Phase I/II study of iodine 131 metaiodobenzylguanidine in chemoresistant neuroblastoma: a United Kingdom Children's Cancer Study Group investigation.

PURPOSE: The goal of this study was to evaluate the toxicity of iodine 131 metaiodobenzylguanidine (mIBG) in metastatic neuroblastoma. PATIENTS AND METHODS: A multicenter phase I study of 131I mIBG has been undertaken by the United Kingdom Children's Cancer Study Group (UKCCSG) in children with advanced chemoresistant neuroblastoma. Activity prescription was based on a prescribed whole-body radiation dose, which was established for individual patients by performing an initial tracer investigation with 75 MBq of 131I mIBG. An activity was derived from this pharmacokinetic study that would deliver an initial whole-body-absorbed radiation dose of 1 Gy. Subsequent dose escalations were based on observed toxicity. RESULTS: Twenty-five patients, aged 1 to 10 years, were treated with prescribed whole-body dose levels of 1.0 Gy (n = 2), 2.0 Gy (n = 13), and 2.5 Gy (n = 10). This necessitated administration of 2.4 to 12.1 GBq of activity. Hematologic, hepatic, kidney, and adrenal toxicity were observed, with bone marrow suppression being the principal dose-limiting toxicity. Bone marrow toxicity increased with prescribed whole-body-absorbed radiation dose, with 80% of patients developing grade 3 or 4 thrombocytopenia at a prescribed whole-body radiation dose of 2.5 Gy. Objective evidence of tumor response was seen in soft tissue (primary or nodal disease), bone, and bone marrow, with an overall response rate of 33% (partial response, n = 8; static disease, n = 9; progressive disease, n = 7). CONCLUSIONS: This study has established an effective method of activity prescription that predicts subsequent toxicity, with the maximally tolerated dose being sufficient activity to deliver a whole-body-absorbed radiation dose of 2.5 Gy. The objective response rate is comparable to other single agents in chemoresistant neuroblastoma and suggests that 131I mIBG may be a useful method for targeting radiotherapy in metastatic neuroblastoma.

The treatment of resistant neuroblastoma with 131I-mIBG: alternative methods of dose prescription.

A UK multi-centre study has been carried out to collect medical and dosimetry data from treatments with 131I-metaiodobenzylguanidine (mIBG) for patients suffering from resistant neuroblastoma. All data have been acquired in a standardised way, following strict physics and clinical protocols. The accuracy of three different methods of dose prescription was studied. The results show that the most accurate method involved the use of an initial tracer study to determine the therapeutic activity required to deliver a predetermined absorbed whole-body (WB) dose.

Curettage after mifepristone-induced abortion: frequency, timing, and indications.

OBJECTIVE: To characterize women who underwent curettage after medical abortion with mifepristone and vaginal misoprostol, to describe when curettage occurred and the reasons for the intervention, and to categorize the indications for curettage according to a simple classification schema. METHODS: These analyses used data from two multisite, randomized controlled trials sponsored by Abortion Rights Mobilization. In the first study, women pregnant less than 63 days received 200 mg of mifepristone and 800 microg of vaginal misoprostol to use 48 hours after taking mifepristone. In the second study, women pregnant less than 56 days were randomly assigned to insert vaginal misoprostol at 1, 2, or 3 days after mifepristone administration. Case report forms and clinical case notes of all women who underwent curettage were examined. RESULTS: Of the 4393 women enrolled in both studies, 116 (2.6%, 95% confidence interval 2.1%, 3.1%) curettages were identified. The gestational age and a history of prior elective abortion were associated with the rate of curettage. The distribution of indications for curettage included bleeding, 61 (53%); continuing pregnancy, 17 (15%); patient request, 36 (31%); and indeterminate, 2 (1.7%). The timing of curettage differed by the indication and scheduled interval between study visits. The distribution of the timing was bimodal. One subset of women, 44 (38%), underwent curettage in the first study week and another subset, 43 (37%), during weeks 3-5. CONCLUSION: Curettage after medical abortion with mifepristone and vaginal misoprostol is rare. At least one half of the curettages were performed for persistent bleeding several weeks after treatment. Both acute heavy bleeding and continuing pregnancy are extremely rare.

Organizational impact on medicine: the HMO concept.

This paper examines the role of physicians within the HMO (health maintenance organization) context. The development of HMOs in the United States is traced from their origins to the present time. The literature reveals the emergence of four factors within the practice of medicine; a shift of control away from physicians, the reduction of their prestige, the redefinition of medical quality and increased patient control over the treatment regimen. The paper concludes that (a) while physicians remain relatively powerful, some of their control and prestige are eroded by the organizational setting, (b) HMO physicians must pay greater attention to colleagues, personnel and patients than their fee-for-service counterparts and (c) definitions of medical quality are becoming increasingly rationalized.

