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 ...

Between December 1990 and January 1994, bone marrow (BM) samples from 151 patients with multiple myeloma (MM), including 117 patients evaluated at diagnosis, were collected for cytogenetic analysis. A total of 129 patients had assessable metaphases (100 patients at diagnosis). Cytogenetic studies were performed on BM cells after longterm cultures (6 days) with stimulation of cultures by granulocyte-macrophage colony-stimulating factor (GM-CSF), GM-CSF plus interleukin (IL)-6, IL-3 plus IL-6, or GM-CSF plus IL-3 plus IL-6 to improve myeloma cell growth, and 91 patients had an additional unstimulated culture. Sixty-six patients (51%) had cytogenetic abnormalities, including 47 of 100 patients at diagnosis (47%) and 17 of 24 patients at relapse (71%; P = .04). The aberration rate increased with stage (P = .007), BM plasmacytosis (P = .003), beta 2 microglobulin level (P = .001), C-reactive protein (CRP) level (P = .001), and Ki-67 (P = .007). The abnormality detection rate was higher in stimulated than unstimulated cultures, and the difference was statistically significant (P < .01). Hyperdiploidy was observed in 39 patients (30% of patients with an assessable karyotype) and hypodiploidy in 19 patients (15%). Among numeric changes, gains predominantly involved chromosomes 3, 5, 7, 9, 11, 15, 19 and losses, chromosomes 8, 13, 14, and X. The most frequent loss was loss of chromosome 13, observed in 22 patients (15%), including 18 patients at diagnosis (12%). We observed frequent structural changes of chromosomes 1 (15%) and 14 (10%) but also a 5% incidence of 19q13 abnormality and two patients with translocation t(1;16)(p11;p11). By using the proportional hazard univariate model, patients with abnormal karyotypes were demonstrated to have 2.5-fold greater chance of death than patients with normal karyotypes (P < .014). Despite a multivariate approach with the same model, the respective roles of karyotype abnormality, age, stage, and beta 2 microglobulin level could not be clearly ascertained. From these results we conclude that cytogenetic analysis using stimulation of cultures by cytokine(s) may be a promising method to identify about 50% of cytogenetic abnormalities in patients with newly diagnosed MM. Cytogenetic analysis may help to define a high-risk population that would benefit from intensive therapeutic approaches.

This analysis demonstrates that rituximab infusion was rapidly followed by activation of complement, B-lymphocyte cytolysis, and TNF-alpha release.

Over a period of 14 years, we treated 70 cases of acute promyelocytic leukemia (APL) with 3 different chemotherapy protocols. In protocol 1, patients received high dose daunorubicin (DNR) alone for induction, followed by regular reinduction courses and continuous maintenance therapy with 6 mercaptopurine (6 MP) and methotrexate (MTX) during 3 years. In protocol 2, induction with high dose DNR and Ara C was also followed by regular reinduction courses, but without continuous maintenance therapy. Protocol 3 randomized high dose Amsacrine (AMSA) or Rubidazone in association with Ara C, for induction and consolidation, this was followed by reinduction courses and continuous maintenance therapy with 6 MP and MTX. During the induction all patients received, prophylactic heparinization and platelet transfusions. Fifty six patients (80%) achieved complete remission (CR), 13 patients (18.5%) had early death (ED) or hypoplastic death (HD), and 1 patient had true resistant leukemia. Only two patients died of hemorrhage. Median actuarial disease free survival (DFS) was 16.5 months and a plateau at 29.1% was reached after 29 months. Patients with fever at diagnosis had a significantly lower CR rate while age below 20 years and circulating blasts above 0.5 × 10(9)/1 were associated with shorter DFS. The CR rate did not significantly differ between protocols 1, 2 and 3 (87.5%, 80% and 60% respectively) but 9 of the 30 patients on protocols 2 or 3 had ED or HD, compared to 4 of the 40 treated with protocol 1 (p < 0.05). DFS was significantly shorter in protocol 2, which included no continuous maintenance chemotherapy, than in protocols 1 and 3. Median actuarial survival was significantly shorter in patients treated with protocols 2 or 3, compared to protocol 1. These results suggest that high dose DNR alone, associated with adequate prophylaxis of disseminated intravascular coagulation, gives very high CR rates in APL, with short periods of aplasia and limited toxicity. Combinations of an anthracycline or AMSA at the doses used with regular dose Ara C may be too toxic. Although this was not a randomized trial, our findings also suggest a possible benefit of prolonged continuous maintenance therapy with 6 MP and MTX in APL.

BackgroundThe aim was to describe the regulatory B and T cells (Breg and Treg) and T helper 17 (Th17) lymphocytes before and under treatment with biologic drugs, and to assess their potential predictive value as biomarkers of response in rheumatoid arthritis (RA).MethodsThis was a non-randomised, single-centre, prospective study. Patients with active RA (American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010) who required the initiation or switch to any biologic drug except rituximab were included. The main judgement criterion was the frequency and absolute number of CD24hiCD27+ Breg and CD24hiCD38hi T2/Breg cells, CD25hiCD127low Treg and CD45RA−CD161+CCR6+ Th17 cells measured at inclusion in both patients and controls, and after 1, 3 and 6 months of treatment (M1, M3 and M6) in patients with RA, and compared with the M6 response to treatment (EULAR response and Disease Activity Score in 28 joints (DAS28) remission).ResultsThirty-one patients with RA and 17 controls were included. There was a reduction in T2/Breg frequency at M0 in patients (p < 0.001) and absolute numbers (p = 0.014) and in immunopositive vs. immunonegative RA (p = 0.016). DAS28 remission at M6 was associated with increased frequency of Treg (p = 0.01). A higher level of CD24hiCD27+ Breg at baseline was associated with DAS28 remission at M6 (p = 0.04) and a good EULAR response at M6 for abatacept-treated patients (p = 0.01). A lower M0 level of Th17 was associated with a good EULAR response at M6 (p = 0.007), notably under anti-cytokine drugs (p = 0.048).ConclusionsAltogether, these data, although preliminary, suggest that phenotyping of T and B cells has potential value for the stratification of biologic drugs, notably with respect to choosing between abatacept and anti-cytokine blockade.