Assessing the economic value of antihypertensive medications.

OBJECTIVE: To assess the economic value of antihypertensive medications by comparing the likelihood of coronary heart disease and stroke events and subsequent event treatment costs. STUDY DESIGN: Duration of blood pressure reduction was used to profile event risk reduction of three antihypertensive medications. METHODS: We used clinical data to determine the duration of blood pressure reduction achieved with use of two angiotensin converting enzyme inhibitors and one angiotensin II receptor antagonist. We then used trough-to-peak ratios to calculate the reduction in risk of coronary heart disease and stroke events associated with each medication. RESULTS: Across a number of different event treatment cost and population size estimates, the economic value of different medications can be assessed. CONCLUSION: Our method for assessing the economic value of antihypertensive medications can be applied to other drug classes and can be further refined by integrating patient population and other risk-related data.

Adoptive immunotherapy with donor mononuclear cell infusions to treat relapse of acute leukemia or myelodysplasia after allogeneic bone marrow transplantation.

Relapse remains a significant problem after allogeneic bone marrow transplantation (BMT). For patients with relapsed chronic myelogenous leukemia (CML), infusions of donor mononuclear cells (MNC) provide a potent graft-versus-leukemia (GVL) reaction inducing complete remissions in the majority of patients. Little is known about the efficacy of donor MNC infusions for patients who relapse with other diseases. We have studied the GVL effects of donor MNC in eight patients with relapsed acute leukemia or myelodysplasia (MDS). One patient with relapsed MDS achieved complete remission and another patient had a transient response. Five of six non-responders died of progressive leukemia and one non-responder died of complications during second BMT. Three patients developed grade I-II acute GVHD responsive to immunosuppression. These data, and review of the literature, suggest that GVL induction with donor MNC infusions is less effective for patients with relapsed acute leukemia than for patients with relapsed CML; too few patients with relapsed MDS have been treated to draw definite conclusions. However, some patients respond, and given the high mortality associated with alternative procedures such as second BMT, donor MNC infusions are a reasonable approach for relapsed acute leukemia and MDS after allogeneic BMT.

Neural cell-adhesion molecule (CD 56)-positive, t(8;21) acute myeloid leukemia (AML, M-2) and granulocytic sarcoma.

A 49-year-old man with t(8; 21) acute myeloid leukemia relapsed 8 months after successful induction chemotherapy with a paraspinal granulocytic sarcoma. There was no evidence of leukemia in the bone marrow at relapse. At initial presentation, the blasts co-expressed CD 15, CD 33, CD 34, CD 45, CD 19, and CD 56 (a neural cell-adhesion molecule). Expression of certain cell-adhesion molecules on leukemic blasts may determine a tendency to develop extramedullary relapse. The co-expression of CD 56 may have a role in the predisposition of t(8; 21) AML to develop GS.

Lineage switch in Philadelphia chromosome-positive acute lymphoblastic leukemia.

BACKGROUND: An 8-year-old boy, initially diagnosed with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) (French-American-British [FAB]-L1), relapsed with Ph+ acute myelogenous leukemia (AML) (FAB-M2) 21 months after successful ALL treatment with standard therapy. METHODS: The initial ALL presentation and subsequent AML relapse were analyzed by conventional morphologic, cytochemical, immunophenotypic, and cytogenetic studies. RESULTS: Molecular analysis based on the polymerase chain reaction identified the presence of a bcr-I-abl fusion transcript at initial ALL presentation, the completion of ALL therapy, and AML relapse. CONCLUSIONS: The cytogenetic and molecular results support a common clonal origin for this process. This is a case of lineage switch in a Ph+ acute leukemia. This case thus illustrates a manifestation of heterogeneous lineage differentiation among Ph+ acute leukemias.

Sensitive detection of occult breast cancer by the reverse-transcriptase polymerase chain reaction.