Radiation dosimetry for 131I-mIBG therapy of neuroblastoma.

This paper describes the methodology which can be used to determine whole-body, red marrow, blood, bladder, liver, and tumour doses delivered during 131I-mIBG therapy of neuroblastoma. The methodology is based on the Physics Protocol used in a multi-centre study undertaken by the United Kingdom Children's Cancer Study Group (UKCCSG). In this study, the estimates of the doses delivered, using 2.4-12.1 GBq 131I-mIBG, were in the following ranges: whole body, 0.14-0.65 mGy MBq-1; red marrow, 0.17-0.63 mGy MBq-1; blood, 0.04-0.17 mGy MBq-1; bladder, 2.2-5.3 mGy MBq-1; liver, 0.3-1.9 mGy MBq-1; and tumour, 0.2-16.6 mGy MBq-1.

Randomized trial of oral versus vaginal misoprostol at one day after mifepristone for early medical abortion.

Mifepristone was recently approved in the United States. Regimens with shorter intervals may be more acceptable. The objective of this study was to determine whether the oral route of misoprostol was as effective as the vaginal route of misoprostol 1 day after mifepristone. A prospective, open-labeled, randomized trial of healthy adult women up to 63 days pregnant and wanting a medical abortion were randomized to use either two doses of oral misoprostol 400 microg taken 2 h apart or misoprostol 800 microg vaginally. Women self-administered misoprostol 1 day after taking one-third of the standard dose of mifepristone (200 mg) orally. Women then returned to the clinic up to 5 days later for a repeat sonogram evaluation. A dose of vaginal misoprostol was administered to women with a continuing pregnancy who then returned 1 day later to Day 15. The primary outcome measures were a complete medical abortion by the first or by the second follow-up visits. Surgical intervention was indicated for continuing pregnancy at the second follow-up visit, excessive bleeding, or persistent products of conception 5 weeks later. One thousand one hundred sixty-eight women were enrolled. Of the 1144 (98%) women who complied with their random assignment, two oral doses of misoprostol (800 microg total) were 90% effective at inducing an abortion by the first follow-up visit, compared with one dose of misoprostol by vagina of 97% (chi(2) = 23.95, p = 0.001). By the second follow-up visit, the complete abortion rate was 95% for oral misoprostol and 99% for vaginal misoprostol (chi(2) = 21.76, p = 0.001). There were minimal differences in side effects. Women preferred the oral route. The trial demonstrated that although two doses of oral misoprostol were effective, the vaginal misoprostol was more effective at inducing an early medical abortion at 1 day after low-dose mifepristone, and the regimen could be extended to 63 days gestation.

Mifepristone abortion in minors.

Approximately one-third of pregnant teenagers in the U.S. choose abortion. This prospective study evaluated whether medical abortion with mifepristone and misoprostol is physically and emotionally acceptable in adolescents. Adolescents 14- to 17-years-old, with pregnancies < or =56 days gestation, and seeking abortion services with parental consent from at least one parent were enrolled. Mifepristone (200 mg) was administered, followed 2 days later by 800 microg of misoprostol administered vaginally. Follow-up visit occurred on Day 4-8 to confirm abortion completion. Questionnaires regarding acceptability of the procedure as well as emotional coping were administered at the initial visit, at the follow-up visit, and by phone at 4 weeks postabortion. All 28 adolescents had complete medical abortions without complications or surgical intervention, and five minors did not require misoprostol. At the Day 4-8 follow-up visit, 75% of teens found the procedure acceptable, and that increased to 96% by the 4-week visit. Although 57% reported stress and 43% reported fear initially, by 4 weeks postabortion only 21% of the teens reported stress, and 8% were still experiencing fear. In addition, the minors' satisfaction with their abortion decision increased from 43% to 79% by 4 weeks postabortion. Medical abortion with mifepristone and misoprostol was highly effective and well tolerated, physically and emotionally, by adolescents in our sample. A larger clinical trial is needed to generalize these findings to other adolescent populations seeking medical abortion services.

Mifepristone and misoprostol for early abortion when no gestational sac is present.

