has been minimal, and responses elicited include antibody responses to defined melanoma antigens and CD8 T-cell responses to important melanoma antigens (eg, MAGE-3, MART-1, gp100, and tyrosinase). In a pilot phase III randomised, double-blind trial of the vaccine in resected AJCC stage III melanoma, disease-free survival was twice as long and mortality at 2 years was half that of patients given placebo. The vaccine was particularly effective when antimelanoma immune responses were stimulated. This ability was enhanced by the encapsulation of the vaccine into interleukin-2 liposomes, said Bystryn. He was confident that vaccines are now an accepted, although still experimental, adjuvant means of fighting high-risk, post-resection melanoma. Peter Harrigan
Genetics of brain cancer yields to study symposium on the genetics of brain cancer held at Harvard Medical School (Boston, MA, USA) on June 24 indicated that, although knowledge is rapidly increasing, a complete understanding of braincancer genetics is still a long way off. Harold Varmus (US National Institutes of Health, Bethesda, MD, USA) described an experimental system in which transgenic mice have been engineered so that only astrocytes and glial precursor cells express a cell-surface receptor for subgroup A avian leukosis viruses. By injecting genetically engineered leukosis viruses into the brains of young mice, Varmus and Eric Holland have been able to transfer genes suspected of causing gliomas into animals. In one experiment, basic fibroblast growth factor, which is overexpressed in most high-grade gliomas, induced glial cells to multiply and migrate but did not produce tumours (Proc Natl Acad Sci USA 1998; 95: 1218–23). But tumours did occur when a gene encoding a mutated version of epidermal growth factor receptor, which is also overexpressed in gliomas, was injected into mice lacking INK4a, a gene whose products help regulate the activity of the tumour-suppressor genes Rb and p53.
A
Malfunctioning p53 genes are common in tumour cells, including some types of brain cancer. But Frank McKeon (Harvard Medical School, Boston, MA) sketched a picture of p53 not acting alone but in consort with other genes. McKeon has identified one such gene, p73, on the tip of chromosome 1, a region containing many tumour suppressor genes (Cell 1997; 90: 809–19). He also described the recent identification of p63 on chromosome 3, which, he said, produces six proteins, all different to the one protein produced from p53. Three of the proteins encoded by p63, however, have the same binding sites as p53 but unlike p53 do not carry a transactivating factor capable of turning on other genes. p63 proteins could, therefore compete and interfere with normal p53 function. Other speakers included Paul Kliehues (International Agency for Research on Cancer, Lyon, France) who described how pathogenically different gliomas have different genetic pathways, and Xandra Breakefield (Massachusetts General Hospital, Boston, MA, USA) who talked about using herpesvirus vectors for gene therapy of brain cancer. Peter Wehrwein
THE LANCET • Vol 352 • July 4, 1998
News in brief Misoprostol misuse The mothers of 47 of 96 Brazilian children diagnosed with Möbius syndrome took misoprostol in the first trimester of pregnancy, report Anne Pastuszak (University of Toronto, Canada) and colleagues (N Engl J Med 1998; 338: 1881–85). Only three mothers of 96 infants with neural-tube defects had taken the drug (odds ratio 29·7, 95% CI 11·6–76·0). “Attempted abortion with misoprostol is associated with an increased risk of Möbius syndrome in infants”, conclude the authors (see Lancet May 30, p 1624–27). Breast-cancer surgery timing Does the timing of breast-cancer surgery affect survival? New York clinicians asked 614 premenopausal women having such surgery about menstrual cycle length and date of last menses. From 1978 to 1981, and from 1982 to 1983, surgery at the time of ovulation was associated with a lower risk of death than that done at the time of menses (relative risks for the two time intervals were 0·43 and 0·25, respectively). The same association was not seen from 1984 to 1988 (RR 1·48). These results “should not be used to support recommendations that surgeons perform breast carcinoma surgery on any particular days of the menstrual cycle”, write the authors (Cancer 1998; 83: 76–88). Not now, I have a headache Daily headaches are surprisingly common, reported researchers from Johns Hopkins School of Public Health (Baltimore, MD, USA) at the recent meeting of the American Association for the Study of Headache (San Francisco, CA, USA; June 26–28). Of 13 343 people aged 18–65 interviewed about their headaches, 4·1% reported more than 180 headaches a year, 53% of headaches were chronic tension-type headaches, and frequent headaches were nearly twice as common in women as in men. Bowel-disease genes Scientists are a step closer to understanding inflammatory bowel disease. A genome-wide study has pinpointed regions on chromosomes 1p, 3q, and 4q that may contain genes that trigger disease onset (Proc Natl Acad Sci USA 1998; 95: 7502–07).