PURPOSE: Detection of occult carcinoma in patients with breast cancer may aid the establishment of prognosis and development of new therapeutic approaches. To improve on existing methods of detection, we have developed a reverse-transcriptase polymerase chain reaction (RT-PCR) assay for keratin 19 (K19) transcripts to identify mammary carcinoma cells in the peripheral blood and bone marrow of patients with breast cancer. PATIENTS AND METHODS: Peripheral-blood or bone marrow samples obtained from 34 patients with stages I to IV breast cancer and 39 control subjects without breast cancer were screened for K19 mRNA by nested primer PCR. RESULTS: In reconstitution experiments, K19 RT-PCR reliably detected 10 mammary carcinoma cells in 1 million normal peripheral-blood mononuclear (PBMN) cells. Four of 19 patients with stage IV breast cancer had detectable K19 transcript in peripheral blood. Five of six patients with histologically negative bone marrow biopsies following preablative chemotherapy and before autologous bone marrow transplant (BMT) were positive by this assay. Stem-cell apheresis harvests obtained from one of these patients and three additional patients immediately before BMT were all K19-negative. K19 RT-PCR analysis of CSF from a breast cancer patient with known carcinomatous meningitis was also positive. Thirty-eight of 39 non-breast cancer patients had negative K19 RT-PCR assays. The one exception was a patient with chronic myelogenous leukemia. CONCLUSION: RT-PCR of K19 is a sensitive, specific, and rapid method for detection of occult mammary carcinoma cells in the peripheral blood and bone marrow of patients with breast cancer. The presence of residual breast cancer cells in histologically normal bone marrow aspirates but not in stem-cell apheresis harvests is a frequent finding. This assay may be useful in diagnosing metastatic disease, as well as in monitoring the effectiveness of systemic therapy.

Development of a sensitive, highly controlled assay for molecular detection of the Philadelphia chromosome in patients with chronic myelogenous leukemia.

The Philadelphia chromosome (Ph1), present in > or = 95% of chronic myelogenous leukemia (CML) patients, is a well-characterized translocation that results in a unique chimeric gene product (BCR/ABL) with transforming capability. Molecular methods utilizing the polymerase chain reaction (PCR) to detect BCR/ABL mRNA transcripts has been useful for detecting minimal residual disease (MRD) after treatment, as well as for establishing the diagnosis of CML. Amplification-based assays for the BCR/ABL transcript, however, have shown variable reproducibility and sensitivity. This variability may be largely due to technical differences and insufficient controls. In this report, we describe the development of a highly controlled, reproducible, and sensitive PCR assay to detect Ph1 that is well suited to clinical and research applications. A validation study of 82 samples was performed consisting of 25 dilutions of K562 cells (Ph1+) into normal cultured B cells, 26 pre- and post-transplant peripheral blood samples from CML patients, 16 peripheral blood samples for diagnosis of CML, and 15 peripheral blood samples from healthy individuals. RNA isolated from 3 to 5 million leukocytes was reverse transcribed (RT) and amplified by nested primer PCR. The products were characterized using agarose gel electrophoresis. Approximately 1000 Ph1-positive cells admixed with 10(6) normal cells were detectable after one round of amplification. In 60% of assays where one Ph1-positive cell was admixed with 10(6) normal cells, a BCR/ABL product was detectable after nested primer PCR. Specific measures to ensure accurate results in routine testing included (a) assessing RNA integrity and adequate cDNA preparation by detection of the constitutively expressed ABL mRNA, (b) monitoring sensitivity with the addition and detection of K562 RNA mixed with RNA from unknown samples (failure to detect the "spiked" K562 RNA indicates the presence of inhibitors or ribonucleases within the unknown RNA sample), (c) detection of nucleic acid contaminants by using negative controls in every assay, and (d) duplicate analysis of all samples and controls. Internally, this assay was 100% reproducible. Our results verify that nested primer RT-PCR is a fast, sensitive alternative to cytogenetic or Southern blot analysis for monitoring MRD after treatment and for diagnosis of CML. In addition, the highly controlled detection scheme presented here can be used as a general model for the development of other amplification-based detection assays.

Induction of graft-versus-host disease as immunotherapy for relapsed chronic myeloid leukemia.

