Hormone therapy for management of menopausal symptoms: understanding [corrected] breast cancer risk.

Since the publication of the Women's Health Initiative, women seeking relief from menopausal symptoms often express concerns about the risk of hormone therapy (HT). In women at increased risk for breast cancer or with a personal history of breast cancer, the decision to use HT for the treatment of menopausal symptoms must be carefully considered in the context of the most recent literature. It is well established that HT is the most effective treatment for climacteric symptoms and sexual dysfunction. The evidence to date on the use of HT in women with a history of breast cancer is complicated by the fact that the majority of breast cancers are estrogen responsive and the concern about risk of recurrence. Over the past decade, survival after breast cancer treatment has continued to improve resulting in millions of survivors worldwide. As a result of breast cancer therapies, the prevalence of menopausal symptoms is increasing in survivors, and both clinicians and patients are seeking safe and effective therapies for symptom management. This article will review the role of HT in the treatment of menopausal symptoms in women without breast cancer and those with a personal history of breast cancer or those who are at increased risk of breast cancer. Management of menopause-related symptoms will be reviewed with a focus on strategies to improve quality of life.

Dye-dilution techniques using aminohippurate sodium: do they accurately reflect amniotic fluid volume?

OBJECTIVE: To determine whether the dye-dilution technique using aminohippurate sodium accurately measures amniotic fluid volume. METHODS: Singleton pregnancies with intact membranes undergoing a Cesarean delivery had their amniotic fluid volume assessed by the dye-dilution technique and direct measurement. RESULTS: Fifteen women were prospectively assessed. Six patients had their amniocentesis on the delivery table and nine patients at 4-24 h prior to the Cesarean delivery. The six women undergoing an amniocentesis just before delivery had good concordance between the dye-determined and direct measurement of amniotic fluid volume (r = 0.99, p = < 0.001). Among the nine women with varying times from amniocentesis to direct measurement, the correlation was not significant (r = 0.36, p = 0.08). The percentage difference between the dye-determined and directly measured amniotic fluid volume was significantly smaller in the women undergoing amniocentesis just prior to delivery (7%) than in the women with varying times from amniocentesis to delivery (37%, P < 0.001). CONCLUSION: Dye-determined amniotic fluid volume accurately reflects actual amniotic fluid volume but the dye-determined concentrations, in vivo, may undergo rapid changes.

Utilization of parenteral nutrition in patients receiving peripheral blood stem cell transplantation.

A paucity of information is available on the use of parenteral nutrition (PN) in patients undergoing peripheral blood stem cell transplantation (PBSCT). To characterize the utilization of PN in patients undergoing PBSCT, we conducted a retrospective chart review study on adult patients receiving autologous and allogeneic PBSCT. Data collection included nutritional parameters such as indications for PN, days of PN administration, and PN-associated complications (i.e., metabolic, infectious, and mechanical). Outcome parameters assessed included length of hospitalization, days to engraftment, graft versus host disease (GVHD), and veno-occlusive disease (VOD). A total of twenty-one consecutive patients were evaluated with 12 receiving allogeneic PBSCT and 9 receiving autologous PBSCT. The allogeneic group received PN for a mean of 25 days compared to 21 days for the autologous group. The rate of metabolic abnormalities was significantly higher in the allogeneic group compared to the autologous group (1.02 abnormalities/PN days vs 0.61 abnormalities/PN day, p < 0.05), but mechanical and infectious complications were similar between the two groups. Length of hospitalization, days to engraftment, incidence of GVHD and VOD did not differ significantly between the two groups. However, mortality prior to discharge was significantly higher in the allogeneic vs autologous group (58% vs 0%, p < 0.05). We conclude that allogeneic PBSCT patients appear to be at a greater risk for metabolic complications while receiving PN as compared to autologous PBSCT patients. As nausea and vomiting are two primary reasons for initiation of PN in this patient population, further studies of aggressive antiemetic therapy may prove to decrease the need for PN in PBSCT patients.

Double heterozygosity for the codon beta 39 C-to-T nonsense mutation and a triplicate alpha-globin gene locus can cause "dominantly" inherited beta-thalassemia intermedia.

BACKGROUND: A beta-thalassemia intermedia phenotype can be caused by multiple genotypes. METHODS: We studied a family where the mother was hematologically normal and both father and daughter had beta-thalassemia intermedia. RESULTS: Both affected individuals were heterozygous for a codon 39 CAG-to-TAG mutation. They also were heterozygous for a triplicate alpha-globin gene locus (alphaalphaalpha(anti 3.7)). CONCLUSIONS: This compound heterozygous condition of a beta39 C-to-T mutation and triplicate alpha-globin gene increases alpha:beta-globin chain imbalance and accounts for the presence of beta-thalassemia intermedia. The proband received both an abnormal beta-globin gene and a triplicate alpha-globin locus from her father. Although the phenotype seems to be dominantly inherited, because of independent segregation of the alpha- and beta-globin genes, it is more accurately an example of polygenic inheritance.