The study was conducted to determine whether the administration of mifepristone followed by vaginal misoprostol can induce an abortion in early pregnancy when no gestational sac is present on sonogram. This report presents a prospective, pilot study of 30 healthy adult women, pregnant and seeking an abortion, and with no gestational sac on sonogram. All women had a baseline serum chorionic gonadotropin (hCG) level measured prior to using mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 48 h later, and then returned up to 4 days later for a repeat sonogram and serum hCG level. Women with initial hCG levels > 2000 IU/L were evaluated for ectopic pregnancy. At the first follow-up visit, if the hCG decreased by >50%, the women were followed with home pregnancy (25 IU/L) tests weekly until negative. If the levels did not decrease by 50%, a second dose of misoprostol was given. Surgical intervention was indicated for persistent hCG levels or excessive bleeding. Of the 30 women enrolled, the mean number of days of amenorrhea was 40 (SD 9) days. Two women had surgical intervention for continuing pregnancy, 2 had ectopic pregnancies, and 1 was lost to follow-up. Complete medical abortions occurred in 25/30 (88%) women, but when recalculated, in 25/27 (93%) women who completed the protocol and who did not have an ectopic pregnancy. There was 1 adverse event in a woman with an ongoing pregnancy who then received methotrexate. She was hospitalized a day later with a complicated pelvic infection and likely methotrexate-induced pneumonitis. Twenty-three women had a decrease in hCG at first follow-up visit of >50%. All 27 women who completed the protocol found the overall regimen acceptable. Mifepristone followed at 48 h by vaginal misoprostol were effective and acceptable in inducing an abortion in very early pregnancy. There may be a higher incidence of failure in very early pregnancies. Documentation of a complete abortion by hCG level is necessary to ensure the pregnancy is neither ongoing nor ectopic.

Low-dose mifepristone followed by vaginal misoprostol at 48 hours for abortion up to 63 days.

The aim of this study was to compare the effectiveness, side effects, and acceptability of one-third the standard dose of mifepristone, i.e., 200 mg, and vaginal misoprostol 800 microg to induce abortion in subjects < or =56 days pregnant with subjects 57-63 days pregnant. A prospective multicenter trial enrolled healthy women > or =18 years, < or =63 days pregnant, and wanting an abortion. Women received mifepristone 200 mg orally, followed by misoprostol 800 microg vaginally, and returned 1-4 days later for ultrasound evaluation. A second dose of misoprostol was administered, if necessary. Surgical intervention was indicated for continuing pregnancy, excessive bleeding, or persistent products of conception 5 weeks later. Of 1137 subjects, 829 were in the < or =56 days pregnant group and 308 in the 57-63 days pregnant group. In all, 34 subjects had surgical intervention and 16 were lost to follow-up. Complete medical abortions occurred in 97% of subjects < or =56 days pregnant and 96% in the 57-63 days pregnant group. In all, 88% of subjects in the < or =56 days pregnant and 92% in the 57-63 days pregnant group bled within 4 h of using vaginal misoprostol. Comparing subjects < or =56 days pregnant with 57-63 days pregnant, there was less diarrhea (20% vs 29%, p = 0.002) and vomiting (33% vs 44%, p = 0.001), although side effects were acceptable to 82% of subjects in both groups. One subject in the < or =56 day group required a transfusion for delayed excessive bleeding. Although bleeding (p = 0.01) and pain (p = 0.02) were less acceptable in the 57-63 day group, 91% of subjects in both groups reported that the overall procedure was acceptable. In summary, low-dose mifepristone 200 mg and home administration of vaginal misoprostol 800 microg at 48 h were highly effective and acceptable to women < or =63 days pregnant, thereby expanding the number of women who can access a medical abortion.

PIP: The aim of this study was to compare the effectiveness, side effects, and acceptability of one-third the standard dose of mifepristone, i.e. 200 mg, and vaginal misoprostol 800 mcg to induce abortion in subjects 56 or fewer days pregnant with subjects 57-63 days pregnant. A prospective multicenter trial enrolled healthy women aged 18 years or older, 63 or fewer days pregnant, and wanting an abortion. Women received mifepristone 200 mg orally, followed by misoprostol 800 mcg vaginally, and returned 1-4 days later for ultrasound evaluation. A second dose of misoprostol was administered, if necessary. Surgical intervention was indicated for continuing pregnancy, excessive bleeding, or persistent products of conception 5 weeks later. Of 1137 subjects, 829 were in the 56 days or fewer pregnant group and 308 in the 57-63 days pregnant group. In all, 34 subjects had surgical intervention and 16 were lost to follow-up. Complete medical abortions occurred in 97% of subjects 56 or fewer days pregnant and 96% in the 57-63 days pregnant group. In all, 88% of subjects in the 56 days or fewer pregnant and 92% in the 57-63 days pregnant group bled within 4 hours of using vaginal misoprostol. Comparing subjects 56 or fewer days pregnant with 57-63 days pregnant, there was less diarrhea (20% vs. 29%, p = 0.0002) and vomiting (33% vs. 44%, p = 0.001), although side effects were acceptable to 82% of subjects in both groups. 1 subject in the 56 or fewer days group required a transfusion for delayed excessive bleeding. Although bleeding (p = 0.01) and pain (p = 0.02) were less acceptable in the 57-63 days group. 91% of subjects in both groups reported that the overall procedure was acceptable. In summary, low-dose mifepristone 200 mg and home administration of vaginal misoprostol 800 mcg at 48 hours were highly effective and acceptable to women 63 or fewer days pregnant, thereby expanding the number of women who can access a medical abortion.