BACKGROUND: The ability of allogeneic bone marrow transplantation to cure chronic myeloid leukemia (CML) is due to both the conditioning regimen and the antileukemic effects of the lymphocytes in the grafted marrow. We studied the ability of interferon alfa-2b and infusions of mononuclear cells from the marrow donor to induce a graft-versus-leukemia reaction in patients with CML in relapse after bone marrow transplantation. METHODS: Eleven patients with relapsed CML after allogeneic bone marrow transplantation were treated with interferon alfa-2b and infusions of mononuclear cells. The patients were monitored for toxic effects, for hematologic and cytogenetic responses, and, with use of the polymerase chain reaction, for elimination of cells containing the bcr/abl messenger RNA transcript characteristic of the leukemic cells. RESULTS: Six of the eight patients with stable CML after relapse had complete remissions according to molecular genetic criteria, since no cells with bcr/abl messenger RNA transcripts were detected (the method can identify 1 leukemic cell among 1 million normal cells). The three patients with accelerated CML after relapse did not enter remission. Myelosuppression was prominent in eight patients. Grade I acute graft-versus-host disease (GVHD) occurred in six patients, and grade III acute GVHD occurred in three. Limited chronic GVHD developed in five patients. CONCLUSIONS: The induction of a graft-versus-leukemia reaction with interferon alfa-2b and infusions of donor mononuclear cells in patients with CML in relapse after bone marrow transplantation is an effective antileukemic therapy that may offer an alternative to a second marrow transplantation.

Salvage immunotherapy using donor leukocyte infusions as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation: efficacy and toxicity of a defined T-cell dose.

Eight patients who had hematologic relapse of chronic myelogenous leukemia (CML) after undergoing allogeneic bone marrow transplantation (BMT) were treated with leukocyte infusions from the original bone marrow donors. All patients had previously received marrow grafts from HLA-identical siblings. Six patients were in the accelerated phase of their disease and two were in blast crisis. Each patient received a predetermined T-cell dose within a narrow range of 2.5 to 5.0 x 10(8) T cells/kg. Three patients also received short courses of therapy with alpha interferon to control elevated white blood cell counts within the first several weeks after leukocyte transfusions. Seven of eight evaluable patients developed graft-versus-host disease (GVHD) at a median of 32 days after the initial infusion. One patient had fatal GVHD. A second patient had grade 3 acute GVHD, which has responded to immunosuppressive therapy. The remaining patients all had mild grade I GVHD. Six patients continue to require modest doses of prednisone more than 6 months after infusion. Four patients developed marrow aplasia, which in three patients required marrow boosts from the original donors. Two of these three patients have normal hematopoietic function, whereas the third patient remains growth factor and transfusion dependent. Both patients treated in blast crisis have died, one from GVHD and one from disease progression. All six patients in the accelerated phase are alive and in cytogenetic remission at a median of 42 weeks after infusion. Five of these six patients are in molecular remission. This study demonstrates that leukocyte infusions that administered a defined T-cell dose can exert a profound graft-versus-leukemia effect and are an effective form of salvage immunotherapy in allogeneic marrow transplant recipients. This therapeutic approach appears to be a viable alternative to existing chemotherapeutic and immunomodulatory strategies for the treatment of relapsed CML.

Linking core competencies to customer needs: strategic marketing of health care services.

Firms often are encouraged to develop expertise, or core competencies, that lead to innovative products and services. The authors present a market research study that enabled a health care service provider to link its core technological competencies to customer needs. Although potential customers did not explicitly value the technology itself, links could be made between technological competencies and more valued service dimensions such as communication flows, meeting deadlines, and staff responsiveness. Improving strategic marketing and service quality delivery can be realized through market research linking customer needs to a firm's core competencies.

Molecular remission occurring after donor leukocyte infusions for the treatment of relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation.

Donor leukocyte infusions were administered to a patient who had relapsed with chronic myelogenous leukemia after having failed two successive HLA-matched allogeneic bone marrow transplants. Serial cytogenetic, restriction fragment length polymorphism, and polymerase chain reaction studies of the patient's marrow and blood after receiving donor leukocyte infusions revealed disappearance of the leukemic clone and the establishment of complete donor chimerism. An antileukemic response in this patient occurred initially in the absence of clinically evident graft-versus-host disease (GVHD), but complete eradication of the leukemic clone did not occur until after the onset of GVHD. The patient is now 48 weeks post infusion and remains in complete remission. This case demonstrates that leukocyte infusions are an effective form of adoptive immunotherapy which can result in a sustained molecular remission.

Detection of circulating donor white blood cells in patients receiving multiple transfusions.