A novel sensitive and selective bioassay for human type I interferons.

We describe a novel MxA gene-induction assay for type I interferons (IFN-alpha and IFN-beta) based on the specific induction of the MxA gene in cultured human cells. Accumulated intracellular MxA protein is determined by immunologic measurement by a rapid method using commercially available materials. IFN activity can be measured accurately over a concentration range of 0.1-30 IU/ml. In contrast, type II IFN and other cytokines are not significantly detected. The MxA-induction assay has advantages in terms of specificity, reliability, and sensitivity over other methods for assaying type I IFN. It has also been adapted and validated for measuring the titers of anti-IFN-beta neutralizing antibodies in human sera.

A novel bioassay for the determination of neutralizing antibodies to IFN-beta1b.

We have adapted the new MxA gene-induction bioassay to measure neutralizing antibodies to interferon-beta1b (IFN-beta1b, the active ingredient in Betaseron) in sera from patients treated with Betaseron. This antibody assay has been validated to quantify neutralizing titers of 1:20 and above, with a precision of +/- 0.20 in log10. We have used this MxA gene-induction antibody assay to reinvestigate serum samples from multiple sclerosis (MS) patients treated with Betaseron. The titers measured were closely comparable to those obtained in antiviral assays. Data obtained by both methods show that neutralizing antibodies may appear and subsequently disappear over time in the sera of some patients treated with Betaseron. Sera from some patients contain binding antibodies to IFN-beta1b. It was shown that binding antibody titers do not correlate quantitatively or qualitatively with neutralizing antibody titers, and indeed, a number of patients develop high levels of binding antibodies but never form measurable levels of neutralizing antibodies.

Thrombotic thrombocytopenic purpura: evolution across 15 years.

Thrombotic thrombocytopenic purpura (TTP) was originally described 70 years ago. It is considered an uncommon disorder with a reported occurrence rate of one case per 1 million patients. Mortality has decreased from almost 100% early on to 30-50% with the advent of newer treatment methods. We reviewed 41 patients with a diagnosis of TTP spanning the years 1980 to mid 1994. We found a much higher case rate, one per 6000 hospital admissions, and an overall death rate of 40%. However, isolating 5 year periods we noted a marked fall in mortality from 54% (1980-1984), 44% (1985-1989), to 18% (1990-1994). Previous reports describe relapsing TTP and report an incidence of 7-15% although very recent data suggests a higher incidence. In our study, we found an overall relapse rate of 25% and by 5 year periods 23% (1980-1984), 13% (1985-1989), and 46% (1990-1994). We suggest that the improvement in survival and the increase in relapse rate are related and reflect more effective therapy for this once almost always fatal disease. Patients now survive their initial episode and thus are at risk for recurrence. Identification of risk factors for relapse will require further study.

Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia.

The Southwest Oncology Group analyzed outcome with cytotoxic chemotherapy for previously untreated acute myeloblastic leukemia (AML) from 1982 through 1986. Results with acute promyelocytic leukemia (APL) prompted comparison with patients from 1986 through 1991 and analysis of factors contributing to APL results. Patient and disease characteristics and treatment outcome were compared for all evaluable patients, with more detailed analysis of factors affecting APL treatment outcome. From 1982 through 1986, median survival and disease-free survival in 45 APL patients were 106 months and greater than 105 months, respectively, versus 6 and 14 months for 417 other AML patients. Such differences were not seen from 1986 through 1991. In the 141 APL patients from 1982 through 1991, after adjusting for significant patient and disease characteristics, higher daunomycin (DNR) doses during induction were significantly associated with higher complete remission rates (P < .0001), longer survival (P < .0001), and longer DFS (P < .0001). Cytosine arabinoside (Ara-C) induction dose, the inclusion of other chemotherapy agents in induction, postremission therapy (consolidation, maintenance, or bone marrow transplantation) other than DNR, APL subtype, and patient age did not appear to significantly affect outcome of APL, except for a significant detrimental effect of high-dose Ara-C in consolidation (P = .0042). Morphologic AML subtypes other than APL did not affect outcome. We conclude that high-dose DNR selectively increases survival in APL. This good survival is important for evaluation of combined all-trans retinoic acid (ATRA)/chemotherapy protocols and for planning future combinations of chemotherapy and ATRA. These results illustrate the need to individualize chemotherapy for subtypes of AML. Therapeutic response of APL is independent of age. Except for APL, morphologic subclassification of AML contributed little prognostic information.