Absolute 99Tcm-DMSA renal uptake in children: optimum time to scan.

Absolute renal uptake was measured at 2, 4 and 6 h in 27 patients in order to determine a more convenient time for uptake compared with the 6-h measurement proposed by other authors. Measurements made at 2 and 4 h would need to be increased by 20 and 6%, respectively, to convert to the value at 6 h. Measurements at 4 h are a reasonable compromise to achieve a high-count/low-background image in a reasonable time and to obtain a good estimate of the predicted 6 h uptake at a single scanning session. The percent renal uptake at 6 h, U(6), can be derived from the percent uptake measured at t hours after injection, U(t), using the following formula: U(6) = U(t) x CF(t), where CF(t) = 1.0 + 0.03 (6 - t) for 4 < or = t < or = 6.

Anxieties and attitudes towards abortion in women presenting for medical and surgical abortions.

OBJECTIVE: To examine the differences in anxiety levels and attitudes towards abortion between women having an early medical abortion and women having a surgical (manual vacuum aspiration) abortion. METHODS: Women who presented for an early medical abortion or a surgical abortion at an urban, free-standing abortion clinic were invited to participate in this study. Fifty-nine women having a medical abortion and 43 women having a surgical abortion answered questionnaires before their scheduled abortion, and again 2 to 4 weeks after the abortion. Thirty women were interviewed about their answers. RESULTS: Anxiety levels were similar in both groups before the abortion procedure. Anti-choice views about abortion were seen in 60.5% of women having a medical abortion and in 37.3% of women having a surgical abortion (P = .027). Women who were pro-choice had a mean anxiety score of 5.0 (range, 0-10) before and 2.7 after the abortion, whereas women who were anti-choice had a mean anxiety score of 5.2 before and 4.4 after the abortion (P = .005). CONCLUSION: It is important for providers of abortion care to understand that women undergoing a medical abortion may be more ambivalent about abortion than women undergoing a surgical abortion, and women who are anti-choice but having an abortion may have unresolved anxiety after the procedure.

Professional considerations for providing mifepristone-induced abortion.

Primary care clinicians who provide comprehensive reproductive heath care can now offer patients mifepristone (Mifeprex) as an abortifacient option. Clinicians, however, must first determine if the state in which they practice has regulations specifying who can perform abortions and dispense drugs, and they must consider clinical office zoning ordinances, staffing, public relations issues, and reimbursement. This article discusses the pharmacology of mifepristone and misoprostol, professional considerations, and how to prevent and manage adverse effects and complications of medical abortion.

A comparison of the Abortion Rights Mobilization and Population Council trials.

We compared the published results of the 1994-1995 Population Council (PC) trial to those from the 1996-1997 Abortion Rights Mobilization (ARM) trial to determine whether 200 mg mifepristone with 800 micrograms vaginal misoprostol is more effective and has fewer side effects than 600 mg mifepristone with 400 micrograms oral misoprostol. The complete medical abortion rate was lower in the PC trial than the ARM trial: 92% compared with 97% up to 49 days LMP (p < 0.05) and 83% versus 96% from 50 to 56 days LMP (p < 0.05). Nausea and vomiting were reported more frequently in the PC trial. The overall acceptability of the procedure was lower in the PC trial (88%) than in the ARM trial (94%), (p < 0.05). Mifepristone can be reduced from 600 to 200 mg when followed by vaginal misoprostol without loss of efficacy. Vaginal misoprostol extends the efficacy to 56 days LMP and is associated with less nausea and vomiting. Home use of misoprostol is safe and acceptable to women and decreases the number of required visits from three to two in most cases.

Delayed access to health care: risk factors, reasons, and consequences.