Significant morbidities are associated with the routine administration of blood products. Although the exact etiology of these complications may be unknown, many are thought to arise from the incidental cotransfusion of "donor" lymphocytes. We have developed an assay to detect small numbers of male white blood cells (WBCs) circulating in female patients who have received multiple blood transfusions using the polymerase chain reaction (PCR). Twenty female patients undergoing major surgical procedures were studied and received an average of 9.3 U of packed red blood cells (4.8 U from male donors) and 11.7 U of platelets (6.1 U from male donors). DNA was extracted from whole blood or peripheral blood buffy coats posttransfusion and PCR performed using oligonucleotides designed to amplify a segment within the repetitive Y-chromosome DYZ1 locus. Posttransfusion, 15 of 20 women showed evidence of circulating male WBCs for an average of 2.0 days (range, 1 to 6). We conclude that (1) DYZ1 PCR analysis is a useful approach for the detection of small numbers of circulating transfused male WBCs in female patients; and (2) circulating donor WBCs persist for a mean of 2.0 days in the majority of women receiving multiple transfusions. Future application of this technique may detect persisting or proliferating WBCs and lead to an improved understanding of common transfusion-related morbidities.

A clinicopathologic study of familial chronic lymphocytic leukemia.

The familial occurrence of chronic lymphocytic leukemia was studied using morphologic, immunophenotypic, cytogenetic, and immunoglobulin gene rearrangement analyses. Three of six siblings developed chronic lymphocytic leukemia. One (patient 1) died 9 years after the diagnosis of chronic lymphocytic leukemia at age 67 years. The other two patients, ages 64 and 68 years (patients 2 and 3, respectively), are alive after chronic lymphocytic leukemia was diagnosed 11 and 4 years ago, respectively. Using the Rye classification, patient 2 and patient 3 had Stage I and Stage O disease, respectively. In contrast, patient 1 had Stage IV disease. The bone marrow of patient 2 was 90% cellular, with sheets of mature lymphocytes, and that of patient 3 was 70% cellular, with a nodular pattern of similar cells. Both patients 2 and 3 had normal karyotypes. Immunophenotyping studies revealed that patient 3 had an expanded population of B cells with minimal to no detectable expression of surface immunoglobulins and membrane-bound light chains. In contrast, the B-cell population of patient 2 expressed immunoglobulins M, D, and Kappa light chains. Gene rearrangement studies performed on these two patients revealed different but distinct patterns of heavy chain rearrangement. This may represent an evolution of two different clones of chronic lymphocytic leukemia in this family.

Prognostic significance of Philadelphia chromosome-positive cells detected by the polymerase chain reaction after allogeneic bone marrow transplant for chronic myelogenous leukemia.

Although rare cells expressing the bcr/abl fusion transcript can be detected by the polymerase chain reaction (PCR) in patient blood or marrow after allogeneic bone marrow transplant (BMT) for Philadelphia chromosome (Ph+)-positive chronic myelogenous leukemia (CML), the prognostic significance of this finding is unknown. This paper reports clinical, cytogenetic, and molecular data derived from 64 CML patients following allogeneic BMT. Nested primer PCR was performed on patient blood and bone marrow samples to detect the presence of residual bcr/abl (+) cells in CML patients considered to be in clinical remission at the time of study. Bcr/abl transcripts were detected in 37 of 64 patients for at least one timepoint post-BMT. Thirteen of these 37 bcr/abl (+) patients have subsequently relapsed, as defined by clinical and/or persistent cytogenetic findings, in contrast to 0 relapses among the 27 bcr/abl (-) patients (P = .0025). The median time from first (+) bcr/abl PCR signal to relapse was 150 days (range 90 to 832). Fifty-four patients were studied at two or more timepoints post-BMT: five of eight patients persistently bcr/abl (+) have relapsed; 5 of 23 patients with both bcr/abl (+) and (-) assays during follow-up have relapsed; and none of 23 patients persistently (-) have relapsed (cumulative actuarial relapse rates 77%, 20%, and 0%, respectively, P = .0017). These data indicate that among CML patients in apparent clinical remission after BMT, nested primer bcr/abl PCR can define subgroups with low, intermediate, and high risk of relapse. The pattern of bcr/abl PCR detection after transplant may aid in the development of trials designed to reduce the risk of relapse, or allow for early intervention in patients who fail to clear the malignant clone.

An evaluation of the impact of maternity care coordination on Medicaid birth outcomes in North Carolina.