Postpartum plasma exchange for atypical preeclampsia-eclampsia as HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome.

OBJECTIVE: Our purpose was to investigate the postpartum use of plasma exchange in patients considered to have atypical preeclampsia-eclampsia manifested as persistent HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome with or without evidence of other organ injury. STUDY DESIGN: During a 10-year period, 18 patients with HELLP syndrome were treated post partum with single or multiple plasma exchange with fresh-frozen plasma. Each patient was entered into the clinical trial either because of persistent evidence of atypical preeclampsia-eclampsia as HELLP syndrome > 72 hours after delivery (group 1) or with evidence of worsening HELLP syndrome at any time post partum in association with single- or multiple-organ injury (group 2). All procedures were performed with the IBM 2997 Cell Separator (IBM, Cobe Laboratories, Inc., Lakewood, Colo.) system. Maternal and perinatal outcomes were the main outcomes studied. RESULTS: In the absence of other disease conditions, the 9 patients in group 1 with persistent postpartum HELLP syndrome complicated only by severe clinical expressions of preeclampsia-eclampsia responded rapidly to one or two plasma exchange procedures with few complications and no maternal deaths. In contrast, in the 9 patients of group 2 with HELLP syndrome presentations complicated by other organ disease, the response to plasma exchange was variable and there were two deaths in this group. CONCLUSION: The current series of patients details the successful postpartum application of plasma exchange therapy for unremitting HELLP syndrome but reveals that a uniformly positive response to this therapy will not always be observed when there is additional single or multiple organ injury.

Treatment of acute myelogenous leukemia in patients over 50 years of age with V-TAD: a Southwest Oncology Group study.

Acute myelogenous leukemia (AML) in the elderly continues to have a poor prognosis and new treatment approaches are needed. This Phase II trial was undertaken to evaluate the complete remission rate and toxicity of a chemotherapeutic regimen including etoposide and 6-thioguanine, combined with reduced doses of cytosine arabinoside and daunorubicin (V-TAD) in individuals greater than 50 years of age with AML. Thirty-five patients, ranging in age from 51 to 80 years (median, 66 years), were registered onto the study. Twenty-nine patients were entered at the first dose level (daunomycin 20 mg/m2 days 1 and 2, ara-C 75 mg/m2 days 1-5, 6-thioguanine 75 mg/m2 every 12 hr days 1-5, and etoposide 50 mg/m2 days 1, 2, and 3) and six patients underwent therapy at the second dose level (ara-C 75 mg/m2 days 1-7 with the remainder of the regimen unchanged). After achieving a complete remission, patients underwent two to three consolidation cycles of chemotherapy. Thirty-one patients were evaluable for response. Thirteen patients (ten of twenty-five at the first dose level and three of six at the second dose level) achieved a complete remission (42%). Median remission duration was 6 months (range 1-21 months). The current regimen, while tolerated, did not result in improved survival compared with prior treatment regimens because of a high incidence of resistant and recurrent leukemia.

The intrapartum platelet count in patients with HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome: is it predictive of later hemorrhagic complications?

OBJECTIVE: We wished to determine in patients with HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) whether (1) there is an intrapartum threshold platelet count that is predictive of immediate or delayed hemorrhagic complications and (2) whether prophylactic platelet transfusion at delivery prevents these outcomes. STUDY DESIGN: In this retrospective, descriptive study, the peripartal courses of 132 patients with class 1 (< or = 50,000/microliters platelet nadir) and 160 patients with class 2 (> 50,000 but < or = 100,000/microliters platelet nadir) HELLP syndrome were reviewed with special attention to laboratory data, evidence of hemorrhage, and details of platelet transfusion therapy. RESULTS: A higher incidence of postpartum hemorrhagic complications (p < 0.001) occurred in class 1 versus class 2 HELLP pregnancies. The tendency to have postpartum incisional bleeding after abdominal or vaginal delivery was related to the degree of thrombocytopenia (p = 0.006). The antepartum threshold platelet count most predictive of subsequent postpartum hemorrhagic complications was < or = 40,000/microliters. The prophylactic administration of platelets does not appear to have either significantly decreased the incidence of postpartum hemorrhagic complications or significantly hastened normalization of the postpartum platelet count. CONCLUSIONS: Although bleeding in the gravid patient is related to more factors than platelet count alone, patients with HELLP syndrome in whom an intrapartum platelet count above 40,000/microliters maintained are unlikely to have clinically significant postpartum bleeding. Patients with intrapartum platelet counts < or = 40,000/microliters, however, are at significant risk for postpartum bleeding, but prophylactic platelet transfusion at delivery does not ensure a significantly lower incidence of postpartum hemorrhagic complications.