OBJECTIVE: To determine characteristics of patients reporting delays in care before hospitalization and the reasons for those delays. DESIGN: Survey; personal interviews. SETTING: Five hospitals in Massachusetts. PATIENTS: Subjects were drawn from a consecutive sample of all adult patients (excluding obstetrics or psychiatry patients) hospitalized during the first 6 months of 1987 as part of a larger study of hospital costs. For the current study, if patients were re-admitted, we included in our analysis only data on the first admission during the study period. We obtained usable survey data from 12,068 of 17,231 eligible patients. RESULTS: Delays in care were reported by 16% of patients. The odds of reporting delays in care among patients who were black, poor, uninsured, or without a regular physician were 40% to 80% greater than those for other patients (P less than 0.01). Most patients who reported delays thought that their problem was not serious (64%). Cost was an important factor in delaying care for patients in lower socioeconomic positions; the odds of delaying care because of cost for patients who were both poor and uninsured were 12 times greater than the odds for other patients (P less than 0.001). After controlling for diagnosis-related groups (DRGs) and severity, patients who reported delays had 9% longer hospital stays compared with others (P less than 0.001). CONCLUSIONS: Patients generally thought to be disadvantaged are at especially high risk for delaying care for conditions that eventually lead to hospitalization. Because these delays are associated with longer hospital stays and potentially poorer health outcomes, interventions that reduce delays seem especially important.

Dosimetry of iodine 131 metaiodobenzylguanidine for treatment of resistant neuroblastoma: results of a UK study.

In 1987, the United Kingdom Children's Cancer Study Group (UKCCSG) set up a multi-centre study to investigate the toxicity of iodine 131 metaiodobenzylguanidine (mIBG) in the treatment of resistant neuroblastoma. Since December 1987, 25 children suffering from neuroblastoma have been treated with 131I-mIBG at six UK centres. All centres followed standardised physics and clinical protocols to provide consistent toxicity and dosimetry data. These protocols describe the methods employed for both the tracer study using 131I-mIBG and the subsequent therapy. Whole-body dosimetry calculations were performed on data from the tracer study. The activity administered for therapy was the amount predicted to deliver a predefined whole-body dose. Estimates of doses delivered to various organs during treatment are given in Table 1.

Vaginal misoprostol administered 1, 2, or 3 days after mifepristone for early medical abortion: A randomized trial.

CONTEXT: The conventional timing of misoprostol administration after mifepristone for medical abortion is 2 days, but more flexible intervals, which may make the regimen more convenient, have not been studied. OBJECTIVE: To determine whether vaginal misoprostol administered 1, 2, or 3 days after mifepristone influences safety or effectiveness for abortion at up to 56 days' gestation. DESIGN: Prospective, randomized, open-label trial conducted from March 1998 to June 1999. SETTING: Sixteen US primary care and referral abortion facilities. PATIENTS: A total of 2295 healthy patients aged 18 years or older who were 56 or fewer days pregnant. Forty (1.7%) were lost to follow-up. INTERVENTIONS: Patients received 200 mg of oral mifepristone and were randomly assigned to self-administer 800 microg of vaginal misoprostol at home 1 (n = 745), 2 (n = 778), or 3 (n = 772) days later. Women returned to the clinic up to 8 days after mifepristone for ultrasonographic evaluation. A second dose of misoprostol was administered if the abortion was not complete. Patients with continuing pregnancy, excessive bleeding, or retained pregnancy tissue 5 weeks later received an aspiration curettage. MAIN OUTCOME MEASURES: Effectiveness of the procedure (ie, a complete medical abortion without surgical intervention), adverse effects, acceptability of the procedure based on patient questionnaires, reasons for surgical intervention, and adverse outcomes, compared among the study groups. RESULTS: Of the 2255 women completing follow-up, complete medical abortion rates were 98% (95% confidence interval [CI], 97%-99%) among those using misoprostol after 1 day, 98% (95% CI, 97%-99%) for those using misoprostol after 2 days, and 96% (95% CI, 95%-97%) among those using misoprostol after 3 days. Fifty-five subjects aborted before taking misoprostol, 9 had early surgery, and 103 did not take misoprostol on their assigned day. No blood transfusions were required. Cramping and nausea were the most common adverse effects reported, with similar percentages of patients in all 3 groups reporting such effects. Thirteen unexpected or serious adverse events occurred: 6 in those using misoprostol after 1 day; 4 in those using it after 2 days; and 3 in those using it after 3 days. Nearly all women (>90%) found the procedure to be acceptable. CONCLUSIONS: Our results suggest that vaginal misoprostol, 800 microg, can be used from 1 to 3 days after mifepristone, 200 mg, for early medical abortion, and need not be administered strictly 48 hours after mifepristone. JAMA. 2000;284:1948-1953.