BACKGROUND: Care coordination is an important component of the enhanced prenatal care services provided under the recent expansions of the Medicaid program. The effect of maternity care coordination services on birth outcomes in North Carolina was assessed by comparing women on Medicaid who did and did not receive these services. METHODS: Health program data files, including Medicaid claims paid for maternity care coordination, were linked to 1988 and 1989 live birth certificates. Simple comparisons of percentages and rates were supplemented by a logistic regression analysis. RESULTS: Among women on Medicaid who did not receive maternity care coordination services, the low birth weight rate was 21% higher, the very low birth weight rate was 62% higher, and the infant mortality rate was 23% higher than among women on Medicaid who did receive such services. It was estimated that, for each $1.00 spent on maternity care coordination, Medicaid saved $2.02 in medical costs for newborns up to 60 days of age. Among the women who did receive maternity care coordination, those receiving it for 3 or more months had better outcomes than those receiving it for less than 3 months. CONCLUSIONS: These results suggest that maternity care coordination can be effective in reducing low birth weight, infant mortality, and newborn medical care costs among babies born to women in poverty.

Application of the polymerase chain reaction for detection of minimal residual disease of hematologic malignancies.

Current induction therapies for acute and chronic leukemias and the lymphomas have achieved significant complete remission rates. Despite this initial success, disease recurrence remains a major problem. Relapse from clinically undetectable residual malignant cells is the most likely mechanism of recurrence. Of crucial importance to the clinician is the accurate detection of residual malignant cells prior to clinical relapse. Standard approaches to evaluate for this minimal residual disease (MRD) allow detection only when the malignant clone exceeds 1%. Patients in remission, however, may frequently have residual neoplastic cells that are far below this level. Recently, several investigators have adapted the polymerase chain reaction (PCR) to detect tumor-specific DNA or RNA sequences. This approach is highly sensitive (able to detect 1 malignant cell in 10(6) normal cells). The application of this technique to the study of MRD thus far has been limited to tumors in which specific DNA or RNA sequence data are available. This review describes the application of PCR to the detection of MRD in patients with chronic myelogenous leukemia, acute lymphoblastic leukemia, and follicular small cleaved cell lymphoma. Because the number of clinical studies and length of follow-up is limited, detection of MRD by PCR is at present largely a research tool and the biological significance of MRD as determined by PCR must await further studies.

Linkage relationship of X-linked juvenile retinoschisis with Xp22.1-p22.3 probes.

Linkage analysis was performed to evaluate the relationship between the locus for X-linked juvenile retinoschisis (RS) and five X-chromosomal markers-RC8 (DXS9), SE3.2L (DXS16), 99-6 (DXS41), D2 (DXS43), and 782 (DXS85)-all mapped to the interval Xp22.1-p22.3. Seven U.S. families with 56 affected males were studied. No recombinants were found between RS and DXS9 with a maximum lod score (Z) of 4.93 at a recombination fraction of zero. Obligate recombinants were found for RS with DXS16, DXS41, DXS43, and DXS85. Multipoint linkage analysis and consideration of recombination events within pedigrees suggest that DXS41 and DXS43, and also DXS41 and DXS16, flank RS and that DXS85 lies outside the interval DXS41-DXS43. Our pedigrees provide no evidence for genetic heterogeneity of RS, with five of our families individually showing evidence of linkage. (Z greater than 2.0) to the least one of these probes from Xp22.1-p22.3.

Detection of Philadelphia chromosome-positive cells from glass slide smears using the polymerase chain reaction.

Southern and Northern blot hybridization studies and the polymerase chain reaction (PCR) have been used to analyze the bcr-abl gene complex in chronic myelogenous leukemia (CML). Because fresh or cryopreserved cells may not always be available for molecular analyses, we investigated the possibility of using routinely prepared glass slide smears of blood or bone marrow as our source of cellular material. Cellular RNA was prepared directly from the blood or bone marrow smears using a modified RNA extraction procedure. cDNA was synthesized from RNA and amplified with PCR using bcr and abl-specific primers. Using this procedure, the bcr-abl fusion gene was detected by PCR in 21 of 21 patients with CML. Three patients who had undergone allogenic bone marrow transplantation (BMT) for CML were also studied by PCR. bcr-abl was identified transiently in one patient, persisted in one patient after BMT for 2 years until relapse occurred, and was absent in one patient to 18 months after BMT. We have shown that PCR can detect the bcr-abl gene of CML using material from glass-slide smears. This technique may be useful as a general approach in evaluating archival hematologic specimens for the expression of critical gene products.