Plasma exchange for preeclampsia: II. Unsuccessful antepartum utilization for severe preeclampsia with or without HELLP syndrome.

OBJECTIVE: To explore the efficacy of plasmapheresis/plasma exchange as the primary therapy to arrest and reverse the progression of severe preeclampsia with or without HELLP syndrome in order to postpone delivery and improve perinatal outcome in very preterm pregnancies. STUDY DESIGN: In this case series of patients managed over a 4-year period from 1984 to 1987, seven gravidas with severe preterm preeclampsia underwent 1-2 plasmaphereses/plasma exchange procedures using the IBM 2997 Cell Separator with continuous electronic fetal heart rate monitoring (n = 7 patients) and central cardiovascular monitoring (n = 3 patients). RESULTS: The seven patients (one with HELLP syndrome, six without HELLP) presented between 24 and 30 weeks gestation and, despite plasmapheresis/plasma exchange, the severity of each study subject's preeclampsia persisted without clinically significant improvement. Maternal-fetal deterioration required cesarean delivery in all cases within 48 (in four patients within < 36) hours of therapy. No clinically significant adverse effect of plasma exchange therapy was recorded during cardiovascular and laboratory monitoring; two fetuses developed repetitive late decelerations during exchange despite adequate maternal fluid preload. The only patient with HELLP syndrome developed eclampsia as her third plasma exchange within 25 hours was being initiated. Significant problems with fluid retention and displacement (variable amounts of pulmonary edema, pleural effusions, large volume ascites) were encountered in all patients. Four neonates died (24-27 weeks/438-820 g) and three survived intact (740, 950, and 1,280 g). One mother (case 5) developed end-stage renal disease 21 months postpartum. CONCLUSIONS: The application of plasmapheresis/plasma exchange therapy as described in order to prolong very preterm pregnancies in the undelivered patient with severe preeclampsia/eclampsia with or without HELLP syndrome did not produced encouraging results. Patients in general were exposed to additional medical and surgical risk without a corresponding improvement in perinatal outcome.

Plasma exchange for preeclampsia: III. Immediate peripartal utilization for selected patients with HELLP syndrome.

OBJECTIVE: To explore the potential efficacy of plasma exchange as an ancillary interventive therapeutic tool immediately before or after delivery in the patient with severe preeclampsia/eclampsia and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. STUDY DESIGN: Two gravidas with complicated severe preeclampsia/eclampsia/HELLP syndrome were treated emergently in the immediate peripartal period with single-volume plasma exchange and fresh frozen plasma fluid replacement using the IBM 2997 Cell Separator. RESULTS: Despite multiple platelet unit infusions, one primigravida in active labor at 5 cm cervical dilation and 39 weeks' gestation remained at a platelet count of 14,000/microL and began to ooze from her guns. A second primigravida remained obtunded, oliguric, and thrombocytopenic with epistaxis and hematuria following cesarean delivery and platelet transfusions. A single expedited 3-liter plasma exchange procedure reversed the rapidly deteriorating clinical situation for each patient and accelerated recovery from HELLP syndrome. Both patients and progeny suffered no permanent sequelae. CONCLUSION: Based on our experience, we believe that the therapeutic modality of plasma exchange with fresh frozen plasma can be employed effectively for the pregnant patient with severe atypical HELLP syndrome that progressively worsens during labor or the early puerperium despite the use of conventional transfusion therapy.

Recombinant vaccine development: a novel approach to ectoparasite control. A review of development of a recombinant vaccine for hypodermosis based on hypodermin A.

Cattle grubs (Hypoderma lineatum and H. bovis) are obligate parasites of cattle for most of their one year life cycle. Previously exposed animals become resistant to productive reinfestation, presumably as a result of immune system involvement, suggesting potential control by vaccination. Research progress towards development and utilization of a recombinant subunit vaccine for hypodermosis is described.

Bone marrow transplantation: a new treatment approach for Mississippians.

Bone marrow transplantation makes it possible to treat patients with malignancies using doses of systemic chemotherapy and/or radiotherapy that otherwise would result in fatal hematologic toxicity. This approach has found its widest application in the treatment of hematologic malignancies, but it is also being used for aplastic anemia, severe immunodeficiency diseases, and selected solid tumors. The University of Mississippi will soon (October, 1991) be able to offer this treatment approach to Mississippians; therefore the indications, the general technique, and results of transplantation for a variety of diseases are reviewed herein.

