The review article in this issue by Goldberg et al. and the accompanying editorial by Hale and Zinberg were sent to G.D. Searle, the manufacturer of misoprostol, which offers the following:To the Editor: The article by Goldberg et al. on misoprostol and pregnancy 1 , the accompanying editorial by Hale and Zinberg, 2 and the events surrounding the approval by the Food and Drug Administration (FDA) of mifepristone for the termination of pregnancy raise important issues. Searle has been invited to clarify its position and actions in this regard. We at Searle share the overriding concern of Hale and Zinberg that physicians be supported in providing the most appropriate care for their patients. We also wish to emphasize our commitment to working collegially with all relevant parties.Our product, Cytotec (misoprostol), was approved by the FDA in 1988 for the prevention of gastric ulcers associated with the use of nonsteroidal antiinflammatory drugs. This is the only approved indication for Cytotec, and we are prohibited by FDA regulations from promoting or even suggesting its use for any other purpose. Since 1988, the Cytotec label has always carried a "black box" warning against its use in pregnant women because of its potential to cause serious adverse events, including miscarriage.Our letter of August 23, 2000, to health care professionals was, therefore, an elaboration of this long-standing warning, consistent with our continuing duty to inform health care professionals about possible risks. It resulted from lengthy discussions between Searle and the FDA after reports were received of uterine rupture in connection with the offlabel use of Cytotec in pregnant women. The FDA requested that we make a labeling change to clarify further the serious risks and to consider sending a letter to health care professionals. Our August 23 letter was a result of this dialogue and was developed in consultation with the FDA. We continue to work with the FDA to resolve issues related to the language in the label regarding the risk of adverse events. However, these discussions have not included consideration of any alteration to Cytotec's approved indication.We particularly wish to clarify the timing of the letter dated August 23. The fact that it was distributed just over a month before the FDA approval of mifepristone was entirely coincidental. We had no specific knowledge about the status of regulatory action on mifepristone, which had been pending for several years.With regard to the article by Goldberg et al., the authors find evidence of efficacy when misoprostol is used in pregnant women. However, as the authors correctly note, "misoprostol is not approved for any of these indications in the United States." We fully support the role of physicians, using their professional judgment, to prescribe an approved pharmaceutical product for a use outside of its FDA-approved indication in the best interest of their patients, on the basis of published research, expert clinical opinion, or their own clinical experience.In conclusion, as ...

We analyzed the prognostic value of p53 mutations for response to chemotherapy and survival in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic lymphocytic leukemia (CLL). Mutations were detected by single-stranded conformation polymorphism (SSCP) analysis of exons 4 to 10 of the P53 gene, and confirmed by direct sequencing. A p53 mutation was found in 16 of 107 (15%) AML, 20 of 182 (11%) MDS, and 9 of 81 (11%) CLL tested. In AML, three of nine (33%) mutated cases and 66 of 81 (81%) nonmutated cases treated with intensive chemotherapy achieved complete remission (CR) (P = .005) and none of five mutated cases and three of six nonmutated cases treated by low-dose Ara C achieved CR or partial remission (PR) (P = .06). Median actuarial survival was 2.5 months in mutated cases, and 15 months in nonmutated cases (P < 10(-5)). In the MDS patients who received chemotherapy (intensive chemotherapy or low-dose Ara C), 1 of 13 (8%) mutated cases and 23 of 38 (60%) nonmutated cases achieved CR or PR (P = .004), and median actuarial survival was 2.5 and 13.5 months, respectively (P < 10(-5)). In all MDS cases (treated and untreated), the survival difference between mutated cases and nonmutated cases was also highly significant. In CLL, 1 of 8 (12.5%) mutated cases treated by chemotherapy (chlorambucil and/or CHOP and/or fludarabine) responded, as compared with 29 of 36 (80%) nonmutated cases (P = .02). In all CLL cases, survival from p53 analysis was significantly shorter in mutated cases (median 7 months) than in nonmutated cases (median not reached) (P < 10(-5)). In 35 of the 45 mutated cases of AML, MDS, and CLL, cytogenetic analysis or SSCP and sequence findings showed loss of the nonmutated P53 allele. Our findings show that p53 mutations are a strong prognostic indicator of response to chemotherapy and survival in AML, MDS, and CLL. The usual association of p53 mutations to loss of the nonmutated P53 allele, in those disorders, ie, to absence of normal p53 in tumor cells, suggests that p53 mutations could induce drug resistance, at least in part, by interfering with normal apoptotic pathways in tumor cells.

Our findings suggest that, contrary to what is seen in most other neoplasias, p53 mutations in newly diagnosed BL and L3 ALL are not associated with extensive tumor mass or poor response to intensive therapeutic regimens. It is hypothesized that this difference with most tumors could be due to the fact that p53 mutations in BL and L3 ALL are generally associated with persistence of a normal residual p53 allele, contrary to what is observed in the majority of tumors.

The p16 protein is a cyclin inhibitor encoded by a gene located in 9p21, which may have antioncogenic properties, and is inactivated by homozygous p16 gene deletion or, less often, point mutation in several types of solid tumors often associated to cytogenetic evidence of 9p21 deletion. We looked for homozygous deletion and point mutation of the p16 gene in acute lymphoblastic leukemia (ALL), where 9p21 deletion or rearrangement are also nonrandom cytogenetic findings. Other hematologic malignancies including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), and myeloma were also studied. Homozygous deletion of the p16 gene was seen in 9 of the 63 (14%) ALL analyzed, including 6/39 precursor B-ALL, 3/12 T-ALL, and 0/12 Burkitt's ALL. Three of the 7 ALL with 9p rearrangement (including 3 of the 5 patients where this rearrangement was clearly associated to 9p21 monosomy) had homozygous deletion compared to 5 of the 55 patients with normal 9p (the last patient with homozygous deletion was not successfully karyotyped). Single stranded conformation polymorphism analysis of exons 1 and 2 of the p16 gene was performed in 88 cases of ALL, including the 63 patients analyzed by Southern blot. Twenty-six of the cases had 9p rearrangement, associated to 9p21 monosomy in at least 12 cases. A missense point mutation, at codon 49 (nucleotide 164), was seen in only 1 of the 88 patients. No homozygous deletion and no point mutation of the p16 gene was seen in AML, MDS, CLL, and myeloma. Homozygous deletion of interferon alpha genes (situated close to p16 gene in 9p21) was seen in only 3 of the 9 ALL patients with p16 gene homozygous deletion, and none of the ALL without p16 gene homozygous deletion. Our findings suggest that homozygous deletion of the p16 gene is seen in about 15% of ALL cases, is not restricted to cases with cytogenetically detectable 9p deletion, and could have a pathogenetic role in this malignancy. On the other hand, p16 point mutations are very rare in ALL, and we found no p16 homozygous deletions or mutations in the other hematologic malignancies studied.