40
Melanoma vaccine promise increases
E
xpectations that vaccines for post-resection treatment of malignant melanoma will be effective are realistic, said Jean-Claude Bystryn (New York Medical Center, New York, USA) at Dermatology 2000 (Singapore; June 18–20). Vaccines are also being assessed for treatment of lymphomas and autoimmune disease, he added. Bystryn told delegates that the rationale for testing vaccines against melanoma was their ability to stimulate a patient’s immune response to a tumour, thus preventing or delaying disease progression. Many vaccines are now being tested in clinical trials, and they differ according to the purity of the antigens they contain, he said, adding that vaccines containing a single antigen seemed to be less effective than those with multiple antigens. The main difficulty so far, said Bystryn, has been choosing the correct antigens. Bystryn and colleagues are testing a polyvalent vaccine derived
from melanoma surface antigens. So far, more than 500 patients have been treated. Toxicity has been minimal, and responses elicited include antibody responses to defined melanoma antigens and CD8 T-cell responses to important melanoma antigens (eg, MAGE-3, MART-1, gp100, and tyrosinase). In a pilot phase III randomised, double-blind trial of the vaccine in resected AJCC stage III melanoma, disease-free survival was twice as long and mortality at 2 years was half that of patients given placebo. The vaccine was particularly effective when antimelanoma immune responses were stimulated. This ability was enhanced by the encapsulation of the vaccine into interleukin-2 liposomes, said Bystryn. He was confident that vaccines are now an accepted, although still experimental, adjuvant means of fighting high-risk, post-resection melanoma. Peter Harrigan
Genetics of brain cancer yields to study symposium on the genetics of brain cancer held at Harvard Medical School (Boston, MA, USA) on June 24 indicated that, although knowledge is rapidly increasing, a complete understanding of braincancer genetics is still a long way off. Harold Varmus (US National Institutes of Health, Bethesda, MD, USA) described an experimental system in which transgenic mice have been engineered so that only astrocytes and glial precursor cells express a cell-surface receptor for subgroup A avian leukosis viruses. By injecting genetically engineered leukosis viruses into the brains of young mice, Varmus and Eric Holland have been able to transfer genes suspected of causing gliomas into animals. In one experiment, basic fibroblast growth factor, which is overexpressed in most high-grade gliomas, induced glial cells to multiply and migrate but did not produce tumours (Proc Natl Acad Sci USA 1998; 95: 1218–23). But tumours did occur when a gene encoding a mutated version of epidermal growth factor receptor, which is also overexpressed in gliomas, was injected into mice lacking INK4a, a gene whose products help regulate the activity of the tumour-suppressor genes Rb and p53.
A
Malfunctioning p53 genes are common in tumour cells, including some types of brain cancer. But Frank McKeon (Harvard Medical School, Boston, MA) sketched a picture of p53 not acting alone but in consort with other genes. McKeon has identified one such gene, p73, on the tip of chromosome 1, a region containing many tumour suppressor genes (Cell 1997; 90: 809–19). He also described the recent identification of p63 on chromosome 3, which, he said, produces six proteins, all different to the one protein produced from p53. Three of the proteins encoded by p63, however, have the same binding sites as p53 but unlike p53 do not carry a transactivating factor capable of turning on other genes. p63 proteins could, therefore compete and interfere with normal p53 function. Other speakers included Paul Kliehues (International Agency for Research on Cancer, Lyon, France) who described how pathogenically different gliomas have different genetic pathways, and Xandra Breakefield (Massachusetts General Hospital, Boston, MA, USA) who talked about using herpesvirus vectors for gene therapy of brain cancer. Peter Wehrwein
THE LANCET • Vol 352 • July 4, 1998