Unfavorable histologies of non-Hodgkin's lymphoma treated with ProMACE-CytaBOM: a groupwide Southwest Oncology Group study.

Chemotherapy using cyclophosphamide, doxorubicin, etoposide, cytarabine, bleomycin, vincristine, methotrexate with leucovorin, and prednisone (ProMACE-CytoBOM) for patients with intermediate- and high-grade non-Hodgkin's lymphomas was tested by the Southwest Oncology Group (SWOG) to confirm the activity of the regimen and to test the feasibility and safety of administering third-generation drug regimens in a cooperative group setting. On day 1, cyclophosphamide, doxorubicin, and etoposide were administered, followed by cytarabine, bleomycin, vincristine and methotrexate with leucovorin given on day 8. There were 51 complete remissions (CRs) among 78 previously untreated patients (65%) having clinical stage II-IV disease. The median length of follow-up is 37.9 months with 57% of patients alive at 3 years and 50% of CR patients free of disease at 3 years. Patients with diffuse large-cell lymphoma have the best survival (63% at 3 years) and relapse-free survival (RFS; 68% at 3 years with no relapses seen after 14 months). Administration of ProMACE-CytoBOM is feasible and safe in a cooperative group setting with 84% of 537 courses of treatment given exactly according to schedule and fatal toxicities seen in five patients (6%). ProMACE-CytaBOM may represent improved treatment for diffuse large-cell lymphoma, but the modest differences compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) indicate the need for a prospective randomized comparative trial.

Pregnancy complicated by preeclampsia-eclampsia with the syndrome of hemolysis, elevated liver enzymes, and low platelet count: how rapid is postpartum recovery?

The rapidity of postpartum disease recovery for severe preeclampsia associated with hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome) has not been well studied. Between January 1980 and March 1989, 158 pregnancies with preeclampsia-eclampsia complicated by HELLP syndrome were managed at the University of Mississippi Medical Center. The 70 patients with platelet nadir below 50,000/microL (class 1 HELLP syndrome) required as long as 11 days for all members to achieve a platelet recovery concentration of more than 100,000/microL, whereas all 88 gravidas with platelet nadir between 50,000-100,000/microL (class 2 HELLP syndrome) exceeded this platelet concentration by the sixth postpartum day, a statistically significant difference (P less than .0001). The interval between delivery and the onset of diuresis (mean +/- SD) was significantly longer in class 1 than in class 2 patients with milder disease (22.7 +/- 18.9 compared with 15.9 +/- 11.1 hours). Significantly more postpartum days were required in class 1 than in class 2 HELLP parturients for the lactic dehydrogenase (LDH) concentration to decrease below 500 IU/L (4.2 +/- 4.9 compared with 3.2 +/- 2.7 days). No women in the class 2 group required plasma exchange therapy to effect disease arrest and reversal, but 11 of 58 severely ill women in class 1 were treated with this modality. We conclude that the platelet count and LDH serum concentration, as indicators of HELLP severity and recovery, are clinically useful tools and that a more protracted postpartum recovery period should be expected for progressively severe expressions of HELLP syndrome.

Plasma exchange for preeclampsia. I. Postpartum use for persistently severe preeclampsia-eclampsia with HELLP syndrome.

The postpartum use of plasma exchange with fresh-frozen plasma was assessed in a group of seven women with severe preeclampsia-eclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) that persisted greater than 72 hours after delivery. During the study interval in which a total of 107 gravid women with HELLP syndrome were seen in our referral center, these seven patients (6.5%) demonstrated persistent thrombocytopenia (platelet count usually less than 30,000/mm3), rising lactic dehydrogenase (greater than 1000 IU/L) and evidence of multiorgan dysfunction. The seven case histories emphasize the variety of clinical and laboratory profiles that can be encountered in this small group of gravid women at risk for severe morbidity or mortality. Up to three 3 L plasma exchanges were required to effect permanent disease arrest and reversal. Utilization of the IBM 2997 Cell Separator system permitted bedside performance of procedures with enhanced convenience and optimal medical management. Successful plasma exchange was associated with (1) sustained increases in the mean platelet count at 24, 48, and 72 hours that were 2.2, 3.6, and 4.5 times the preexchange platelet counts and (2) a decreasing trend in lactic dehydrogenase concentrations below 1000 IU/L within 48 hours of exchange plasmapheresis. The current series of patients supports our recommendation that a trial of plasma exchange(s) with fresh-frozen plasma be considered for treatment of the infrequent postpartum case of HELLP syndrome that fails to abate within 72 hours of delivery and in which other evidence develops of an ongoing, widespread, and life-threatening thrombotic microangiopathy.